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Location-Dependent Differences in Cardiac and Skeletal Muscle Dysfunction Associated With Truncating Titin (ttn.2) Variants.
BACKGROUND: Truncating variants in the TTN gene (TTNtv), encoding the giant sarcomeric protein titin, cause a range of human cardiac and skeletal muscle disorders of varying penetrance and severity. The effects of variant location on clinical manifestations are incompletely understood. METHODS: We generated 6 zebrafish lines carrying truncating ttn.2 variants in the Z-disk, I-band, A-band, and M-band titin regions. Expression of titin transcripts and protein levels was evaluated using quantitative polymerase chain reaction and proteomics. Phenotype analysis was performed during embryonic development and in adult hearts. RESULTS: Homozygous embryos from all lines except the C-terminal line, e232, showed a significant reduction of Z-disk and I-band ttn.2 transcripts, but A-band and M-band transcript levels were reduced only in lines with truncations distal to the cronos promoter. These homozygous embryos uniformly died by 7 to 10 days postfertilization with marked impairment of cardiac morphology and function. Skeletal muscle motility and sarcomere organization were more disrupted in mutants with truncations distal to the cronos promoter compared with those proximal. In contrast, homozygous e232 embryos, which lacked only the titin kinase and M-band regions, had relatively preserved cardiac function with incorporation of truncated Ttn.2/Cronos protein and normal sarcomere assembly, but selective degradation of fast skeletal muscle sarcomeres. All heterozygous embryos were phenotypically indistinguishable from wild type. High-frequency echocardiography in adult heterozygous fish showed reduced ventricular contraction under resting conditions in A-band mutants. Heterozygous Z-disk and I-band mutants had no significant baseline impairment but were unable to augment ventricular contraction in response to acute adrenaline exposure, indicating a lack of cardiac reserve. CONCLUSIONS: Our data suggest that cardiac and skeletal muscle dysfunction associated with truncating ttn.2 variants is influenced by age, variant location, and the amount of functional titin protein. The distinctive phenotype associated with distal C-terminal truncations may reflect different requirements for C-terminal titin for maintenance of fast, slow, and cardiac muscle sarcomeres.
Exercise in Inherited Cardiomyopathies: Optimizing the Dose-Response Curve.
Exercise is generally considered beneficial for cardiovascular health, but for patients with inherited cardiomyopathies, exercise can be a source of anxiety due to concerns about arrhythmia risk and disease progression. In the general population, exercise avoidance can impact cardiometabolic health and diminished fitness is a risk factor for heart failure. At the other extreme, sustained high levels of exercise in competitive endurance athletes have been associated with an increased risk of some arrhythmias. Defining optimal threshold levels for exercise participation is not straightforward and one-size-fits-all recommendations are unlikely to be successful. In the context of inherited cardiomyopathies, the impact of exercise on myocardial function and arrhythmias depends on factors such as exercise frequency, intensity, and duration, as well as the type of cardiomyopathy, underlying genotype, and other unique intrinsic traits in each individual. This review outlines current knowledge with respect to the impact of exercise in hypertrophic, arrhythmogenic, and dilated cardiomyopathies based on studies in human cohorts and animal models. Several disease-specific and genotype-specific risk factors are highlighted, although our understanding of these factors remains incomplete. Importantly, although exercise activities remain restricted for those with high-risk features, emerging evidence suggests that moderate-to-high levels of exercise may be safe and beneficial for many patients. Harnessing the cardioprotective power of exercise holds enormous promise for expanding personalized strategies for cardiomyopathy treatment and prevention.
Coronavirus research topics, tracking twenty years of research.
Research publications aimed at understanding the various aspects of Coronaviruses, particularly COVID-19, have significantly shaped our knowledge base. While the urgency to monitor COVID-19 in real-time has decreased, the continual influx of new research of monthly articles underscores the importance of systematic review and analysis to deepen our understanding of the pandemic's broad impact. To explore research trends and innovations in this space, we developed a pipeline using natural language processing techniques. This pipeline systematically catalogues and synthesises the vast array of research articles, leading to the creation of a dataset with more than eight hundred thousand articles from July 2002 to May 2024. This paper describes the content of this dataset and provides the necessary information to make this dataset accessible and reusable for future research. Our approach aggregates and organises global research related to Coronaviruses into thematic clusters such as vaccine development, public health strategies, infection mechanisms, mental health issues, and economic consequences. Also, we have leveraged the contribution of health experts to review and revise the dataset.
Environmental Risk Factors Are Associated With the Natural History of Familial Dilated Cardiomyopathy.
BACKGROUND: Familial dilated cardiomyopathy (DCM) is characterized by marked variability in phenotypic penetrance. The extent to which this is determined by patient-specific environmental factors is unknown. METHODS AND RESULTS: A retrospective longitudinal cohort study was performed in families with DCM-causing genetic variants. Environmental factors were classified into 2 subsets based on evidence for a causal link to depressed myocardial contractility, termed (1) DCM-promoting factors and (2) heart failure comorbidities. These factors were correlated with DCM diagnosis and disease trajectory after accounting for relevant confounders and familial relatedness. A total of 105 probands and family members were recruited: 51 genotype positive, phenotype positive, 24 genotype positive, phenotype negative, and 30 genotype negative, phenotype negative. Demographic characteristics were similar between the 3 genotype groups. DCM-promoting environmental factors (eg, alcohol excess) were enriched in genotype-positive, phenotype-positive individuals compared with genotype-positive, phenotype-negative (P<0.001) and genotype-negative, phenotype-negative (P=0.003) individuals and were significantly associated with age at DCM onset (hazard ratio, 2.01; P=0.014). Heart failure comorbidities (eg, diabetes) had a similar prevalence in genotype-positive, phenotype-positive and genotype-negative, phenotype-negative individuals but were significantly reduced in the genotype-positive, phenotype-negative group. Fluctuations in left ventricular ejection fraction during follow-up were linked to changes in environmental factors in 35 of 45 (78%) of instances: 32 (91%) of these were DCM-promoting factors. CONCLUSIONS: We identified distinct subsets of environmental factors that affect DCM penetrance and trajectory. Our data highlight DCM-promoting environmental factors as key determinants of penetrance and natural history. Collectively, these findings provide a new framework for risk factor assessment in familial DCM and have important implications for clinical management.
Cardiovascular Workforce Sustainability Sector Consultation: Recommendations From an Australian Stakeholder Summit.
In 2023, a joint National Cardiovascular Workforce Sustainability Summit was convened by the Australian Cardiovascular Alliance (ACvA), the Cardiac Society of Australia and New Zealand, and the National Heart Foundation of Australia, to facilitate a national conversation towards developing a workforce sustainability strategy within the cardiovascular research sector. This initiative stemmed from a previous study conducted by the ACvA which revealed that almost 70% of early and mid-career cardiovascular researchers surveyed had contemplated leaving the sector. Summit attendees reported sector-wide challenges to career progression and retention across three key themes: 1) well-being and career satisfaction, 2) learning and development, and 3) resource allocation. The summit also identified a need for greater collaboration and multidisciplinary approaches to research to foster growth towards a more sustainable sector. Key recommendations from the Summit included: 1) establish metrics to monitor progress towards a more sustainable sector and signpost improvement in workforce sustainability; 2) establish a collective partnership between central bodies for unified advocacy and monitoring of metrics; and 3) develop a collaborative, strategic and targeted approach to guide and facilitate training programs that have been developed by shared sector-wide philosophy.
Loss of Sec-1 Family Domain-Containing 1 (scfd1) Causes Severe Cardiac Defects and Endoplasmic Reticulum Stress in Zebrafish
Dilated cardiomyopathy (DCM) is a common heart muscle disorder that frequently leads to heart failure, arrhythmias, and death. While DCM is often heritable, disease-causing mutations are identified in only ~30% of cases. In a forward genetic mutagenesis screen, we identified a novel zebrafish mutant, heart and head (hahvcc43), characterized by early-onset cardiomyopathy and craniofacial defects. Linkage analysis and next-generation sequencing identified a nonsense variant in the highly conserved scfd1 gene, also known as sly1, that encodes sec1 family domain-containing 1. Sec1/Munc18 proteins, such as Scfd1, are involved in membrane fusion regulating endoplasmic reticulum (ER)/Golgi transport. CRISPR/Cas9-engineered scfd1vcc44 null mutants showed severe cardiac and craniofacial defects and embryonic lethality that recapitulated the phenotype of hahvcc43 mutants. Electron micrographs of scfd1-depleted cardiomyocytes showed reduced myofibril width and sarcomere density, as well as reticular network disorganization and fragmentation of Golgi stacks. Furthermore, quantitative PCR analysis showed upregulation of ER stress response and apoptosis markers. Both heterozygous hahvcc43 mutants and scfd1vcc44 mutants survived to adulthood, showing chamber dilation and reduced ventricular contraction. Collectively, our data implicate scfd1 loss-of-function as the genetic defect at the hahvcc43 locus and provide new insights into the role of scfd1 in cardiac development and function.
Titin-related Cardiomyopathy: Is it a Distinct Disease?
PURPOSE OF REVIEW: Truncating TTN variants (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM), but the underlying mechanisms are incompletely understood and effective therapeutic strategies are lacking. Here we review recent data that shed new light on the functional consequences of TTNtv and how these effects may vary with mutation location. RECENT FINDINGS: Whether TTNtv act by haploinsufficiency or dominant negative effects has been hotly debated. New evidence now implicates both mechanisms in TTNtv-related DCM, showing reduced titin content and persistent truncated titin that may be incorporated into protein aggregates. The extent to which aggregate formation and protein quality control defects differ with TTNtv location and contribute to contractile dysfunction is unresolved. TTNtv-associated DCM has a complex etiology that involves varying combinations of wild-type titin deficiency and dominant negative effects of truncated mutant titin. Therapeutic strategies to improve protein handling may be beneficial in some cases.
Mechanisms of TTNtv-related dilated cardiomyopathy: Insights from zebrafish models
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 TTN gene, which encodes the giant sarcomeric protein titin (TTNtv), are the most common genetic cause of DCM, but exactly how TTNtv promote cardiomyocyte dysfunction is not known. Although rodent models have been widely used to investigate titin biology, they have had limited utility for TTNtv-related DCM. In recent years, zebrafish (Danio rerio) 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 TTNtv 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.
A Langendorff-like system to quantify cardiac pump function in adult zebrafish.
Zebrafish are increasingly used as a vertebrate model to study human cardiovascular disorders. Although heart structure and function are readily visualized in zebrafish embryos because of their optical transparency, the lack of effective tools for evaluating the hearts of older, nontransparent fish has been a major limiting factor. The recent development of high-frequency echocardiography has been an important advance for in vivo cardiac assessment, but it necessitates anesthesia and has limited ability to study acute interventions. We report the development of an alternative experimental ex vivo technique for quantifying heart size and function that resembles the Langendorff heart preparations that have been widely used in mammalian models. Dissected adult zebrafish hearts were perfused with a calcium-containing buffer, and a beat frequency was maintained with electrical stimulation. The impact of pacing frequency, flow rate and perfusate calcium concentration on ventricular performance (including end-diastolic and end-systolic volumes, ejection fraction, radial strain, and maximal velocities of shortening and relaxation) were evaluated and optimal conditions defined. We determined the effects of age on heart function in wild-type male and female zebrafish, and successfully detected hypercontractile and hypocontractile responses after adrenergic stimulation or doxorubicin treatment, respectively. Good correlations were found between indices of cardiac contractility obtained with high-frequency echocardiography and with the ex vivo technique in a subset of fish studied with both methods. The ex vivo beating heart preparation is a valuable addition to the cardiac function tool kit that will expand the use of adult zebrafish for cardiovascular research.
A-Band Titin Truncation in Zebrafish Causes Dilated Cardiomyopathy and Hemodynamic Stress Intolerance.
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 ( ttnatv/+) survived into adulthood and spontaneously developed DCM. Six-month-old ttnatv/+ 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 ttnatv/+ 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.
Genetics of Atrial Fibrillation: State of the Art in 2017.
Genetic variation is an important determinant of atrial fibrillation (AF) susceptibility. Numerous rare variants in protein-coding sequences of genes have been associated with AF in families and in early-onset cases, and chromosomal loci harbouring common risk variants have been mapped in AF cohorts. Many of these loci are in non-coding regions of the human genome and are thought to contain regulatory sequences that modulate gene expression. Disease genes implicated to date have predominantly encoded cardiac ion channels, with predicted mutation effects on the atrial action potential duration. More recent studies have expanded the spectrum of disease-associated genes to include myocardial structural components and have highlighted an unsuspected role for cardiac transcription factors. These paradigm-shifting discoveries suggest that abnormalities of atrial specification arising during cardiac development might provide a template for AF in later adult life. With the escalating pace of variant discovery, there is an increasing need for mechanistic studies not only to evaluate single variants, but also to determine the collective effects of each person's burden of rare and common genetic variants, co-morbidities and lifestyle factors on the atrial substrate for arrhythmogenesis. Elucidation of an individual's genetic predisposition and modifiable environmental risk factors will facilitate personalised approaches to AF treatment.
Standardized echocardiographic assessment of cardiac function in normal adult zebrafish and heart disease models.
The zebrafish (Danio rerio) is an increasingly popular model organism in cardiovascular research. Major insights into cardiac developmental processes have been gained by studies of embryonic zebrafish. However, the utility of zebrafish for modeling adult-onset heart disease has been limited by a lack of robust methods for in vivo evaluation of cardiac function. We established a physiological protocol for underwater zebrafish echocardiography using high frequency ultrasound, and evaluated its reliability in detecting altered cardiac function in two disease models. Serial assessment of cardiac function was performed in wild-type zebrafish aged 3 to 12 months and the effects of anesthetic agents, age, sex and background strain were evaluated. There was a varying extent of bradycardia and ventricular contractile impairment with different anesthetic drugs and doses, with tricaine 0.75 mmol l-1 having a relatively more favorable profile. When compared with males, female fish were larger and had more measurement variability. Although age-related increments in ventricular chamber size were greater in females than males, there were no sex differences when data were normalized to body size. Systolic ventricular function was similar in both sexes at all time points, but differences in diastolic function were evident from 6 months onwards. Wild-type fish of both sexes showed a reliance on atrial contraction for ventricular diastolic filling. Echocardiographic evaluation of adult zebrafish with diphtheria toxin-induced myocarditis or anemia-induced volume overload accurately identified ventricular dilation and altered contraction, with suites of B-mode, ventricular strain, pulsed-wave Doppler and tissue Doppler indices showing concordant changes indicative of myocardial hypocontractility or hypercontractility, respectively. Repeatability, intra-observer and inter-observer correlations for echocardiographic measurements were high. We demonstrate that high frequency echocardiography allows reliable in vivo cardiac assessment in adult zebrafish and make recommendations for optimizing data acquisition and analysis. This enabling technology reveals new insights into zebrafish cardiac physiology and provides an imaging platform for zebrafish-based translational research.
The two-pore domain potassium channel, TWIK-1, has a role in the regulation of heart rate and atrial size.
The two-pore domain potassium (K(+)) channel TWIK-1 (or K2P1.1) contributes to background K(+) conductance in diverse cell types. TWIK-1, encoded by the KCNK1 gene, is present in the human heart with robust expression in the atria, however its physiological significance is unknown. To evaluate the cardiac effects of TWIK-1 deficiency, we studied zebrafish embryos after knockdown of the two KCNK1 orthologues, kcnk1a and kcnk1b. Knockdown of kcnk1a or kcnk1b individually caused bradycardia and atrial dilation (p<0.001 vs. controls), while ventricular stroke volume was preserved. Combined knockdown of both kcnk1a and kcnk1b resulted in a more severe phenotype, which was partially reversed by co-injection of wild-type human KCNK1 mRNA, but not by a dominant negative variant of human KCNK1 mRNA. To determine whether genetic variants in KCNK1 might cause atrial fibrillation (AF), we sequenced protein-coding regions in two independent cohorts of patients (373 subjects) and identified three non-synonymous variants, p.R171H, p.I198M and p.G236S, that were all located in highly conserved amino acid residues. In transfected mammalian cells, zebrafish and wild-type human TWIK-1 channels had a similar cellular distribution with predominant localization in the endosomal compartment. Two-electrode voltage-clamp experiments using Xenopus oocytes showed that both zebrafish and wild-type human TWIK-1 channels produced K(+) currents that are sensitive to external K(+) concentration as well as acidic pH. There were no effects of the three KCNK1 variants on cellular localization, current amplitude or reversal potential at pH7.4 or pH6. Our data indicate that TWIK-1 has a highly conserved role in cardiac function and is required for normal heart rate and atrial morphology. Despite the functional importance of TWIK-1 in the atrium, genetic variation in KCNK1 is not a common primary cause of human AF.
Zebrafish as a universal in vivo model for plasmonic nanoparticle medicine
The zebrafish embryo has been evaluated as an in vivo model for plasmonic nanobubble (PNB) generation and detection at nanoscale. The embryo is easily observed and manipulated utilizing the same methodology as for application of PNBs in vitro. Injection and irradiation of gold nanoparticles with a short laser pulse resulted in generation of PNBs in zebrafish with the similar parameters as for PNBs generated in water and cultured living cells. These PNBs do not result in systemic damage, thus we demonstrated in vivo model for rapid and precise testing of plasmonic nanotechnologies .