Long-term effectiveness of ARRY-371797 in people with dilated cardiomyopathy and a faulty LMNA gene: a plain language summary.

WHAT IS THIS PLAIN LANGUAGE SUMMARY ABOUT?: This summary explains the results of a long-term extension study on the effects of a specific medicine. A long-term extension study allows people who have already completed a research study to continue taking treatment. Researchers can then look at how a treatment works over a long period of time. This extension study looked at the effects of a medicine called ARRY-371797 (also known as PF-07265803) in people with dilated cardiomyopathy (DCM for short) caused by a faulty lamin A/C gene (also known as the LMNA gene). This condition is called LMNA-related DCM. In people with LMNA-related DCM, the heart muscle becomes thinner and weaker than normal. This can lead to heart failure, where the heart is unable to pump enough blood around the body. The extension study allowed people who had completed an earlier 48-week study to continue taking ARRY-371797 for another 96 weeks (around 22 months). WHAT WERE THE RESULTS OF THE EXTENSION STUDY?: 8 people joined the extension study and continued with the dose of ARRY-371797 that they had taken in the first study. This means that people could have taken ARRY-371797 continuously for up to 144 weeks (around 2 years and 9 months). Using the 6-minute walk test (6MWT for short), researchers regularly checked people taking ARRY-371797 to see how far they could walk. Throughout the extension study, people were able to walk further than they could before they started taking ARRY-371797. This suggests that people could maintain the improvements in their ability to do daily activities with long-term ARRY-371797 treatment. Researchers also looked at how severe people's heart failure was by using a test that measures levels of a biomarker called NT-proBNP. A biomarker is something found in the body that can be measured to indicate the extent of a disease. Throughout this study, the levels of NT-proBNP in people's blood was lower than before they started taking ARRY-371797. This suggests that they maintained stable heart function. Using the Kansas City Cardiomyopathy Questionnaire (KCCQ for short), researchers asked people about their quality of life, and if they experienced any side effects. A side effect is something that people feel while taking a treatment. Researchers evaluate if a side effect is related to the treatment or not. Some improvement in KCCQ response during the study was seen, although results were varied. There were no serious side effects that were considered related to treatment with ARRY-371797. WHAT DO THE RESULTS OF THE EXTENSION STUDY MEAN?: Researchers found that the improvements in functional capacity and heart function seen with ARRY-371797 treatment in the original study were maintained with long-term treatment. Larger studies are needed to determine if ARRY-371797 could be an effective treatment for people with LMNA-related DCM. One such study (called REALM-DCM) was started in 2018 but ended early, as it was unlikely to show a clear treatment benefit of ARRY-371797. Phase 2 long-term extension study (NCT02351856) Phase 2 study (NCT02057341) Phase 3 REALM-DCM study (NCT03439514).

Plain Language Summary of Publication of the safety and efficacy of ARRY-371797 in people with dilated cardiomyopathy and a faulty LMNA gene.

WHAT IS THIS PLAIN LANGUAGE SUMMARY ABOUT?: This plain language summary describes the results of a study looking at the effects of a medicine called ARRY-371797 (also known as PF-07265803) in people with dilated cardiomyopathy (DCM for short) caused by a faulty LMNA gene. This condition is called LMNA-related DCM. DCM happens when the heart becomes bigger and weaker than normal, impacting functional capacity and leading to symptoms of heart failure. This means the heart is not able to pump blood around the body as easily, and people are unable to do as much in their daily lives (like getting dressed and going shopping). People may inherit a faulty LMNA gene from one of their parents, or a faulty LMNA gene may develop when mistakes happen during cell growth and replication. ARRY-371797 targets a specific mechanism in the body that can lead to heart problems in people with a faulty LMNA gene. As ARRY-371797 is not currently approved for use outside of clinical trials, it doesn't currently have an easily recognizable trade name. WHAT WERE THE RESULTS?: 12 American people (average age 50 years) with LMNA-related DCM took part in the study and received 400 mg or 100 mg of ARRY-371797 twice daily for 48 weeks. People knew which dose of ARRY-371797 they were taking. People were checked after 4, 12, 24, 36 and 48 weeks of taking ARRY-371797 to see how far they could walk in the 6-minute walk test (6MWT for short). The level of NT-proBNP in their blood was also measured. NT-proBNP is a biomarker used to measure the severity of heart failure. A biomarker is something found in the body that can be measured to indicate the extent of a disease. -After taking ARRY-371797 for 12 weeks, people were able to walk further in the 6MWT and had lower levels of NT-proBNP in their blood. This suggests improvement in functional capacity (exercise tolerance) and heart function. Researchers also asked people about their quality of life using the Kansas City Cardiomyopathy Questionnaire (KCCQ for short), and looked for any side effects. -Researchers saw some improvement in KCCQ scores. -Researchers saw no major side effects that they considered to be related to ARRY-371797 treatment. A side effect is something that people feel was caused by a medicine or treatment. Overall, this study showed that people with LMNA-related DCM who took ARRY-371797 had improved functional capacity (exercise tolerance), improved heart function, and improved quality of life. Phase 2 study (NCT02057341) Phase 2 long-term extension study (NCT02351856) Phase 3 REALM-DCM study (NCT03439514).

Clinical and genetic features of arrhythmogenic cardiomyopathy: diagnosis, management and the heart failure perspective.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an emerging new concept of a life-threatening heart muscle disorder due not only to desmosome gene mutations, but also to non-desmosome genes, such as filamin C, lamin A/C, phospholamban, transmembrane protein 43, titin, SCN5A and RNA binding motif protein 20.Multi-modality imaging along with genetic testing are important tools for risk stratification to tailor treatment to a single patient. Cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE) is the gold standard for evaluating left and right ventricular structure and function, edema, and fibrosis. The identification of regional fibrosis with LGE has prognostic value. The management of ACM involves several aspects: treatment of arrhythmias and heart failure, risk stratification, implantable cardioverter-defibrillator (ICD) placement, exercise restrictions, and life-style changes. The decision for ICD placement in ACM patients is not well established and should be made weighing risks and benefits. However, the presence of specific genotypes can allow a precision medicine approach. In ACM patients with only mild left ventricular dysfunction but phospholamban, filamin C or lamin A/C mutations, an ICD is now considered a reasonable approach. AIM OF REVIEW: We sought to provide an overview of clinical and genetic feature of arrhythmogenic cardiomyopathy providing epidemiology, imaging, diagnostic and treatment information, using a systematic genetic approach.

Serum circulating proteins from pediatric patients with dilated cardiomyopathy cause pathologic remodeling and cardiomyocyte stiffness.

Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy and main indication for heart transplantation in children. Therapies specific to pediatric DCM remain limited due to lack of a disease model. Our previous study showed that treatment of neonatal rat ventricular myocytes (NRVMs) with serum from nonfailing or DCM pediatric patients activates the fetal gene program (FGP). Here we show that serum treatment with proteinase K prevents activation of the FGP, whereas RNase treatment exacerbates it, suggesting that circulating proteins, but not circulating miRNAs, promote these pathological changes. Evaluation of the protein secretome showed that midkine (MDK) is upregulated in DCM serum, and NRVM treatment with MDK activates the FGP. Changes in gene expression in serum-treated NRVMs, evaluated by next-generation RNA-Seq, indicated extracellular matrix remodeling and focal adhesion pathways were upregulated in pediatric DCM serum and in DCM serum-treated NRVMs, suggesting alterations in cellular stiffness. Cellular stiffness was evaluated by Atomic Force Microscopy, which showed an increase in stiffness in DCM serum-treated NRVMs. Of the proteins increased in DCM sera, secreted frizzled-related protein 1 (sFRP1) was a potential candidate for the increase in cellular stiffness, and sFRP1 treatment of NRVMs recapitulated the increase in cellular stiffness observed in response to DCM serum treatment. Our results show that serum circulating proteins promoted pathological changes in gene expression and cellular stiffness, and circulating miRNAs were protective against pathological changes.

ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder.

ZMYND11 is the critical gene in chromosome 10p15.3 microdeletion syndrome, a syndromic cause of intellectual disability. The phenotype of ZMYND11 variants has recently been extended to autism and seizures. We expand on the epilepsy phenotype of 20 individuals with pathogenic variants in ZMYND11. We obtained clinical descriptions of 16 new and nine published individuals, plus detailed case history of two children. New individuals were identified through GeneMatcher, ClinVar and the European Network for Therapies in Rare Epilepsy (NETRE). Genetic evaluation was performed using gene panels or exome sequencing; variants were classified using American College of Medical Genetics (ACMG) criteria. Individuals with ZMYND11 associated epilepsy fell into three groups: (i) atypical benign partial epilepsy or idiopathic focal epilepsy (n = 8); (ii) generalised epilepsies/infantile epileptic encephalopathy (n = 4); (iii) unclassified (n = 8). Seizure prognosis ranged from spontaneous remission to drug resistant. Neurodevelopmental deficits were invariable. Dysmorphic features were variable. Variants were distributed across the gene and mostly de novo with no precise genotype-phenotype correlation. ZMYND11 is one of a small group of chromatin reader genes associated in the pathogenesis of epilepsy, and specifically ABPE. More detailed epilepsy descriptions of larger cohorts and functional studies might reveal genotype-phenotype correlation. The epileptogenic mechanism may be linked to interaction with histone H3.3.

Clinical implementation of pharmacogenomics via a health system-wide research biobank: the University of Colorado experience.

In recent years, the genomics community has witnessed the growth of large research biobanks, which collect DNA samples for research purposes. Depending on how and where the samples are genotyped, biobanks also offer the potential opportunity to return actionable genomic results to the clinical setting. We developed a preemptive clinical pharmacogenomic implementation initiative via a health system-wide research biobank at the University of Colorado. Here, we describe how preemptive return of clinical pharmacogenomic results via a research biobank is feasible, particularly when coupled with strong institutional support to maximize the impact and efficiency of biobank resources, a multidisciplinary implementation team, automated clinical decision support tools, and proactive strategies to engage stakeholders early in the clinical decision support tool development process.

FLNC truncations cause arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease that affects predominantly the right ventricle and is part of the spectrum of arrythmogenic cardiomyopathies (ACMs). ARVC is a genetic condition; however, a pathogenic gene variant is found in only half of patients. OBJECTIVE: Filamin C gene truncations (FLNCtv) have recently been identified in dilated cardiomyopathy with ventricular arrhythmia and sudden cardiac death, a phenotype partially overlapping with ARVC and part of the ACM spectrum. We hypothesised that FLNCtv could be a novel gene associated with ARVC. METHODS: One hundred fifty-six patients meeting 2010 ARVC Task Force Criteria and lacking variants in known ARVC genes were evaluated for FLNC variants. Available family members were tested for cosegregation. RESULTS: We identified two unique FLNCtv variants in two families (c.6565 G>T, p.Glu2189Ter and c.8107delG, p.Asp2703ThrfsTer69), with phenotypes of dominant RV disease fulfilling 'definite' diagnosis of ARVC according to the 2010 Task Force Criteria. Variants in other cardiomyopathy genes were excluded in both kindreds, and segregation analysis revealed that p.Asp2703ThrfsTer69 was a de novo variant. In both families, the disease phenotype was characterised by prominent ventricular arrhythmias and sudden cardiac arrest. CONCLUSION: The identification of FLNCtv as a novel cause of ARVC in two unrelated families expands the spectrum of ARVC non-desmosome disease genes for this disorder. Our findings should prompt inclusion of FLNC genetic testing in ARVC to improve diagnostic yield and testing of at-risk relatives in ARVC.

Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal ß-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and ß-catenin. A pharmacological activator of the WNT/ß-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and ß-catenin, and evidence for targeted activation of the WNT/ß-catenin pathway as a potential treatment for this disease.

Pediatric dilated cardiomyopathy hearts display a unique gene expression profile.

Our previous work showed myocellular differences in pediatric and adult dilated cardiomyopathy (DCM). However, a thorough characterization of the molecular pathways involved in pediatric DCM does not exist, limiting the development of age-specific therapies. To characterize this patient population, we investigated the transcriptome profile of pediatric patients. RNA-Seq from 7 DCM and 7 nonfailing (NF) explanted age-matched pediatric left ventricles (LV) was performed. Changes in gene expression were confirmed by real-time PCR (RT-PCR) in 36 DCM and 21 NF pediatric hearts and in 20 DCM and 10 NF adult hearts. The degree of myocyte hypertrophy was investigated in 4 DCM and 7 NF pediatric hearts and in 4 DCM and 9 NF adult hearts. Changes in gene expression in response to pluripotency-inducing factors were investigated in neonatal rat ventricular myocytes (NRVMs). Transcriptome analysis identified a gene expression profile in children compared with adults with DCM. Additionally, myocyte hypertrophy was not observed in pediatric hearts but was present in adult hearts. Furthermore, treatment of NRVMs with pluripotency-inducing factors recapitulated changes in gene expression observed in the pediatric DCM heart. Pediatric DCM is characterized by unique changes in gene expression that suggest maintenance of an undifferentiated state.

GENETIC CAUSES OF DILATED CARDIOMYOPATHY.

Dilated cardiomyopathy is a disease of the myocardium characterized by left ventricular dilatation and/or dysfunction, affecting both adult and pediatric populations. Almost half of cases are genetically determined with an autosomal pattern of inheritance. Up to 40 genes have been identified affecting proteins of a wide variety of cellular structures such as the sarcomere, the nuclear envelope, the cytoskeleton, the sarcolemma and the intercellular junction. Novel gene mutations have been recently identified thanks to advances in next-generation sequencing technologies. Genetic screening is an essential tool for early diagnosis, risk assessment, prognostic stratification and, possibly, adoption of primary preventive measures in affected patients and their asymptomatic relatives. The purpose of this article is to review the genetic basis of DCM, the known genotype-phenotype correlations, the role of current genetic sequencing techniques in the discovery of novel pathogenic gene mutations and new therapeutic perspectives.