Loss-of-function (LOF) variants in SCN1B, encoding the voltage-gated sodium channel β1/β1B subunits, are linked to neurological and cardiovascular diseases. Scn1b-null mice have spontaneous seizures and ventricular arrhythmias and die by approximately 21 days after birth. β1/β1B Subunits play critical roles in regulating the excitability of ventricular cardiomyocytes and maintaining ventricular rhythmicity. However, whether they also regulate atrial excitability is unknown. We used neonatal Scn1b-null mice to model the effects of SCN1B LOF on atrial physiology in pediatric patients. Scn1b deletion resulted in altered expression of genes associated with atrial dysfunction. Scn1b-null hearts had a significant accumulation of atrial collagen, increased susceptibility to pacing induced atrial fibrillation (AF), sinoatrial node (SAN) dysfunction, and increased numbers of cholinergic neurons in ganglia that innervate the SAN. Atropine reduced the incidence of AF in null animals. Action potential duration was prolonged in null atrial myocytes, with increased late sodium current density and reduced L-type calcium current density. Scn1b LOF results in altered atrial structure and AF, demonstrating the critical role played by Scn1b in atrial physiology during early postnatal mouse development. Our results suggest that SCN1B LOF variants may significantly impact the developing pediatric heart.
Roberto Ramos-Mondragon, Nnamdi Edokobi, Samantha L. Hodges, Shuyun Wang, Alexandra A. Bouza, Chandrika Canugovi, Caroline Scheuing, Lena Juratli, William R. Abel, Sami F. Noujaim, Nageswara R. Madamanchi, Marschall S. Runge, Luis F. Lopez-Santiago, Lori L. Isom
BACKGROUND. Sudden cardiac death (SCD) remains a worldwide public health problem in need of better noninvasive predictive tools. Current guidelines for primary preventive SCD therapies such as implantable cardioverter defibrillators (ICDs) are based on left ventricular ejection fraction (LVEF), but these are imprecise with fewer than 5% of ICDs delivering life-saving therapy per year. Impaired cardiac metabolism and ATP depletion cause arrhythmias in experimental models, but a link between arrhythmias and cardiac energetic abnormalities in people has not been explored, nor the potential for metabolically predicting clinical SCD risk. METHODS. We prospectively measured myocardial energy metabolism noninvasively with phosphorus magnetic resonance spectroscopy in patients with no history of significant arrhythmias prior to scheduled ICD implantation for primary prevention in the setting of reduced LVEF (≤35%). RESULTS. By two different analyses, low myocardial ATP significantly predicted the composite of subsequent appropriate ICD firings for life-threatening arrhythmias and cardiac death over ~10 years. Life-threatening arrhythmia risk was ~3-fold higher in low ATP patients and independent of established risk factors including LVEF. In patients with normal ATP, rates of appropriate ICD firings were several-fold lower than reported rates of ICD complications and inappropriate firings. CONCLUSION. These first data linking in vivo myocardial ATP depletion and subsequent significant arrhythmic events in people suggest an energetic component to clinical life-threatening ventricular arrhythmogenesis. The findings support investigation of metabolic strategies that limit ATP loss to treat or prevent life-threatening cardiac arrhythmias and herald non-invasive metabolic imaging as a complementary SCD risk stratification tool. TRIAL REGISTRATION. NCT00181233. FUNDING. This work was supported by DW Reynolds Foundation, the National Institutes of Health (grants HL61912, HL056882, HL103812, HL132181, HL140034), and the Russell H. Morgan (P.A.B.) and Clarence Doodeman (R.G.W.) Endowments at Johns Hopkins.
T. Jake Samuel, Shenghan Lai, Michael Schär, Katherine C. Wu, Angela M. Steinberg, An-Chi Wei, Mark Anderson, Gordon F. Tomaselli, Gary Gerstenblith, Paul A. Bottomley, Robert G. Weiss
We have previously demonstrated that active immunization with the apolipoprotein B-100 (ApoB-100) peptide P210 reduces experimental atherosclerosis. To advance this immunization strategy to future clinical testing, we explored the possibility of delivering P210 as an antigen using nanoparticles, given this approach has now been used clinically. To that end, we first charactered the responses of T cells to P210 using PBMCs from human subjects with atherosclerotic cardiovascular disease (ASCVD). We then investigated the use of P210 in self-assembling peptide amphiphile micelles (P210-PAM) as a vaccine formulation to reduce atherosclerosis in ApoE-/- mice and its potential mechanisms of action. We also generated and characterized a humanized mouse model with chimeric HLA-A*02:01/Kb in ApoE-/- background to test the efficacy of P210-PAM immunization as a bridge for future clinical testing. P210 provoked T cell activation and memory response in PBMCs of human subjects with ASCVD. Dendritic cell uptake of P210-PAM and its co-staining with MHC-I molecules supported its use as a vaccine formulation. In ApoE-/- mice, immunization with P210-PAM dampened P210-specific CD4+ T cell proliferative response and CD8+ T cell cytolytic response, modulated macrophage phenotype, and significantly reduced aortic atherosclerosis. Potential clinical relevance of P210-PAM immunization was demonstrated by reduced atherosclerosis in the humanized ApoE-/- mouse model expressing chimeric HLA-A*02:01/Kb. Taken together, our data supports the experimental and translational use of P210-PAM as a potential vaccine candidate against human ASCVD.
Kuang-Yuh Chyu, Xiaoning Zhao, Jianchang Zhou, Paul C. Dimayuga, Nicole W.M. Lio, Bojan Cercek, Noah T. Trac, Eun Ji Chung, Prediman K. Shah
Atrial fibrillation (AF), the most common sustained cardiac arrhythmia and a major risk factor for stroke, often arises through ectopic electrical impulses derived from the pulmonary veins (PV). Sequence variants in enhancers controlling expression of the transcription factor PITX2, which is expressed in the cardiomyocytes (CMs) of the PV and left atrium (LA), have been implicated in AF predisposition. Single nuclei multiomic profiling of RNA and analysis of chromatin accessibility combined with spectral clustering uncovered distinct PV- and LA-enriched CM cell states. Pitx2 mutant PV and LA CMs exhibited gene expression changes consistent with cardiac dysfunction through cell-type-distinct, PITX2-directed, cis-regulatory grammars controlling target gene expression. The perturbed network targets in each CM were enriched in distinct human AF-predisposition genes, suggesting combinatorial risk for AF-genesis. Our data further reveals that PV and LA Pitx2 mutant CMs signal to endothelial and endocardial cells through BMP10 signaling with pathogenic potential. This work provides a multiomic framework for interrogating the basis of AF-predisposition in the PV of humans.
Jeffrey D. Steimle, Francisco J. Grisanti Canozo, Minjun Park, Zachary A. Kadow, Md. Abul Hassan Samee, James F. Martin
Metabolic stress is an important cause of pathological atrial remodeling and atrial fibrillation. AMPK is a ubiquitous master metabolic regulator, yet its biological function in the atria is poorly understood in both health and disease. We investigated the impact of atrium-selective cardiac AMPK deletion on electrophysiological and structural remodeling in mice. Loss of atrial AMPK expression caused atrial changes in electrophysiological properties and atrial ectopic activity prior to the onset of spontaneous atrial fibrillation. Concomitant transcriptional downregulation of connexins and atrial ion channel subunits manifested with delayed left atrial activation and repolarization. The early molecular and electrophysiological abnormalities preceded left atrial structural remodeling and interstitial fibrosis. AMPK inactivation induced downregulation of transcription factors (Mef2c and Pitx2c) linked to connexin and ion channel transcriptional reprogramming. Thus, AMPK plays an essential homeostatic role in atria, protecting against adverse remodeling potentially by regulating key transcription factors that control the expression of atrial ion channels and gap junction proteins.
Kevin N. Su, Yina Ma, Marine Cacheux, Zeki Ilkan, Nour Raad, Grace K. Muller, Xiaohong Wu, Nicole Guerrera, Stephanie L. Thorn, Albert J. Sinusas, Marc Foretz, Benoit Viollet, Joseph G. Akar, Fadi G. Akar, Lawrence H. Young
Human induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) can model heritable arrhythmias to personalize therapies for individual patients. Although atrial fibrillation (AF) is a leading cause of cardiovascular morbidity and mortality, current platforms to generate iPSC-atrial (a) CMs are inadequate for modeling AF. We applied a combinatorial engineering approach, which integrated multiple physiological cues, including metabolic conditioning and electrical stimulation, to generate mature iPSC-aCMs. Using the patient’s own atrial tissue as a gold standard benchmark, we assessed the electrophysiological, structural, metabolic, and molecular maturation of iPSC-aCMs. Unbiased transcriptomic analysis and inference from gene regulatory networks identified key gene expression pathways and transcription factors mediating atrial development and maturation. Only mature iPSC-aCMs generated from patients with heritable AF carrying the non-ion channel gene (NPPA) mutation showed enhanced expression and function of a cardiac potassium channel and revealed mitochondrial electron transport chain dysfunction. Collectively, we propose that ion channel remodeling in conjunction with metabolic defects created an electrophysiological substrate for AF. Overall, our electro-metabolic approach generated mature human iPSC-aCMs that unmasked the underlying mechanism of the first non-ion channel gene, NPPA, that causes AF. Our maturation approach will allow for the investigation of the molecular underpinnings of heritable AF and the development of personalized therapies.
Olivia T. Ly, Hanna Chen, Grace E. Brown, Liang Hong, Xinge Wang, Yong Duk Han, Mahmud Arif Pavel, Arvind Sridhar, Mark Maienschein-Cline, Brandon Chalazan, Sang-Ging Ong, Khaled Abdelhady, Malek Massad, Lona Ernst Rizkallah, Jalees Rehman, Salman R. Khetani, Dawood Darbar
Amyloidosis involves stepwise growth of fibrils assembled from soluble precursors. Transthyretin (TTR) naturally folds into a stable tetramer, whereas conditions and mutations that foster aberrant monomer formations facilitate TTR oligomeric aggregation and subsequent fibril extension. We investigated the early assembly of oligomers by WT TTR compared with its V30M and V122I variants. We monitored time-dependent redistribution among monomer, dimer, tetramer, and oligomer contents in the presence and absence of multimeric TTR seeds. The seeds were artificially constructed recombinant multimers that contained 20–40 TTR subunits via engineered biotin-streptavidin (SA) interactions. As expected, these multimer seeds rapidly nucleated TTR monomers into larger complexes, while having less effect on dimers and tetramers. In vivo, SA-induced multimers formed TTR-like deposits in the heart and the kidney following i.v. injection in mice. While all 3 variants prominently deposited glomerulus in the kidney, only V30M resulted in extensive deposition in the heart. The cardiac TTR deposits varied in size and shape and were localized in the intermyofibrillar space along the capillaries. These results are consistent with the notion of monomeric TTR engaging in high-avidity interactions with tissue amyloids. Our multimeric induction approach provides a model for studying the initiation of TTR deposition in the heart.
Li Gao, Xinfang Xie, Pan Liu, Jing Jin
Shortness of breath, chest pain, and palpitations occur as post-acute sequelae of COVID-19 (PASC), but whether symptoms are associated with echocardiographic abnormalities, cardiac biomarkers, or markers of systemic inflammation remains unknown. In a cross-sectional analysis, we assessed symptoms, performed echocardiograms, and measured biomarkers among adults >8 weeks after confirmed SARS-CoV-2 infection. We modeled associations between symptoms and baseline characteristics, echocardiographic findings, and biomarkers using logistic regression. We enrolled 102 participants at a median 7.2 months (IQR 4.1-9.1) following COVID-19 onset; 47 individuals reported dyspnea, chest pain, or palpitations. Median age was 52 years (range 24-86) and 41% were women. Female sex, hospitalization, IgG antibody to SARS-CoV-2 receptor binding domain and C-reactive protein were associated with symptoms. Regarding echocardiographic findings, 4/47 (9%) with symptoms had pericardial effusions compared to 0/55 without symptoms (p=0.038); those with effusions had a median 4 symptoms compared to 1 without (p<0.001). There was no strong evidence for a relationship between symptoms and echocardiographic functional parameters or other biomarkers. Among adults >8 weeks after SARS-CoV-2 infection, SARS-CoV-2 RBD antibodies, markers of inflammation and, possibly, pericardial effusions are associated with cardiopulmonary symptoms. Investigation into inflammation as a mechanism underlying PASC is warranted.
Matthew S. Durstenfeld, Michael J. Peluso, J. Daniel Kelly, Sithu Win, Shreya Swaminathan, Danny Li, Victor M. Arechiga, Victor Antonio Zepeda, Kaiwen Sun, Shirley J. Shao, Christopher Hill, Mireya I. Arreguin, Scott Lu, Rebecca Hoh, Viva W. Tai, Ahmed Chenna, Brandon C. Yee, John W. Winslow, Christos J. Petropoulos, John Kornak, Timothy J. Henrich, Jeffrey N. Martin, Steven G. Deeks, Priscilla Y. Hsue
BACKGROUND. Although traditional lipid parameters and coronary imaging techniques are valuable for cardiovascular disease (CVD) risk prediction, better diagnostic tests are still needed. METHODS. In a prospective, observational study, 795 subjects had extensive cardiometabolic profiling, including emerging biomarkers, such as apolipoprotein E (ApoE)-containing HDL-cholesterol. Coronary artery calcium (CAC) score was assessed in the entire cohort, and quantitative coronary computed tomography angiographic (CCTA) characterization (Medis, Qangio) of total (TB), non-calcified (NCB) and fibrous plaque burden (FB) was performed in a sub-cohort (n=300) of patients stratified by concentration of ApoE-HDL-C. Total and HDL-containing apolipoprotein C-III (ApoC-III) were also measured. RESULTS. Most patients had a clinical diagnosis of coronary artery disease (CAD) (n=80.4% of 795), with mean age of 59 years, male (57%) and about half on statin treatment. The low ApoE-HDL-C group had more severe stenosis (11% vs. 2%, overall P<0.001), with higher CAC as compared to high ApoE-HDL-C. On quantitative CCTA, high ApoE-HDL-C group had lower NCB (β=-0.24, P=0.0001), which tended to be significant in fully adjusted model (β=-0.32, P=0.001) and altered by ApoC-III in HDL levels. Low ApoE-HDL-C was significantly associated with LDL particle number (β=0.31; P=0.0001). Finally, when stratified by FB, ApoC-III in HDL showed a more robust predictive value of CAD over ApoE-HDL-C (AUC: 0.705, P=0.0001) in a fully adjusted model. CONCLUSIONS. ApoE-containing HDL-C showed a significant association with early coronary plaque characteristics and is affected by the presence of ApoC-III, indicating that low ApoE-HDL-C and high ApoC-III may be important markers of CVD severity. CLINICAL TRIAL REGISTRATION. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01621594. FUNDING. This work was supported by the National Heart, Lung and Blood Institute (NHLBI) at the National Institutes of Health Intramural Research Program. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Alexander V. Sorokin, Nidhi Patel, Khaled M. Abdelrahman, Clarence Ling, Mart Reimund, Giorgio Graziano, Maureen Sampson, Martin Playford, Amit K. Dey, Aarthi Reddy, Heather L. Teague, Michael Stagliano, Marcelo Amar, Marcus Y. Chen, Nehal Mehta, Alan T. Remaley
Ca2+ is critical for cardiac electrical conduction and contractility, and aberrant Ca2+ homeostasis causes arrhythmia and heart failure. Chromatin remodeling modulates gene expression involved in cardiac sarcomere assembly and postnatal heart function. However, the chromatin remodeling-regulatory cardiac Ca2+ homeostasis is unknown. Here, we found that Znhit1, a core subunit of the SRCAP remodeling complex, was essential for heart function. Deletion of Znhit1 in postnatal heart of mice resulted in arrhythmia, idiopathic vacuolar cardiomyopathy, rapid heart failure and premature sudden death. In addition, the level of Casq1, a sarcoplasmic reticulum (SR) Ca2+ regulatory protein, was massively elevated while SERCA2a showed reduced protein level. Mechanistically, the Znhit1 modulated the expression of Casq1 and SERCA2a through depositing H2A.Z at their promoters. Deletion of Casq1 could substantially alleviate the vacuolar formation in Znhit1 cKO mice. These findings have demonstrated that Znhit1 is required for post-natal heart function and maintains cardiac Ca2+ homeostasis, and accumulation of Casq1 might be a causative factor for vacuolar cardiomyopathy.
Yingchao Shi, Wenli Fan, Mingjie Xu, Xinhua Lin, Wukui Zhao, Zhongzhou Yang
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