Publications by authors named "Diane Fatkin"

102 Publications

Arrhythmic Phenotypes Are a Defining Feature of Dilated Cardiomyopathy-Associated Variants: A Systematic Review.

Circ Genom Precis Med 2021 Dec 24:CIRCGEN121003432. Epub 2021 Dec 24.

Molecular Cardiology Division, Victor Chang Cardiac Research Institute (J.I.V., D.F.).

Background: Variants in the gene, that encodes the cardiac sodium channel, Nav1.5, are associated with a highly arrhythmogenic form of dilated cardiomyopathy (DCM). Our aim was to review the phenotypes, natural history, functional effects, and treatment outcomes of DCM-associated rare variants.

Methods: A systematic review of reported DCM-associated rare variants was undertaken using PubMed and Embase.

Results: Eighteen rare variants in 29 families with DCM (173 affected individuals) were identified. Eleven variants had undergone experimental evaluation, with 7 of these resulting in increased sustained current flow during the action potential (eg, increased window current) and at resting membrane potentials (eg, creation of a new gating pore current). These variants were located in transmembrane voltage-sensing domains and had a consistent phenotype characterized by frequent multifocal narrow and broad complex ventricular premature beats (VPB; 72% of affected relatives), ventricular arrhythmias (33%), atrial arrhythmias (32%), sudden cardiac death (13%), and DCM (56%). This VPB-predominant phenotype was not seen with 1 variant that increased late sodium current, or with variants that reduced peak current density or had mixed effects. In the latter groups, affected individuals mainly showed sinus node dysfunction, conduction defects, and atrial arrhythmias, with infrequent VPB and VA. DCM did not occur in the absence of arrhythmias for any variant. Twelve studies (23 total patients) reported treatment success in the VPB-predominant cardiomyopathy using sodium channel-blocking drug therapy.

Conclusions: variants can present with a diverse spectrum of primary arrhythmic features. A majority of DCM-associated variants cause a multifocal VPB-predominant cardiomyopathy that is reversible with sodium channel blocking drug therapy. Early recognition of the distinctive phenotype and prompt genetic testing to identify variant carriers are needed. Our findings have implications for interpretation and management of variants found in DCM patients with and without arrhythmias.
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http://dx.doi.org/10.1161/CIRCGEN.121.003432DOI Listing
December 2021

Phenotypic Expression, Natural History, and Risk Stratification of Cardiomyopathy Caused by Filamin C Truncating Variants.

Circulation 2021 11 30;144(20):1600-1611. Epub 2021 Sep 30.

Stanford Center for Inherited Cardiovascular Disease, CA (V.N.P., E.A.A., C.R.).

Background: Filamin C truncating variants () cause a form of arrhythmogenic cardiomyopathy: the mode of presentation, natural history, and risk stratification of remain incompletely explored. We aimed to develop a risk profile for refractory heart failure and life-threatening arrhythmias in a multicenter cohort of carriers.

Methods: carriers were identified from 10 tertiary care centers for genetic cardiomyopathies. Clinical and outcome data were compiled. Composite outcomes were all-cause mortality/heart transplantation/left ventricle assist device (D/HT/LVAD), nonarrhythmic death/HT/LVAD, and sudden cardiac death/major ventricular arrhythmias. Previously established cohorts of 46 patients with and 60 with -related arrhythmogenic cardiomyopathies were used for prognostic comparison.

Results: Eighty-five patients carrying were included (42±15 years, 53% men, 45% probands). Phenotypes were heterogeneous at presentation: 49% dilated cardiomyopathy, 25% arrhythmogenic left dominant cardiomyopathy, 3% arrhythmogenic right ventricular cardiomyopathy. Left ventricular ejection fraction was <50% in 64% of carriers and 34% had right ventricular fractional area changes (RVFAC=(right ventricular end-diastolic area - right ventricular end-systolic area)/right ventricular end-diastolic area) <35%. During follow-up (median time 61 months), 19 (22%) carriers experienced D/HT/LVAD, 13 (15%) experienced nonarrhythmic death/HT/LVAD, and 23 (27%) experienced sudden cardiac death/major ventricular arrhythmias. The sudden cardiac death/major ventricular arrhythmias incidence of carriers did not significantly differ from carriers and carriers. In carriers, left ventricular ejection fraction was associated with the risk of D/HT/LVAD and nonarrhythmic death/HT/LVAD.

Conclusions: Among patients referred to tertiary referral centers, arrhythmogenic cardiomyopathy is phenotypically heterogeneous and characterized by a high risk of life-threatening arrhythmias, which does not seem to be associated with the severity of left ventricular dysfunction.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.053521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595845PMC
November 2021

Modified N-linked glycosylation status predicts trafficking defective human Piezo1 channel mutations.

Commun Biol 2021 09 6;4(1):1038. Epub 2021 Sep 6.

Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, Australia.

Mechanosensitive channels are integral membrane proteins that sense mechanical stimuli. Like most plasma membrane ion channel proteins they must pass through biosynthetic quality control in the endoplasmic reticulum that results in them reaching their destination at the plasma membrane. Here we show that N-linked glycosylation of two highly conserved asparagine residues in the 'cap' region of mechanosensitive Piezo1 channels are necessary for the mature protein to reach the plasma membrane. Both mutation of these asparagines (N2294Q/N2331Q) and treatment with an enzyme that hydrolyses N-linked oligosaccharides (PNGaseF) eliminates the fully glycosylated mature Piezo1 protein. The N-glycans in the cap are a pre-requisite for N-glycosylation in the 'propeller' regions, which are present in loops that are essential for mechanotransduction. Importantly, trafficking-defective Piezo1 variants linked to generalized lymphatic dysplasia and bicuspid aortic valve display reduced fully N-glycosylated Piezo1 protein. Thus the N-linked glycosylation status in vitro correlates with efficient membrane trafficking and will aid in determining the functional impact of Piezo1 variants of unknown significance.
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http://dx.doi.org/10.1038/s42003-021-02528-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421374PMC
September 2021

Contribution of Noncanonical Splice Variants to Truncating Variant Cardiomyopathy.

Circ Genom Precis Med 2021 10 31;14(5):e003389. Epub 2021 Aug 31.

Department of Genetics (P.N.P., K.I., J.A.L.W., A.H., M.Y.J., J.M.G., S.R.D., L.L., B.M., C.E.S., J.G.S.), Harvard Medical School, Boston, MA.

Background: Heterozygous truncating variants cause 10% to 20% of idiopathic dilated cardiomyopathy (DCM). Although variants which disrupt canonical splice signals (ie, invariant dinucleotide of the splice donor site, invariant dinucleotide of the splice acceptor site) at exon-intron junctions are readily recognized as truncating variants, the effects of other nearby sequence variations on splicing and their contribution to disease is uncertain.

Methods: Rare variants of unknown significance located in the splice regions of highly expressed exons from 203 DCM cases, 3329 normal subjects, and clinical variant databases were identified. The effects of these variants on splicing were assessed using an in vitro splice assay.

Results: Splice-altering variants of unknown significance were enriched in DCM cases over controls and present in 2% of DCM patients (=0.002). Application of this method to clinical variant databases demonstrated 20% of similar variants of unknown significance in splice regions affect splicing. Noncanonical splice-altering variants were most frequently located at position +5 of the donor site (=4.4×10) and position -3 of the acceptor site (=0.002). SpliceAI, an emerging in silico prediction tool, had a high positive predictive value (86%-95%) but poor sensitivity (15%-50%) for the detection of splice-altering variants. Alternate exons spliced out of most transcripts frequently lacked the consensus base at +5 donor and -3 acceptor positions.

Conclusions: Noncanonical splice-altering variants in explain 1-2% of DCM and offer a 10-20% increase in the diagnostic power of sequencing in this disease. These data suggest rules that may improve efforts to detect splice-altering variants in other genes and may explain the low percent splicing observed for many alternate exons.
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http://dx.doi.org/10.1161/CIRCGEN.121.003389DOI Listing
October 2021

Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent.

NPJ Genom Med 2021 Jun 16;6(1):51. Epub 2021 Jun 16.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.

Genetic testing is used to optimise the management of inherited cardiovascular disorders that can cause sudden cardiac death. Yet more genotype-phenotype correlation studies from populations not ascertained on clinical symptoms or family history of disease are required to improve understanding of gene penetrance. We performed targeted sequencing of 25 genes used routinely in clinical genetic testing for inherited cardiovascular disorders in a population of 13,131 asymptomatic older individuals (mean age 75 years) enrolled in the ASPREE trial. Participants had no prior history of cardiovascular disease events, dementia or physical disability at enrolment. Variants were classified following ACMG/AMP standards. Sudden and rapid cardiac deaths were clinically adjudicated as ASPREE trial endpoints, and assessed during mean 4.7 years of follow-up. In total, 119 participants had pathogenic/deleterious variants in one of the 25 genes analysed (carrier rate of 1 in 110 or 0.9%). Participants carried variants associated with hypertrophic cardiomyopathy (N = 24), dilated cardiomyopathy (N = 29), arrhythmogenic right-ventricular cardiomyopathy (N = 22), catecholaminergic polymorphic ventricular tachycardia (N = 4), aortopathies (N = 1), and long-QT syndrome (N = 39). Among 119 carriers, two died from presumed sudden/rapid cardiac deaths during follow-up (1.7%); both with pathogenic variants in long-QT syndrome genes (KCNQ1, SCN5A). Among non-carriers, the rate of sudden/rapid cardiac deaths was significantly lower (0.08%, 11/12936, p < 0.001). Variants associated with inherited cardiovascular disorders are found in asymptomatic individuals aged 70 years and older without a history of cardiovascular disease.
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http://dx.doi.org/10.1038/s41525-021-00211-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209162PMC
June 2021

Precision Medicine Approaches to Cardiac Arrhythmias: JACC Focus Seminar 4/5.

J Am Coll Cardiol 2021 05;77(20):2573-2591

Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, Kensington, New South Wales, Australia; Cardiology Department, St Vincent's Hospital, Sydney, New South Wales, Australia; Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

In the initial 3 papers in this Focus Seminar series, the fundamentals and key concepts of precision medicine were reviewed, followed by a focus on precision medicine in the context of vascular disease and cardiomyopathy. For the remaining 2 papers, we focus on precision medicine in the context of arrhythmias. Specifically, in this fourth paper we focus on long QT syndrome, Brugada syndrome, and atrial fibrillation. The final (fifth) paper will deal with catecholaminergic polymorphic ventricular tachycardia. These arrhythmias represent a spectrum of disease ranging from common to relatively rare, with very different genetic and environmental causative factors, and with differing clinical manifestations that range from almost no consequences to lethality in childhood or adolescence if untreated. Accordingly, the emerging precision medicine approaches to these arrhythmias vary significantly, but several common themes include increased use of genetic testing, avoidance of triggers, and personalized risk stratification to guide the use of arrhythmia-specific therapies.
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http://dx.doi.org/10.1016/j.jacc.2021.03.325DOI Listing
May 2021

Contemporary and Future Approaches to Precision Medicine in Inherited Cardiomyopathies: JACC Focus Seminar 3/5.

J Am Coll Cardiol 2021 05;77(20):2551-2572

Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Kensington, New South Wales, Australia; Cardiology Department, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia; The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

Inherited cardiomyopathies are commonly occurring myocardial disorders that are associated with substantial morbidity and mortality. Clinical management strategies have focused on treatment of heart failure and arrhythmic complications in symptomatic patients according to standardized guidelines. Clinicians are now being urged to implement precision medicine, but what does this involve? Advances in understanding of the genetic underpinnings of inherited cardiomyopathies have brought new possibilities for interventions that are tailored to genes, specific variants, or downstream mechanisms. However, the phenotypic variability that can occur with any given pathogenic variant suggests that factors other than single driver gene mutations are often involved. This is propelling a new imperative to elucidate the nuanced ways in which individual combinations of genetic variation, comorbidities, and lifestyle may influence cardiomyopathy phenotypes. Here, Part 3 of a 5-part precision medicine Focus Seminar series reviews the current status and future opportunities for precision medicine in the inherited cardiomyopathies.
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http://dx.doi.org/10.1016/j.jacc.2020.12.072DOI Listing
May 2021

Cardiac Gq Receptors and Calcineurin Activation Are Not Required for the Hypertrophic Response to Mechanical Left Ventricular Pressure Overload.

Front Cell Dev Biol 2021 15;9:639509. Epub 2021 Feb 15.

Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.

Rationale: Gq-coupled receptors are thought to play a critical role in the induction of left ventricular hypertrophy (LVH) secondary to pressure overload, although mechano-sensitive channel activation by a variety of mechanisms has also been proposed, and the relative importance of calcineurin- and calmodulin kinase II (CaMKII)-dependent hypertrophic pathways remains controversial.

Objective: To determine the mechanisms regulating the induction of LVH in response to mechanical pressure overload.

Methods And Results: Transgenic mice with cardiac-targeted inhibition of Gq-coupled receptors (GqI mice) and their non-transgenic littermates (NTL) were subjected to neurohumoral stimulation (continuous, subcutaneous angiotensin II (AngII) infusion for 14 days) or mechanical pressure overload (transverse aortic arch constriction (TAC) for 21 days) to induce LVH. Candidate signaling pathway activation was examined. As expected, LVH observed in NTL mice with AngII infusion was attenuated in heterozygous (GqI) mice and absent in homozygous (GqI) mice. In contrast, LVH due to TAC was unaltered by either heterozygous or homozygous Gq inhibition. Gene expression of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and α-skeletal actin (α-SA) was increased 48 h after AngII infusion or TAC in NTL mice; in GqI mice, the increases in ANP, BNP and α-SA in response to AngII were completely absent, as expected, but all three increased after TAC. Increased nuclear translocation of nuclear factor of activated T-cells c4 (NFATc4), indicating calcineurin pathway activation, occurred in NTL mice with AngII infusion but not TAC, and was prevented in GqI mice infused with AngII. Nuclear and cytoplasmic CaMKIIδ levels increased in both NTL and GqI mice after TAC but not AngII infusion, with increased cytoplasmic phospho- and total histone deacetylase 4 (HDAC4) and increased nuclear myocyte enhancer factor 2 (MEF2) levels.

Conclusion: Cardiac Gq receptors and calcineurin activation are required for neurohumorally mediated LVH but not for LVH induced by mechanical pressure overload (TAC). Rather, TAC-induced LVH is associated with activation of the CaMKII-HDAC4-MEF2 pathway.
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http://dx.doi.org/10.3389/fcell.2021.639509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917224PMC
February 2021

Conserved Role of the Large Conductance Calcium-Activated Potassium Channel, K1.1, in Sinus Node Function and Arrhythmia Risk.

Circ Genom Precis Med 2021 04 25;14(2):e003144. Epub 2021 Feb 25.

Victor Chang Cardiac Research Institute, Darlinghurst (V.N.-K., C.L., A.-K.A., C.D.C., A.J., I.G.H., M.S., M.O., G.T., R.J., R.P.H., A.P.H., D.F.).

Background: encodes the α-subunit of the large-conductance Ca-activated K channel, K1.1, and lies within a linkage interval for atrial fibrillation (AF). Insights into the cardiac functions of K1.1 are limited, and has not been investigated as an AF candidate gene.

Methods: The gene was sequenced in 118 patients with familial AF. The role of K1.1 in normal cardiac structure and function was evaluated in humans, mice, zebrafish, and fly. A novel variant was functionally characterized.

Results: A complex variant was identified in 1 kindred with AF. To evaluate potential disease mechanisms, we first evaluated the distribution of K1.1 in normal hearts using immunostaining and immunogold electron microscopy. K1.1 was seen throughout the atria and ventricles in humans and mice, with strong expression in the sinus node. In an ex vivo murine sinoatrial node preparation, addition of the K1.1 antagonist, paxilline, blunted the increase in beating rate induced by adrenergic receptor stimulation. Knockdown of the K1.1 ortholog, , in zebrafish embryos resulted in sinus bradycardia with dilatation and reduced contraction of the atrium and ventricle. Genetic inactivation of the K1.1 ortholog, , systemically or in adult stages, also slowed the heartbeat and produced fibrillatory cardiac contractions. Electrophysiological characterization of -deficient flies revealed bursts of action potentials, reflecting increased events of fibrillatory arrhythmias. Flies with cardiac-specific overexpression of the human mutant also showed increased heart period and bursts of action potentials, similar to the K1.1 loss-of-function models.

Conclusions: Our data point to a highly conserved role of K1.1 in sinus node function in humans, mice, zebrafish, and fly and suggest that K1.1 loss of function may predispose to AF.
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http://dx.doi.org/10.1161/CIRCGEN.120.003144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058291PMC
April 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Mechanisms of tv-Related Dilated Cardiomyopathy: Insights from Zebrafish Models.

J Cardiovasc Dev Dis 2021 Jan 25;8(2). Epub 2021 Jan 25.

Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia.

Dilated cardiomyopathy (DCM) is a common heart muscle disorder characterized by ventricular dilation and contractile dysfunction that is associated with significant morbidity and mortality. New insights into disease mechanisms and strategies for treatment and prevention are urgently needed. Truncating variants in the gene, which encodes the giant sarcomeric protein titin (tv), are the most common genetic cause of DCM, but exactly how tv promote cardiomyocyte dysfunction is not known. Although rodent models have been widely used to investigate titin biology, they have had limited utility for tv-related DCM. In recent years, zebrafish () have emerged as a powerful alternative model system for studying titin function in the healthy and diseased heart. Optically transparent embryonic zebrafish models have demonstrated key roles of titin in sarcomere assembly and cardiac development. The increasing availability of sophisticated imaging tools for assessment of heart function in adult zebrafish has revolutionized the field and opened new opportunities for modelling human genetic disorders. Genetically modified zebrafish that carry a human A-band tv have now been generated and shown to spontaneously develop DCM with age. This zebrafish model will be a valuable resource for elucidating the phenotype modifying effects of genetic and environmental factors, and for exploring new drug therapies.
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http://dx.doi.org/10.3390/jcdd8020010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912658PMC
January 2021

Genetic Susceptibility to Atrial Fibrillation Is Associated With Atrial Electrical Remodeling and Adverse Post-Ablation Outcome.

JACC Clin Electrophysiol 2020 11 26;6(12):1509-1521. Epub 2020 Aug 26.

Department of Cardiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia. Electronic address:

Objectives: This study sought to assess the atrial electrophysiological properties and post-ablation outcomes in patients with atrial fibrillation (AF) with and without the rs2200733 single nucleotide variant.

Background: The phenotype associated with chromosome 4q25 of the AF-susceptibility locus remains unknown.

Methods: In this study, 102 consecutive patients (ages 61 ± 9 years, 64% male) with paroxysmal or persistent AF were prospectively recruited prior to ablation. Patients were genotyped for rs2200733 and high-density left atrial (LA) electroanatomic maps were created using a multipolar catheter during distal coronary sinus (CS) pacing at 600 ms. Voltage, conduction velocity (CV), CV heterogeneity, and fractionated signals of 6 LA segments were determined. Arrhythmia recurrence was assessed by continuous device (51%) and Holter monitoring.

Results: Overall, 41 patients (40%) were single nucleotide variant carriers (38 heterozygous, 3 homozygous). A mean of 2,239 ± 852 points per patient were collected. Carriers had relatively increased CV heterogeneity (45.7 ± 7.5% vs. 35.9 ± 2.3%; p < 0.001), complex signals (9.4 ± 2.9% vs 6.0 ± 1.2%; p = 0.008), regional LA slowing, or conduction block (31.7 ± 8.2% vs. 17.9 ± 1.9%; p = 0.013) particularly in the posterior and lateral walls. There were no differences in CV, voltage, atrial refractoriness, or sinus node function. At follow-up (median: 27 months; range 19 to 31 months), carriers had lower arrhythmia-free survival (51% vs. 80%; p = 0.003). On multivariable analysis, carrier status was independently associated with CV heterogeneity (p = 0.001), complex signals (p = 0.002), and arrhythmia recurrence (p = 0.019).

Conclusions: These data provide the first evidence that the rs2200733-tagged haplotype alters LA electrical remodeling and is a determinant of long-term outcome following AF ablation. The molecular mechanisms underpinning these changes warrant further investigation.
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http://dx.doi.org/10.1016/j.jacep.2020.05.031DOI Listing
November 2020

Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation From Genome Sequencing.

Circ Genom Precis Med 2020 12 30;13(6):e003030. Epub 2020 Oct 30.

Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, United Kingdom (A.A.B., T.R.W., S.E.H., D.P., A.A.-H., A.W., D.K., N.J.S., D.A.).

Background: Spontaneous coronary artery dissection (SCAD) occurs when an epicardial coronary artery is narrowed or occluded by an intramural hematoma. SCAD mainly affects women and is associated with pregnancy and systemic arteriopathies, particularly fibromuscular dysplasia. Variants in several genes, such as those causing connective tissue disorders, have been implicated; however, the genetic architecture is poorly understood. Here, we aim to better understand the diagnostic yield of rare variant genetic testing among a cohort of SCAD survivors and to identify genes or gene sets that have a significant enrichment of rare variants.

Methods: We sequenced a cohort of 384 SCAD survivors from the United Kingdom, alongside 13 722 UK Biobank controls and a validation cohort of 92 SCAD survivors. We performed a research diagnostic screen for pathogenic variants and exome-wide and gene-set rare variant collapsing analyses.

Results: The majority of patients within both cohorts are female, 29% of the study cohort and 14% validation cohort have a remote arteriopathy. Four cases across the 2 cohorts had a diagnosed connective tissue disorder. We identified pathogenic or likely pathogenic variants in 7 genes (, , , , , , and ) in 14/384 cases in the study cohort and in 1/92 cases in the validation cohort. In our rare variant collapsing analysis, was the highest-ranked gene, and several functionally plausible genes were enriched for rare variants, although no gene achieved study-wide statistical significance. Gene-set enrichment analysis suggested a role for additional genes involved in renal function.

Conclusions: By studying the largest sequenced cohort of SCAD survivors, we demonstrate that, based on current knowledge, only a small proportion have a pathogenic variant that could explain their disease. Our findings strengthen the overlap between SCAD and renal and connective tissue disorders, and we highlight several new genes for future validation.
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http://dx.doi.org/10.1161/CIRCGEN.120.003030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748045PMC
December 2020

Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the Gene.

Circ Heart Fail 2020 10 23;13(10):e006832. Epub 2020 Sep 23.

Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Centro de Investigación en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain (M.A.R.-C., P.G.-P.).

Background: Truncating variants in the gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers.

Methods: Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%).

Results: Median follow-up was 49 (18-105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; =0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95% CI, 1.04-3.44]; =0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95% CI, 1.30-2.04]; <0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis (=0.07).

Conclusions: TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006832DOI Listing
October 2020

In vitro cell stretching technology (IsoStretcher) as an approach to unravel Piezo1-mediated cardiac mechanotransduction.

Prog Biophys Mol Biol 2021 01 5;159:22-33. Epub 2020 Aug 5.

Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; Institute of Medical Biotechnology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany; School in Advanced Optical Technologies, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany; Muscle Research Center Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.

The transformation of electrical signals into mechanical action of the heart underlying blood circulation results in mechanical stimuli during active contraction or passive filling distention, which conversely modulate electrical signals. This feedback mechanism is known as cardiac mechano-electric coupling (MEC). The cardiac MEC involves complex activation of mechanical biosensors initiating short-term and long-term effects through Ca signals in cardiomyocytes in acute and chronic pressure overload scenarios (e.g. cardiac hypertrophy). Although it is largely still unknown how mechanical forces alter cardiac function at the molecular level, mechanosensitive channels, including the recently discovered family of Piezo channels, have been thought to play a major role in the cardiac MEC and are also suspected to contribute to development of cardiac hypertrophy and heart failure. The earliest reports of mechanosensitive channel activity recognized that their gating could be controlled by membrane stretch. In this article, we provide an overview of the stretch devices, which have been employed for studies of the effects of mechanical stimuli on muscle and heart cells. We also describe novel experiments examining the activity of Piezo1 channels under multiaxial stretch applied using polydimethylsiloxane (PDMS) stretch chambers and IsoStretcher technology to achieve isotropic stretching stimulation to cultured HL-1 cardiac muscle cells which express an appreciable amount of Piezo1.
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http://dx.doi.org/10.1016/j.pbiomolbio.2020.07.003DOI Listing
January 2021

Spontaneous Coronary Artery Dissection and Fibromuscular Dysplasia: Vasculopathies With a Predilection for Women.

Heart Lung Circ 2021 Jan 6;30(1):27-35. Epub 2020 Jul 6.

Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, NSW, Australia; St Vincent's Clinical School, St Vincent's Hospital, Sydney, NSW, Australia; Faculty of Medicine, University of NSW, Sydney, NSW, Australia. Electronic address:

The burden of cardiovascular disease in women is being increasingly appreciated. Nevertheless, both clinicians and the general public are largely unaware that cardiovascular disease is the leading cause of death worldwide in women in all countries and that outcomes after a heart attack are worse for women than men. Of note, certain types of cardiovascular disease have a predilection for women, including spontaneous coronary artery dissection (SCAD) and fibromuscular dysplasia (FMD). Although uncommon, SCAD is being increasingly recognised as the cause of an acute coronary syndrome (ACS) and can recur. It is a potentially fatal, under-diagnosed condition that affects relatively young women, who often have few traditional risk factors, and is the commonest cause of a myocardial infarction associated with pregnancy. In contrast, FMD often remains silent but when manifested can also cause major sequelae, including renal infarction, stroke, cervical artery dissection and gut infarction. Here we provide an update on the diagnosis, aetiology and management of these important disorders that overwhelmingly affect women.
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http://dx.doi.org/10.1016/j.hlc.2020.05.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710561PMC
January 2021

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Nat Commun 2020 05 21;11(1):2542. Epub 2020 May 21.

Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
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http://dx.doi.org/10.1038/s41467-020-15706-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242331PMC
May 2020

Patients With Genetic Heart Disease and COVID-19: A Cardiac Society of Australia and New Zealand (CSANZ) Consensus Statement.

Heart Lung Circ 2020 Jul 30;29(7):e85-e87. Epub 2020 Apr 30.

Waikato Hospital, Hamilton, New Zealand.

In the context of the current global COVID-19 pandemic, this Consensus Statement provides current recommendations for patients with, or at risk of developing, genetic heart disease, and for their health care management and service provision in Australia and New Zealand. Apart from general recommendations, there are specific recommendations for the following conditions: cardiomyopathy, Brugada syndrome (including in children), long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Other recommendations are relevant to patient self-care and primary health care.
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http://dx.doi.org/10.1016/j.hlc.2020.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192105PMC
July 2020

Variants of Uncertain Significance and "Missing Pathogenicity".

J Am Heart Assoc 2020 02 3;9(3):e015588. Epub 2020 Feb 3.

Molecular Cardiology Division Victor Chang Cardiac Research Institute Darlinghurst Australia.

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http://dx.doi.org/10.1161/JAHA.119.015588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033868PMC
February 2020

Amyloid Cardiomyopathy.

Heart Lung Circ 2020 Apr 17;29(4):575-583. Epub 2019 Dec 17.

Cardiology Department, St. Vincent's Hospital, Sydney NSW, Australia; Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Sydney NSW, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney NSW, Australia. Electronic address:

Amyloid cardiomyopathy is emerging as an important and under-recognised cause of heart failure and cardiac arrhythmias, especially in older adults. This disorder is characterised by extracellular deposition of amyloid fibrils that form due to misfolding of secreted light chains (AL) or transthyretin protein (ATTR). In ATTR, amyloid aggregates typically result from excessive accumulation of wild-type transthyretin (ATTRwt) or from protein structural defects caused by TTR gene variants (ATTRv). Amyloid fibril deposition may predominantly affect the heart or show multi-system involvement. Previously considered to be rare and inexorably progressive with no specific therapy, there has been enormous recent interest in ATTR cardiomyopathy due to upwardly-revised estimates of disease prevalence together with development of disease-modifying interventions. Because of this, there is a clinical imperative to have a high index of suspicion to identify potential cases and to be aware of contemporary diagnostic methods and treatment options. Genetic testing should be offered to all patients with proven ATTR to access the benefits of new therapies specific to ATTRv and allow predictive testing of family members. With heightened awareness of amyloid cardiomyopathy and expanded use of genetic testing, a substantial rise in the numbers of asymptomatic individuals who are carriers of pathogenic variants is expected, and optimal strategies for monitoring and treatment of these individuals at risk need to be determined. Pre-emptive administration of fibril-modifying therapies provides an unprecedented opportunity for disease prevention and promises to change amyloid cardiomyopathy from being a fatal to a treatable disorder.
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http://dx.doi.org/10.1016/j.hlc.2019.11.019DOI Listing
April 2020

Familial Dilated Cardiomyopathy.

Heart Lung Circ 2020 Apr 17;29(4):566-574. Epub 2019 Dec 17.

Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Sydney, NSW, Australia; Cardiology Department, St. Vincent's Hospital, Sydney, NSW, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia. Electronic address:

Advances in human genome sequencing have re-invigorated genetics studies of dilated cardiomyopathy (DCM), facilitating genetic testing and clinical applications. With a range of genetic testing options now available, new challenges arise for data interpretation and identifying single pathogenic variants from the many thousands of rare variants present in every individual. There is accumulating evidence that genetic factors have an important role in the pathogenesis of DCM. However, although more than 100 genes have been implicated to date, the sensitivity of genetic testing, even in familial disease, is only ∼25-40%. As more patients are genotyped, nuanced information about disease phenotypes is emerging including variability in age of onset and penetrance of DCM, as well as additional cardiac and extra-cardiac features. Genotype-phenotype correlations have also identified a subset of genes that can be highly arrhythmogenic or show frequent progression to heart failure. Recognition of variants in these genes is important as this may impact on the timing of implantable cardioverter-defibrillators or heart transplantation. Finding a causative variant in a patient with DCM allows predictive testing of family members and provides an opportunity for preventative intervention. Diagnostic imaging modalities such as speckle-tracking echocardiography and cardiac magnetic resonance imaging are increasingly being used to detect and monitor pre-clinical ventricular dysfunction in asymptomatic variant carriers. Although there are several examples of successful genotype-based therapy, optimal strategies for implementation of precision medicine in familial DCM remain to be determined. Identification of modifiable co-morbidities and lifestyle factors that exacerbate or protect against DCM development in genetically-predisposed individuals remains a key component of family management.
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http://dx.doi.org/10.1016/j.hlc.2019.11.018DOI Listing
April 2020

Polygenic Risk Scores in Coronary Artery Disease and Atrial Fibrillation.

Heart Lung Circ 2020 Apr 27;29(4):634-640. Epub 2019 Dec 27.

Auckland City hospital, Auckland District Health Board, Auckland, New Zealand; Faculty of Medical and Health Science, University of Auckland, Auckland, New Zealand.

Coronary artery disease (CAD) and atrial fibrillation (AF) are two highly prevalent cardiovascular disorders that are associated with substantial morbidity and mortality. Conventional clinical risk factors for these disorders may not be identified prior to mid-adult life when pathophysiological processes are already established. A better understanding of the genetic underpinnings of disease should facilitate early detection of individuals at risk and preventative intervention. Single rare variants of large effect size that are causative for CAD, AF, or predisposing factors such as hypertension or hyperlipidaemia, may give rise to familial forms of disease. However, in most individuals, CAD and AF are complex traits in which combinations of genetic and acquired factors play a role. Common genetic variants that affect disease susceptibility have been identified by genome-wide association studies, but the predictive value of any single variant is limited. To address this issue, polygenic risk scores (PRS), comprised of suites of disease-associated common variants have been devised. In CAD and AF, incorporation of PRS into risk stratification algorithms has provided incremental prognostic information to clinical factors alone. The long-term health and economic benefits of PRS-guided clinical management remain to be determined however, and further evidence-based data are required.
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http://dx.doi.org/10.1016/j.hlc.2019.12.004DOI Listing
April 2020

Precision Medicine in the Management of Dilated Cardiomyopathy: JACC State-of-the-Art Review.

J Am Coll Cardiol 2019 12;74(23):2921-2938

Department of Genetics, Harvard Medical School, Boston, Massachusetts; Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.

Precision medicine promises to dramatically improve patient outcomes and reduce health care costs through a shift in focus from disease treatment to prevention and individualized therapies. For families with inherited cardiomyopathies, efforts to date have been directed toward discovery and functional characterization of single disease-causing variants. With advances in sequencing, the cataloging of personal genetic variation has been expedited, providing improved insights into the key importance of the genes in which variants occur. These advances have propelled seminal opportunities for successful variant-targeted disease-reversing therapy. New challenges have also emerged-particularly interpretation of the rapidly rising numbers of "variants of unknown significance." For treatments based on patient genotype to be feasible on a wider scale, these obstacles need to be overcome. Here the authors focus on genetics of dilated cardiomyopathy and provide a roadmap for implementing genomic information into future patient management.
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http://dx.doi.org/10.1016/j.jacc.2019.10.011DOI Listing
December 2019

Genetics of atrial cardiomyopathy.

Curr Opin Cardiol 2019 05;34(3):275-281

Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Darlinghurst.

Purpose Of Review: Atrial cardiomyopathy is a frequently encountered but underappreciated clinical entity that is characterized by altered atrial size and function. Although traditionally considered a primary atrial disorder, atrial cardiomyopathy was recently redefined to include secondary atrial remodelling. This conceptual shift has implications for the scope of etiological factors and intervention strategies. Our aim was to evaluate the potential contribution of genetics to atrial cardiomyopathy.

Recent Findings: Although the genetics of atrial cardiomyopathy is relatively unexplored, extensive efforts have been made to identify the genetic underpinnings of atrial fibrillation, which is a common complication of atrial cardiomyopathy. Interestingly, in-silico and functional studies suggest that atrial fibrillation-associated genetic variants mainly act by generating a proarrhythmogenic atrial cardiomyopathic substrate. Investigating the genetic basis of primary defects in atrial structure and function, as well as the genetic contributions to cardiac disorders, comorbidities and lifestyle factors that result in secondary atrial remodelling should expand the spectrum of genetic factors that directly or indirectly cause atrial cardiomyopathy and help to resolve the missing heritability of atrial fibrillation.

Summary: Elucidation of the genetic basis of atrial cardiomyopathy may provide new risk markers and facilitate personalized interventions for complications, such as atrial fibrillation, heart failure, and stroke.
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http://dx.doi.org/10.1097/HCO.0000000000000610DOI Listing
May 2019

Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection.

J Am Coll Cardiol 2019 01;73(1):58-66

Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Kensington, New South Wales, Australia.

Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene.

Objectives: This study sought to test the association between the rs9349379 genotype and SCAD.

Methods: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD.

Results: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence.

Conclusions: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.
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http://dx.doi.org/10.1016/j.jacc.2018.09.085DOI Listing
January 2019

Arrhythmic Genotypes in Familial Dilated Cardiomyopathy: Implications for Genetic Testing and Clinical Management.

Heart Lung Circ 2019 Jan 11;28(1):31-38. Epub 2018 Oct 11.

Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Sydney, NSW, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; Cardiology Department, St. Vincent's Hospital, Sydney, NSW, Australia. Electronic address:

Cardiac arrhythmias are frequently seen in patients with dilated cardiomyopathy (DCM) and can precipitate heart failure and death. In patients with non-ischaemic DCM, evidence for the benefit of an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden cardiac death has recently been questioned. Algorithms devised to identify high-risk individuals who might benefit most from ICD implantation have focussed on clinical criteria with little attention paid to the underlying aetiology of DCM. Malignant ventricular arrhythmias often occur as a nonspecific consequence of DCM but can also be a primary manifestation of disease in heritable forms of DCM and may precede DCM onset. We undertook a literature search and identified 11 genes that have been associated with DCM and ventricular arrhythmias in multiple kindreds. Many of these genes fall into a diagnostic grey zone between left-dominant arrhythmogenic right ventricular cardiomyopathy and arrhythmic DCM. Genes associated predominantly with arrhythmic DCM included LMNA and SCN5A, as well as the more recently-reported DCM disease genes, RBM20, FLNC, and TTN. Recognition of arrhythmic DCM genotypes is important, as this may impact on clinical management. In particular, prophylactic ICD implantation and early referral for heart transplantation may be indicated in genotype-positive individuals. Collectively, these findings argue in favour of including genetic testing in standard-of-care management of familial DCM. Further studies in genotyped patient cohorts are required to establish the long-term health and economic benefits of this strategy.
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http://dx.doi.org/10.1016/j.hlc.2018.09.010DOI Listing
January 2019

ETV1: A New Player in Atrial Remodeling.

Authors:
Diane Fatkin

Circ Res 2018 08;123(5):515-517

From the Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia (D.F.).

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http://dx.doi.org/10.1161/CIRCRESAHA.118.313606DOI Listing
August 2018

A-Band Titin Truncation in Zebrafish Causes Dilated Cardiomyopathy and Hemodynamic Stress Intolerance.

Circ Genom Precis Med 2018 08;11(8):e002135

Molecular Cardiology and Biophysics Division (I.G.H., L.W.W., C.F.S., C.H., R.J., T.J.B., G.T., D.F.).

Background Truncating variants in the TTN gene ( TTNtv) are common in patients with dilated cardiomyopathy (DCM) but also occur in the general population. Whether TTNtv are sufficient to cause DCM or require a second hit for DCM manifestation is an important clinical issue. Methods We generated a zebrafish model of an A-band TTNtv identified in 2 human DCM families in which early-onset disease appeared to be precipitated by ventricular volume overload. Cardiac phenotypes were serially assessed from 0 to 12 months using video microscopy, high-frequency echocardiography, and histopathologic analysis. The effects of sustained hemodynamic stress resulting from an anemia-induced hyperdynamic state were also evaluated. Results Homozygous ttna mutants had severe cardiac dysmorphogenesis and premature death, whereas heterozygous mutants ( ttna) survived into adulthood and spontaneously developed DCM. Six-month-old ttna fish had reduced baseline ventricular systolic function and failed to mount a hypercontractile response when challenged by hemodynamic stress. Pulsed wave and tissue Doppler analysis also revealed unsuspected ventricular diastolic dysfunction in ttna fish with prolonged isovolumic relaxation and increased diastolic passive stiffness in the absence of myocardial fibrosis. These defects reduced diastolic reserve under stress conditions and resulted in disproportionately greater atrial dilation than observed in wild-type fish. Conclusions Heterozygosity for A-band titin truncation is sufficient to cause DCM in adult zebrafish. Abnormalities of systolic and diastolic reserve in titin-truncated fish reduce stress tolerance and may contribute to a substrate for atrial arrhythmogenesis. These data suggest that hemodynamic stress may be an important modifiable risk factor in human TTNtv-related DCM.
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http://dx.doi.org/10.1161/CIRCGEN.118.002135DOI Listing
August 2018

Response to Brodehl et al.

Genet Med 2019 05 28;21(5):1248-1249. Epub 2018 Sep 28.

Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, NSW, Australia.

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http://dx.doi.org/10.1038/s41436-018-0292-1DOI Listing
May 2019
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