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
Takotsubo syndrome (TTS) is an acute, stress-induced cardiomyopathy that occurs predominantly in women after extreme physical and/or emotional stress. To date, our understanding of the molecular basis for TTS remains unknown and, consequently, specific therapies are lacking. Myocardial infiltration of monocytes and macrophages in TTS has been documented in clinical studies. However, the functional importance of these findings remains poorly understood. Here, we show that a single high dose of isoproterenol (ISO) in mice induced a TTS-like cardiomyopathy phenotype characterized by female predominance, severe cardiac dysfunction, and robust myocardial infiltration of macrophages. Single-cell RNA-Seq studies of myocardial immune cells revealed that TTS-like cardiomyopathy is associated with complex activation of innate and adaptive immune cells in the heart, and macrophages were identified as the dominant immune cells. Global macrophage depletion (via clodronate liposome administration) or blockade of macrophage infiltration (via a CCR2 antagonist or in CCR2-KO mice) resulted in recovery of cardiac dysfunction in ISO-challenged mice. In addition, damping myeloid cell activation by HIF1α deficiency or exposure to the immunomodulatory agent bortezomib ameliorated ISO-induced cardiac dysfunction. Collectively, our findings identify macrophages as a critical regulator of TTS pathogenesis that can be targeted for therapeutic gain.
Xudong Liao, Eugene Chang, Xinmiao Tang, Ippei Watanabe, Rongli Zhang, Hyun-Woo Jeong, Ralf H. Adams, Mukesh K. Jain
Remodeling of injured sympathetic nerves on the heart after myocardial infarction (MI) contributes to adverse outcomes such as sudden arrhythmic death, yet the underlying structural mechanisms are poorly understood. We sought to examine microstructural changes on the heart after MI and to directly link these changes with electrical dysfunction. We developed a high-resolution pipeline for anatomically precise alignment of electrical maps with structural myofiber and nerve-fiber maps created by customized computer vision algorithms. Using this integrative approach in a mouse model, we identified distinct structure-function correlates to objectively delineate the infarct border zone, a known source of arrhythmias after MI. During tyramine-induced sympathetic nerve activation, we demonstrated regional patterns of altered electrical conduction aligned directly with altered neuroeffector junction distribution, pointing to potential neural substrates for cardiac arrhythmia. This study establishes a synergistic framework for examining structure-function relationships after MI with microscopic precision that has potential to advance understanding of arrhythmogenic mechanisms.
Ching Zhu, Pradeep S. Rajendran, Peter Hanna, Igor R. Efimov, Guy Salama, Charless C. Fowlkes, Kalyanam Shivkumar
The fibrous annulus of the mitral valve plays an important role in valvular function and cardiac physiology, while normal variation in the size of cardiovascular anatomy may share a genetic link with common and rare disease. We derived automated estimates of mitral valve annular diameter in the 4-chamber view from 32,220 MRI images from the UK Biobank at ventricular systole and diastole as the basis for GWAS. Mitral annular dimensions corresponded to previously described anatomical norms, and GWAS inclusive of 4 population strata identified 10 loci, including possibly novel loci (GOSR2, ERBB4, MCTP2, MCPH1) and genes related to cardiac contractility (BAG3, TTN, RBFOX1). ATAC-Seq of primary mitral valve tissue localized multiple variants to regions of open chromatin in biologically relevant cell types and rs17608766 to an algorithmically predicted enhancer element in GOSR2. We observed strong genetic correlation with measures of contractility and mitral valve disease and clinical correlations with heart failure, cerebrovascular disease, and ventricular arrhythmias. Polygenic scoring of mitral valve annular diameter in systole was predictive of risk mitral valve prolapse across 4 cohorts. In summary, genetic and clinical studies of mitral valve annular diameter revealed genetic determinants of mitral valve biology, while highlighting clinical associations. Polygenic determinants of mitral valve annular diameter may represent an independent risk factor for mitral prolapse. Overall, computationally estimated phenotypes derived at scale from medical imaging represent an important substrate for genetic discovery and clinical risk prediction.
Mengyao Yu, Catherine Tcheandjieu, Adrien Georges, Ke Xiao, Helio Tejeda, Christian Dina, Thierry Le Tourneau, Madalina Fiterau, Renae Judy, Noah L. Tsao, Dulguun Amgalan, Chad J. Munger, Jesse M. Engreitz, Scott M. Damrauer, Nabila Bouatia-Naji, James R. Priest
There is a high prevalence of ventricular arrhythmias related to sudden cardiac death in patients with chronic kidney disease (CKD). To explored the possible mechanism of CKD-related ventricular arrhythmias, a CKD rat model was created, and indoxyl sulfate (IS) was further used in vivo and in vitro. This project used the following methods: patch clamp, electrocardiogram, and some molecular biology experimental techniques. IS was found to be significantly elevated in the serum of CKD rats. Interestingly, the expression levels of the fast transient outward potassium current–related (Ito,f-related) proteins (Kv4.2, Kv4.3, and KChIP2) in the heart of CKD rats and rats treated with IS decreased. IS dose-dependently reduced Ito,f density, accompanied by the decreases in Kv4.2, Kv4.3, and KChIP2 proteins in vitro. IS also prolonged the action potential duration and QT interval, and paroxysmal ventricular tachycardia could be induced by IS. In-depth studies have shown that ROS/p38MAPK, ROS–p44/42 MAPK, and NF-κB signaling pathways play key roles in the reduction of Ito,f density and Ito,f-related proteins caused by IS. These data suggest that IS reduces Ito,f-related proteins and Ito,f density by activating ROS/MAPK and NF-κB signaling pathways, and the action potential duration and QT interval are subsequently prolonged, which contributes to increasing the susceptibility to arrhythmia in CKD.
Jing Yang, Hongxia Li, Chi Zhang, Yafeng Zhou
The molecular mechanisms that drive the acquisition of distinct neural crest cell (NCC) fates is still poorly understood. Here, we identify Prdm6 as an epigenetic modifier that temporally and spatially regulates the expression of NCC specifiers and determines the fate of a subset of migrating Cardiac NCCs (CNCCs). Using transcriptomic analysis, genetic and fate mapping approaches in transgenic mice, we show that disruption of Prdm6 is associated with impaired CNCC differentiation, delamination, and migration, and leads to patent ductus arteriosus (DA)and ventricular noncompaction. Bulk and single-cell RNA-seq analyses of DA and CNCC identify Prdm6 as a regulator of a network of CNCC specification genes including Wnt1, Tfap2b, and Sox9. Loss of Prdm6 in CNCCs diminishes its expression in pre-EMT cluster, resulting in the retention of NCC in the dorsal neural tube. This defect is associated with diminished H4K20 mono-methylation and G1-S progression and augmented Wnt1 transcript levels in pre-EMT and neural tube clusters, which we show is the major driver of the impaired CNCC migration. Altogether, these findings reveal Prdm6 as a key regulator of CNCC differentiation and migration and identify Prdm6 and its regulated network as potential targets for the treatment of congenital heart diseases.
Lingjuan Hong, Na Li, Victor Gasque, Sameet Mehta, Lupeng Ye, Yinyu Wu, Jinyu Li, Andreas Gewies, Jürgen Ruland, Karen K. Hirschi, Anne Eichmann, Caroline Hendry, David van Dijk, Arya Mani
Calcific aortic valve disease (CAVD) is heritable as revealed by recent genome wide association studies. While polymorphisms linked to increased expression of CACNA1C, encoding the CaV1.2 L-type voltage-gated Ca2+ channel, and increased Ca2+ signaling are associated with CAVD, whether increased Ca2+ influx through the druggable CaV1.2 is causal for calcific aortic valve disease is unknown. With surgically removed aortic valves from patients, we confirmed the association between increased CaV1.2 expression and CAVD. We extended our studies with a transgenic mouse model that mimics increased CaV1.2 expression in within aortic valve interstitial cells (VICs). In young mice maintained on normal chow, we observed dystrophic valve lesions that mimic changes found in pre-symptomatic CAVD, and showed activation of chondrogenic and osteogenic transcriptional regulators within these valve lesions. Chronic administration of verapamil, a clinically used CaV1.2 antagonist, slowed the progression of lesion development in vivo. Exploiting VIC cultures we demonstrated that increased Ca2+ influx through CaV1.2 drives signaling programs that lead to myofibroblast activation of VICs and upregulation of genes associated with aortic valve calcification. Our data support a causal role for Ca2+ influx through CaV1.2 in CAVD and suggest that early treatment with Ca2+ channel blockers is an effective therapeutic strategy.
Maiko Matsui, Rihab Bouchareb, Mara Storto, Yasin Hussain, Andrew Gregg, Steven O. Marx, Geoffrey S. Pitt
Myocardial infarction causes pathological changes in the autonomic nervous system, which exacerbate heart failure and predispose to fatal ventricular arrhythmias and sudden death. These changes are characterized by sympathetic activation and parasympathetic dysfunction (reduced vagal tone). Reasons for the central vagal withdrawal and, specifically, whether myocardial infarction causes changes in cardiac vagal afferent neurotransmission that then affect efferent tone, remain unknown. The objective of this study was to evaluate whether myocardial infarction causes changes in vagal neuronal afferent signaling. Using in-vivo neural recordings from the inferior vagal (nodose) ganglia and immunohistochemical analyses, structural and functional alterations in vagal sensory neurons were characterized in a chronic porcine infarct model and compared with normal animals. Myocardial infarction caused an increase in the number of nociceptive neurons, but a paradoxical decrease in functional nociceptive signaling. No changes in mechanosensitive neurons were observed. Notably, nociceptive neurons demonstrated an increase in GABAergic expression. Given that nociceptive signaling through the vagal ganglia increases efferent vagal tone, the results of this study suggest that a decrease in functional nociception, possibly due to an increase in expression of inhibitory neurotransmitters, may contribute to vagal withdrawal after myocardial infarction.
Siamak Salavatian, Jonathan D. Hoang, Naoko Yamaguchi, Zulfiqar A. Lokhandwala, Mohammed Amer Swid, J. Andrew Armour, Jeffrey L. Ardell, Marmar Vaseghi
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