Acute or chronic? Failing left ventricle in a 34 year old

Submission content Introduction: An unusual case of a very young patient without previously known cardiac disease presenting with severe left ventricular failure, detected by a point of care echocardiogram. Main Body: A 34 year old previously well man was brought to hospital after seeing his general practitioner with one month of progressive shortness of breath on exertion. This began around the time the patient received his second covid-19 vaccination. He was sleeping in a chair as he was unable to lie flat. Abnormal observations led the GP to call an ambulance. In the emergency department, the patient required oxygen 5L/min to maintain SpO2 >94%, but he was not in respiratory distress at rest. Blood pressure was 92/53mmHg, mean 67mmHg. Point of care testing for COVID-19 was negative. He was alert, with warm peripheries. Lactate was 1.0mmol/L and he was producing more than 0.5ml/kg/hr of urine. There was no ankle swelling. ECG showed sinus tachycardia. He underwent CT pulmonary angiography which demonstrated no pulmonary embolus, but there was bilateral pulmonary edema. Troponin was 17ng/l, BNP was 2700pg/ml. Furosemide 40mg was given intravenously by the general medical team. Critical care outreach asked for an urgent intensivist review given the highly unusual diagnosis of pulmonary edema in a man of this age. An immediate FUSIC Heart scan identified a dilated left ventricle with end diastolic diameter 7cm and severe global systolic impairment. The right ventricle was not severely impaired, with TAPSE 18mm. There was no significant pericardial effusion. Multiple B lines and trace pulmonary effusions were identified at the lung bases. The patient was urgently discussed with the regional cardiac unit in case of further deterioration, basic images were shared via a cloud system. A potential diagnosis of vaccination-associated myocarditis was considered,1 but in view of the low troponin, the presentation was felt most likely to represent decompensated chronic dilated cardiomyopathy. The patient disclosed a family history of early cardiac death in males. Aggressive diuresis was commenced. The patient was admitted to a monitored bed given the potential risk of arrhythmia or further haemodynamic deterioration. Advice was given that in the event of worsening hypotension, fluids should not be administered but the cardiac centre should be contacted immediately. Formal echocardiography confirmed the POCUS findings, with ejection fraction <35%. He was initiated on ACE inhibitors and beta adrenergic blockade. His symptoms improved and he was able to return home and to work, and is currently undergoing further investigations to establish the etiology of his condition. Conclusion(s): Early echocardiography provided early evidence of a cardiac cause for the patient's presentation and highlighted the severity of the underlying pathology. This directed early aggressive diuresis and safety-netting by virtue of discussion with a tertiary cardiac centre whilst it was established whether this was an acute or decompensated chronic pathology. Ultrasound findings: PLAX, PSAX and A4Ch views demonstrating a severely dilated (7cm end diastolic diameter) left ventricle with global severe systolic impairment.

The added value of molecular-based diagnostics in the African forensic medical setting.

Sudden unexpected infant death (SUDI) is reported to be an extraordinarily high burden in sub-Saharan Africa, with the incidence rate in South Africa among the highest in the world. It is common for the cause of many such infant deaths to remain unexplained even after a full medico-legal death investigation, and then to be categorised as a sudden unexplained infant death (SUID). Fortunately, advances in molecular-based diagnostics allow researchers to identify numerous underlying inherited cardiac arrhythmogenic disorders in many SUDI cases, with a predominance of variants identified in the SCN5A gene. Such cardiac arrhythmogenic-related sudden deaths generally present with no structural alterations of the heart that are macroscopically identifiable at autopsy, therefore highlighting the importance of post mortem genetic testing. We report on a significant genetic finding that was made on a SUDI case in which the cause was ascribed to an acute bacterial pneumonia but it was still subjected to post mortem genetic testing of the SCN5A gene. The literature shows that many SUDI cases diagnosed with inherited cardiac arrhythmogenic disorders have demonstrated a viral prodrome within days of their death. It is therefore not uncommon for these cardiac disorders in infants to be mistaken for flu, viral upper respiratory tract infection or pneumonia, and without the incorporation of post mortem genetic testing, any other contributory causes of these deaths are often disregarded. This study highlights the need for research reporting on the genetics of inherited cardiac disorders in Africa.

Role of Coxsackievirus B3-Induced Immune Responses in the Transition from Myocarditis to Dilated Cardiomyopathy and Heart Failure.

Dilated cardiomyopathy (DCM) is a cardiac disease marked by the stretching and thinning of the heart muscle and impaired left ventricular contractile function. While most patients do not develop significant cardiac diseases from myocarditis, disparate immune responses can affect pathological outcomes, including DCM progression. These altered immune responses, which may be caused by genetic variance, can prolong cytotoxicity, induce direct cleavage of host protein, or encourage atypical wound healing responses that result in tissue scarring and impaired mechanical and electrical heart function. However, it is unclear which alterations within host immune profiles are crucial to dictating the outcomes of myocarditis. Coxsackievirus B3 (CVB3) is a well-studied virus that has been identified as a causal agent of myocarditis in various models, along with other viruses such as adenovirus, parvovirus B19, and SARS-CoV-2. This paper takes CVB3 as a pathogenic example to review the recent advances in understanding virus-induced immune responses and differential gene expression that regulates iron, lipid, and glucose metabolic remodeling, the severity of cardiac tissue damage, and the development of DCM and heart failure.

Severe Heart Failure After Fetal Loss and COVID-19: A Diagnostically Challenging Case With Complicated Timing.

Coronavirus disease 2019 (COVID-19), initially recognized to cause respiratory system complications, has been found to also affect the cardiovascular system leading to myocardial damage and subsequently causing heart failure. Peripartum cardiomyopathy, though an uncommon condition, may also manifest as heart failure toward the end of pregnancy. This atypical case highlights the potential diagnostic overlap between COVID-19 heart failure and peripartum cardiomyopathy. At this point, there is no recommended algorithm used to distinguish one disease from another.

Case report of congenital disorder of glycosylation type Ia combined with dilated cardiomyopathy.

Clinical data and follow-up of a case of congenital disorder of glycosylation type Ia (CDG-Ia) combined with dilated cardiomyopathy admitted to the Department of Cardiology, Children's Hospital of Nanjing Medical University were analyzed retrospectively.The 5-year-old female patient was admitted in December 2016 due to recu-rrent shortness of breath for 2 months.Clinical symptoms and signs included repeated attacks of shortness of breath, physical retardation, malnutrition, binocular esotropia, multiple episodes of hypoglycemia, hepatosplenomegaly, hypotonia and other multi-system damages.Cardiac echocardiography suggested the feature of dilated cardiomyopathy, including the significant enlargement of the left ventricle, and decreased systolic function.Genetic testing revealed a compound heterozygous mutation in the PMM2 gene, and as a result, the patient was diagnosed as CDG-Ia.The patient's condition improved after symptomatic treatments such as Cedilanid, Dopamine, Dobutamine, Furosemide, as well as support treatments like myocardium nutrition, blood sugar maintenance, liver protection, etc.After discharge, the patient was given oral Digoxin, Betaloc, Captopril and diuretics, and hypoglycemia-controlling agents.The patient was followed up every 3-6 months.After more than 2 years of follow-up, the heart function and heart enlargement gradually returned to normal.During the Corona Virus Disease 2019 outbreak, self-withdrawal continued for 2 months.Re-examinations showed decreased cardiac function and enlarged left ventricle again.Medications were resumed again, and the patient was followed up closely.This case report suggested that CDG-Ia may be associated with dilated cardiomyopathy, and the cardiac phenotype may be improved by symptomatic supportive treatment.Copyright © 2021 by the Chinese Medical Association.

A Rare Single Case of COVID-19-Induced Acute Myocarditis and Encephalopathy Presenting Simultaneously.

The ongoing coronavirus disease 2019 (COVID-19) pandemic may result in cardiovascular complications such as myocarditis, while encephalitis is a potentially life-threatening COVID-19-associated central nervous system complication. This case illustrates the possibility of developing severe multisystem symptoms from a COVID-19 infection, despite having received the COVID-19 vaccine within the year. Delay in treatment for myocarditis and encephalopathy can lead to permanent and possibly fatal damage. Our patient, a middle-aged female with a complicated medical history, initially came in without characteristic manifestations of myocarditis such as shortness of breath, chest pain, or arrhythmia, but with an altered mental status. Through further laboratory tests, the patient was diagnosed with myocarditis and encephalopathy, which were resolved within weeks through medical management and physical/occupational therapy. This case presentation describes the first reported case of concomitant COVID-19 myocarditis and encephalitis after receiving a booster dose within the year.

SARS-CoV-2 dilated cardiomyopathy.

SARS-CoV-2 is an emerging cause of viral myocarditis that generates multiple complications, such as dilated cardiomyopathy. We describe a young, obese male patient with severe myocardial involvement by the SARS-CoV-2 virus, who presented with chest pain, elevated cardiac enzymes, non-specific electrocardiographic findings, echocardiogram with evidence of dilated heart disease with reduced ejection fraction, and subsequent verification using magnetic resonance imaging (MRI). The results of the cardiac MRI were typical of viral myocarditis. The patient did not respond to a short course of systemic steroids and the standard management for heart failure, had multiple re-admissions, and, unfortunately, died.

Myocardial Injury and Altered Gene Expression Associated With SARS-CoV-2 Infection or mRNA Vaccination.

SARS CoV-2 enters host cells via its Spike protein moiety binding to the essential cardiac enzyme angiotensin-converting enzyme (ACE) 2, followed by internalization. COVID-19 mRNA vaccines are RNA sequences that are translated into Spike protein, which follows the same ACE2-binding route as the intact virion. In model systems, isolated Spike protein can produce cell damage and altered gene expression, and myocardial injury or myocarditis can occur during COVID-19 or after mRNA vaccination. We investigated 7 COVID-19 and 6 post-mRNA vaccination patients with myocardial injury and found nearly identical alterations in gene expression that would predispose to inflammation, coagulopathy, and myocardial dysfunction.

Challenges for Management of Dilated Cardiomyopathy during COVID-19 Pandemic-A Telemedicine Application.

BACKGROUND AND OBJECTIVES: The 2019 coronavirus pandemic (COVID-19) represented a significant challenge for the medical community. The first aim of this study was to examine the COVID-19 impact on the follow-up of patients with dilated cardiomyopathy (DCM) and to establish the advantages of multiparametric home monitoring. Also, we tried to establish the main prognostic predictors at 2-years follow-up and the value of LV diastolic filling pattern (LVDFP) in increasing mortality and morbidity. MATERIALS AND METHODS: We conducted a prospective study of 142 patients with DCM assessed by in-patient visit in the pre-pandemic period and hybrid (face-to-face, online consultation and telemedicine home monitoring with a dedicated application) during the pandemic period. The statistical analysis compared the strategy used in the pre-pandemic with management during the pandemic, in terms of clinical assessment, hospitalizations/emergency room visits due to HF exacerbation and total mortality. RESULTS: We did not observe significant changes in blood pressure (BP), heart rate (FC), weight and symptoms or an increased rate of adverse drug events between the two periods. We successfully titrated HF medications with close monitoring of HF decompensations, which were similar in number, but were mostly managed at home during the pandemic. There was also no statistically significant difference in emergency room visits due to severe decompensated HF. Mortality in the first and second year of follow-up was between 12.0 and 13%, similar in the pre-pandemic and pandemic periods, but significantly higher in patients with restrictive LVDFP. Clinical improvement or stability after 2 years was more frequent in patients with nonrestrictive LVDFP. The main prognostic predictors at 1 and 2-years follow-up were: the restrictive LVDFP, significantly dilated LV, comorbidities (DM, COPD), older age, associated severe mitral regurgitation and pulmonary hypertension. CONCLUSIONS: The pandemic restrictions determined a marked decrease of the healthcare use, but no significant change in the clinical status of DCM patients under multiparametric home monitoring. At 2-years follow-up, the presence of the restrictive LVDFP was associated with an increased risk of death and with a worse clinical status in DCM patients.

Persistent viral infections and their role in heart disease.

Viral infections are the culprit of many diseases, including inflammation of the heart muscle, known as myocarditis. Acute myocarditis cases have been described in scientific literature, and viruses, such as parvovirus B19, coxsackievirus B3, or more recently, SARS-CoV-2, were the direct cause of cardiac inflammation. If not treated, myocarditis could progress to dilated cardiomyopathy, which permanently impairs the heart and limits a person's lifespan. Accumulated evidence suggests that certain viruses may persist in cardiac tissue after the initial infection, which could open up the door to reactivation under favorable conditions. Whether this chronic infection contributes to, or initiates, cardiac damage over time, remains a pressing issue in the field of virus-induced heart pathology, and it is directly tied to patients' treatment. Previously, large case studies found that a few viruses: parvovirus B19, coxsackievirus, adenovirus, human herpesvirus 6, cytomegalovirus and Epstein-Barr virus, are most commonly found in human endomyocardial biopsy samples derived from patients experiencing cardiac inflammation, or dilated cardiomyopathy. SARS-CoV-2 infection has also been shown to have cardiovascular consequences. This review examines the role of viral persistence in cardiac inflammation and heart disease, and discusses its implications for patients' outcomes.

Hydroxychloroquine Mitigates Dilated Cardiomyopathy Phenotype in Transgenic D94A Mice.

In this study, we aimed to investigate whether short-term and low-dose treatment with hydroxychloroquine (HCQ), an antimalarial drug, can modulate heart function in a preclinical model of dilated cardiomyopathy (DCM) expressing the D94A mutation in cardiac myosin regulatory light chain (RLC) compared with healthy non-transgenic (NTg) littermates. Increased interest in HCQ came with the COVID-19 pandemic, but the risk of cardiotoxic side effects of HCQ raised concerns, especially in patients with an underlying heart condition, e.g., cardiomyopathy. Effects of HCQ treatment vs. placebo (H2O), administered in Tg-D94A vs. NTg mice over one month, were studied by echocardiography and muscle contractile mechanics. Global longitudinal strain analysis showed the HCQ-mediated improvement in heart performance in DCM mice. At the molecular level, HCQ promoted the switch from myosin's super-relaxed (SRX) to disordered relaxed (DRX) state in DCM-D94A hearts. This result indicated more myosin cross-bridges exiting a hypocontractile SRX-OFF state and assuming the DRX-ON state, thus potentially enhancing myosin motor function in DCM mice. This bottom-up investigation of the pharmacological use of HCQ at the level of myosin molecules, muscle fibers, and whole hearts provides novel insights into mechanisms by which HCQ therapy mitigates some abnormal phenotypes in DCM-D94A mice and causes no harm in healthy NTg hearts.

Myocardial recovery in a patient with dilated cardiomyopathy after short-term biventricular assist device support.

Management of patients with end-stage heart failure is still challenging. We report a case of idiopathic dilated cardiomyopathy who went through a challenging course. The case was presented as acute heart failure syndrome, which rapidly declined into cardiogenic shock and cardiac arrest that required an extracorporeal membrane oxygenator, then biventricular assist device implantation for circulatory support. The course was complicated with severe gastrointestinal bleeding and multiorgan failure until achieving full cardiac and organ recovery. The left ventricle ejection fraction improved from 10% to 50% at discharge.

The mRNA-Based Coronavirus Disease-2019 Vaccine-induced Severe Cardiomyopathy: A Rare Incident.

We are presenting a case of severe dilated cardiomyopathy (DCM) post-mRNA-based coronavirus disease-2019 (COVID-19) vaccine (Pfizer-BioNTech) in a young healthy man. After the second dose of the vaccine, his health rapidly declined, and he developed severe DCM with reduced ejection fraction. Investigations for other causes of DCM were unremarkable. Severe DCM following COVID-19 vaccine injection is a rare but serious condition. It also highlights the importance of close follow-up of pericarditis and perimyocarditis cases post-COVID-19 vaccine and we recommend clinicians have a low threshold for using echocardiography for early diagnosis and management.

Meeting the Challenges of Myocarditis: New Opportunities for Prevention, Detection, and Intervention-A Report from the 2021 National Heart, Lung, and Blood Institute Workshop.

The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of international experts to discuss new research opportunities for the prevention, detection, and intervention of myocarditis in May 2021. These experts reviewed the current state of science and identified key gaps and opportunities in basic, diagnostic, translational, and therapeutic frontiers to guide future research in myocarditis. In addition to addressing community-acquired myocarditis, the workshop also focused on emerging causes of myocarditis including immune checkpoint inhibitors and SARS-CoV-2 related myocardial injuries and considered the use of systems biology and artificial intelligence methodologies to define workflows to identify novel mechanisms of disease and new therapeutic targets. A new priority is the investigation of the relationship between social determinants of health (SDoH), including race and economic status, and inflammatory response and outcomes in myocarditis. The result is a proposal for the reclassification of myocarditis that integrates the latest knowledge of immunological pathogenesis to refine estimates of prognosis and target pathway-specific treatments.

Transcriptome analysis uncovers the autophagy-mediated regulatory patterns of the immune microenvironment in dilated cardiomyopathy.

The relationship between autophagy and immunity has been well studied. However, little is known about the role of autophagy in the immune microenvironment during the progression of dilated cardiomyopathy (DCM). Therefore, this study aims to uncover the effect of autophagy on the immune microenvironment in the context of DCM. By investigating the autophagy gene expression differences between healthy donors and DCM samples, 23 dysregulated autophagy genes were identified. Using a series of bioinformatics methods, 13 DCM-related autophagy genes were screened and used to construct a risk prediction model, which can well distinguish DCM and healthy samples. Then, the connections between autophagy and immune responses including infiltrated immunocytes, immune reaction gene-sets and human leukocyte antigen (HLA) genes were systematically evaluated. In addition, two autophagy-mediated expression patterns in DCM were determined via the unsupervised consensus clustering analysis, and the immune characteristics of different patterns were revealed. In conclusion, our study revealed the strong effect of autophagy on the DCM immune microenvironment and provided new insights to understand the pathogenesis and treatment of DCM.

Dilated cardiomyopathy in the era of precision medicine: latest concepts and developments.

Dilated cardiomyopathy (DCM) is an umbrella term entailing a wide variety of genetic and non-genetic etiologies, leading to left ventricular systolic dysfunction and dilatation, not explained by abnormal loading conditions or coronary artery disease. The clinical presentation can vary from asymptomatic to heart failure symptoms or sudden cardiac death (SCD) even in previously asymptomatic individuals. In the last 2 decades, there has been striking progress in the understanding of the complex genetic basis of DCM, with the discovery of additional genes and genotype-phenotype correlation studies. Rigorous clinical work-up of DCM patients, meticulous family screening, and the implementation of advanced imaging techniques pave the way for a more efficient and earlier diagnosis as well as more precise indications for implantable cardioverter defibrillator implantation and prevention of SCD. In the era of precision medicine, genotype-directed therapies have started to emerge. In this review, we focus on updates of the genetic background of DCM, characteristic phenotypes caused by recently described pathogenic variants, specific indications for prevention of SCD in those individuals and genotype-directed treatments under development. Finally, the latest developments in distinguishing athletic heart syndrome from subclinical DCM are described.

COVID-19-induced silent myocarditis and newly developed hypertension in a 3-year-old boy.

BACKGROUND: COVID-19 myocarditis occurs in 7-28% of patients admitted in the hospital with or without multisystem inflammatory syndrome. It may present as fulminant myocarditis. Dilated cardiomyopathy as a sequela of COVID-19 myocarditis has been reported in the pediatric population. However, to date, no case of silent COVID-19 myocarditis progressing to dilated cardiomyopathy has been reported in children. Furthermore, although newly developed hypertension as a sequela of COVID-19 infection has been reported in adults, there is no report of newly developed COVID-induced hypertension in children. We report a 3-year-old boy with silent COVID-19 myocarditis progressing to dilated cardiomyopathy and newly developed systemic hypertension. CASE PRESENTATION: A 3-year-old boy was referred to the emergency department because of respiratory distress. The parents gave a history of SARS-CoV-2 infection in the child 5 months ago that was manifested as fever and cough, for which he was treated as an outpatient. Echocardiographic examination revealed a severe decrease in left ventricular systolic function in favor of dilated cardiomyopathy. Cardiac magnetic resonance imaging established the diagnosis of myocarditis. The patient left ventricular systolic function did not improve after 2 weeks of intravenous inotropic support. Therefore, the child was transferred to another tertiary center with extracorporeal membrane oxygenation and pediatric cardiac transplantation facilities. CONCLUSIONS: COVID-19 can induce silent myocarditis with progression to dilated cardiomyopathy and newly developed systemic hypertension. Thus, a thorough examination of the heart and measurement of blood pressure are mandatory in every child with COVID-19 infection. Cardiac MR is an indispensable tool in the diagnosis, follow-up, and prognostication of COVID-19 myocarditis. Moreover, four-chamber speckle tracking strain imaging showed apical rocking in all the four heart chambers in this child with opposite direction in the failed left ventricle compared with other cardiac chambers. Lastly, the presence of septal flash on M-mode echocardiography, apical rocking and prestretch-rebound stretch patterns on longitudinal strain imaging of the failed left ventricle in this child may be of predictive value for response to cardiac resynchronization therapy.

Multiple biventricular thrombi in a patient with alcoholic cardiomyopathy and COVID-19: A tragic association in a deadly pandemic.

As a primary cause, intracardiac thrombi are seen in a variety of cardiac conditions such as acute anterior myocardial infarctions and dilated cardiomyopathy. However, there are secondary predisposing conditions that increase the risk of clot formation in normally functioning ventricles. Migration or embolization of thrombus produced elsewhere, such as pulmonary thrombo-embolism, may occur at times. However, the current coronavirus disease 2019 (COVID-19) pandemic has resulted in a variety of intracardiac or extracardiac thrombi formations due to systemic inflammation and activation of the clotting system. We present a unique and rare case in association with alcoholic dilated cardiomyopathy and COVID-19, which resulted in the development of multiple biventricular thrombi. Learning objectives: •Significant systolic dysfunction is unusual, especially in people with prolonged alcoholism.•The hypercoagulable condition of coronavirus disease 2019 (COVID-19), combined with myocardial damage secondary to alcohol, can result in extensive intracardiac thrombosis.•Thrombotic manifestations in COVID-19 are associated with a high mortality rate.

SARS-CoV-2 induced myocarditis: Current knowledge about its molecular and pathophysiological mechanisms

The existence of an inflammatory process in the heart muscle, related to a progressive worsening of myocardial function, different etiopathogenetic mechanisms concur and often overlap, thus making the diagnosis and the therapeutic approach complex. As the COVID-19 pandemic progresses, the effects of the disease on the organ systems and in particular on the cardiovascular system are becoming more and more profound. Cardiac involvement is a well-known event with a high percentage of findings in the heart's magnetic field, even in asymptomatic areas. There are numerous uncertainties regarding their evolution, in the long and short term, due not only to a difficult to determine the varied clinical expression and the rarely performed intramyocardial biopsy which additionally presents diagnostic problems but also in part to different clinical prognosis. Today, the new SARS-CoV-2 virus that uses the angiotensin converting enzyme 2 (ACE2) which is present at high levels in myocardial cells as its entrance it can create even severe heart injury. The pathophysiology in all of these cases can involve multiple immune and non-immune mechanisms within organs and vessels and can be occur in the clinical phases. Possible mechanisms of direct and indirect myocardial infarction in patients with COVID-19 include additional lesion and oxygen-rich and generalized inflammation response with myocardial immune hyperactivity (myocarditis). Therefore, these can occur through the excessive release of cytokines, the presence of thrombocytopenia, endocrine damage, heart failure, arrhythmias and more. Patients can show average signs of myocardial damage, and some develop spontaneous cardiac complications, such as heart failure, arrhythmias and, rarely, rare cardiogenic disorders. Pathophysiology in all of these may involve multiple mechanisms within the cytokine cephalic membrane, endocrine damage and thrombogenicity. The diagnosis of this myocardial injuri is mainly based on the myocardial enzyme troponin. This viewpoint paper explains today's knowledge on viral myocarditis, in particular that from SARS-CoV-2 infection, if there is a connection with other possible biomolecular pathogenetic factors that can influence its natural course. In fact, it is for this reason that the pathogenetic mechanisms are analyzed and described. At the same time, its possible interaction with other parameters that are documented risk factors for cardiovascular disease was examined. Although these biomolecular findings were mainly related to necrotic parts of the myocardium, it is important to recognize that myocardial damage early for a better approach and prognosis.

A Case of Severe Left-Ventricular Noncompaction Associated with Splicing Altering Variant in the FHOD3 Gene.

Left ventricular noncompaction (LVNC) is a highly heterogeneous primary disorder of the myocardium. Its clinical features and genetic spectrum strongly overlap with other types of primary cardiomyopathies, in particular, hypertrophic cardiomyopathy. Study and the accumulation of genotype-phenotype correlations are the way to improve the precision of our diagnostics. We present a familial case of LVNC with arrhythmic and thrombotic complications, myocardial fibrosis and heart failure, cosegregating with the splicing variant in the FHOD3 gene. This is the first description of FHOD3-dependent LVNC to our knowledge. We also revise the assumed mechanism of pathogenesis in the case of FHOD3 splicing alterations.