Journal: Circ Res

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Abstract

Silencing Myeloid Netrin-1 Induces Inflammation Resolution and Plaque Regression.

Schlegel MP, Sharma M, Brown EJ, Newman AA, ... Fisher EA, Moore KJ
Rationale: Therapeutic efforts to decrease atherosclerotic cardiovascular disease risk have focused largely on reducing atherogenic lipoproteins, yet lipid lowering therapies alone are insufficient to fully regress plaque burden. We postulate that arterial repair requires resolution of a maladaptive immune response, and that targeting factors that hinder inflammation resolution will facilitate plaque regression. Objective: The guidance molecule netrin-1 is secreted by macrophages in atherosclerotic plaques, where it sustains inflammation by enhancing macrophage survival and blocking macrophage emigration. We tested whether silencing netrin-1 in advanced atherosclerosis could resolve arterial inflammation and regress plaques.
Methods and results:
To temporally silence netrin-1 in myeloid cells, we generated genetically modified mice in which Ntn1 could be selectively deleted in monocytes and macrophages using a tamoxifen-induced CX3CR1-driven cre-recombinase (Ntn1fl/flCx3cr1creERT2+) and littermate control mice (Ntn1fl/flCx3cr1WT). Mice were fed western diet in the setting of hepatic PCSK9 overexpression to render them atherosclerotic, and then treated with tamoxifen to initiate deletion of myeloid netrin-1 (MøΔNtn1) or not in controls (MøWT). Morphometric analyses performed 4 weeks later showed that myeloid Ntn1 silencing reduced plaque burden in the aorta (-50%) and plaque complexity in the aortic root. Monocyte-macrophage tracing experiments revealed lower monocyte recruitment, macrophage retention, and proliferation in MøΔNtn1 compared to MøWT plaques, indicating a restructuring of monocyte-macrophage dynamics in the artery wall upon netrin-1 silencing. Single cell RNA-sequencing of aortic immune cells prior to and after netrin-1 silencing revealed upregulation of gene pathways involved in macrophage phagocytosis and migration, including the Ccr7 chemokine receptor signaling pathway required for macrophage emigration from plaques and atherosclerosis regression. Additionally, plaques from MøΔNtn1 mice showed hallmarks of inflammation resolution, including higher levels of pro-resolving macrophages, interleukin-10, and efferocytosis, as compared to plaques from MøWT mice. Conclusions: Our data show that targeting netrin-1 in advanced atherosclerosis ameliorates atherosclerotic inflammation and promotes plaque regression.




Circ Res: 21 Jul 2021; epub ahead of print
Schlegel MP, Sharma M, Brown EJ, Newman AA, ... Fisher EA, Moore KJ
Circ Res: 21 Jul 2021; epub ahead of print | PMID: 34289717
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Abstract

Brain Hypoxia Is Associated With Neuroglial Injury in Humans Post-Cardiac Arrest.

Hoiland RL, Ainslie PN, Wellington CL, Cooper J, ... Griesdale D, Sekhon M
Rationale: Secondary brain hypoxia portends significant mortality in ischemic brain diseases, yet our understanding of hypoxic ischemic brain injury (HIBI) pathophysiology in humans remains rudimentary. Objective: To quantify the impact of secondary brain hypoxia on injury to the neurovascular unit in patients with HIBI.
Methods and results:
We conducted a prospective interventional study of invasive neuromonitoring in 18 post-cardiac arrest patients with HIBI. The partial pressures of brain tissue O2 (PbtO2) and intracranial pressure were directly measured via intra-parenchymal micro-catheters. To isolate the cerebrovascular bed, we conducted paired sampling of arterial and jugular venous bulb blood and calculated the trans-cerebral release of biomarkers of neurovascular injury and inflammation in the HIBI patients and 14 healthy volunteers for control comparisons. Ten HIBI patients exhibited secondary brain hypoxia (PbtO2<20mmHg), while eight exhibited brain normoxia (PbtO2≥20mmHg). In the patients with secondary brain hypoxia, we observed active cerebral release of glial fibrillary acidic protein (-161[ -3695 - -75] pg/mL; P=0.0078), neurofilament light chain (-231[-370 - -11] pg/mL; P=0.010), total tau (-32[-310 - -3] pg/mL; P=0.0039), neuron specific enolase (-14890[-148813 - -3311] pg/mL; P=0.0039), and ubiquitin carboxy-terminal hydrolase L1 (-14.7[-37.7 - -4.1] pg/mL; P=0.0059) indicating de novo neuroglial injury. This injury was unrelated to the systemic global ischemic burden or cerebral endothelial injury but rather was associated with cerebral release of interleukin-6 (-10.3[-43.0 - -4.2] pg/mL; P=0.0039). No cerebral release of the aforementioned biomarkers was observed in HIBI patients with brain normoxia or the healthy volunteers. Hyperosmolar therapy in the patients with secondary brain hypoxia reduced the partial pressure of jugular venous O2-to-PbtO2 gradient (39.6[34.1-51.1] vs. 32.0[24.5-39.2] mmHg; P=0.0078) and increased PbtO2 (17.0[9.1-19.7] vs. 20.2[11.9-22.7] mmHg; P=0.039) suggesting improved cerebrovascular-to-parenchymal O2 transport. Conclusions: Secondary brain hypoxia is associated with de novo neuroglial injury and cerebral release of interleukin-6. Mitigating cerebrovascular-to-parenchymal limitations to O2 transport is a promising therapeutic strategy for HIBI patients with secondary brain hypoxia.




Circ Res: 20 Jul 2021; epub ahead of print
Hoiland RL, Ainslie PN, Wellington CL, Cooper J, ... Griesdale D, Sekhon M
Circ Res: 20 Jul 2021; epub ahead of print | PMID: 34287000
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Abstract

A Neuroligin Isoform Translated by circNlgn Contributes to Cardiac Remodeling.

Du WW, Xu J, Yang W, Wu N, ... Maksimovic K, Yang BB
Rationale: Fibrotic cardiac remodeling is a maladaptive response to acute or chronic injury that leads to arrythmia and progressive heart failure. The underlying mechanisms remain unclear.Objective: We performed high-throughput RNA sequencing to analyze circular RNA (circRNA) profile in human cardiac disease and developed transgenic mice to explore the roles of circNlgn.
Methods and results:
Using RNA sequencing, we found that circular neuroligin RNA (circNlgn) was highly upregulated in myocardial tissues of patients with selected congenital heart defects with cardiac overload. Back-splicing of the neuroligin gene led to the translation of a circular RNA-derived peptide (Nlgn173) with a 9-amino-acid nuclear localization motif. Binding of this motif to the structural protein LaminB1 facilitated the nuclear localization of Nlgn173. CHIP analysis demonstrated subsequent binding of Nlgn173 to both ING4 and C8orf44-SGK3 promoters, resulting in aberrant collagen deposition, cardiac fibroblast proliferation, and reduced cardiomyocyte viability. Three-dimensional ultrasound imaging of circNlgn transgenic mice showed impaired left ventricular function, with further impairment when subjected to left ventricular pressure overload compared to wild type mice. Nuclear translocation of Nlgn173, dysregulated expression of ING4 and C8orf44-SGK3, and immunohistochemical markers of cardiac fibrosis were detected in a panel of 145 patient specimens. Phenotypic changes observed in left ventricular pressure overload and transgenic mice were abrogated with silencing of circNlgn or its targets ING4 and SGK3. Conclusions: We show that a circular RNA can be translated into a novel protein isoform. Dysregulation of this process contributes to fibrosis and heart failure in cardiac overload-induced remodeling. This mechanism may hold therapeutic implications for cardiac disease.




Circ Res: 14 Jul 2021; epub ahead of print
Du WW, Xu J, Yang W, Wu N, ... Maksimovic K, Yang BB
Circ Res: 14 Jul 2021; epub ahead of print | PMID: 34261347
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Abstract

PDE5 Inhibition Suppresses Ventricular Arrhythmias by Reducing SR Ca Content.

Hutchings DC, Pearman CM, Madders GW, Woods LS, ... Dibb KM, Trafford AW
Rationale: Phosphodiesterase-5 (PDE5) inhibition reduces the occurrence of ventricular arrhythmias following myocardial ischemia. However, the mechanisms of the anti-arrhythmic effects of PDE5 inhibition are unknown. Diastolic calcium (Ca2+) waves lead to arrhythmias by inducing delayed after-depolarizations. Ca2+ waves are initiated when sarcoplasmic reticulum (SR) Ca2+ content reaches a threshold level and the SR releases Ca2+ spontaneously and generates a depolarizing inward sodium-calcium exchange (NCX) current. Objective: To determine the effects of PDE5 inhibition on the propensity for ventricular arrhythmias in a pro-arrhythmic large animal model and establish the role of alterations of intracellular Ca2+ cycling / SR Ca2+ content.
Methods and results:
Arrhythmia burden, monophasic action potentials and beat-to-beat variability of repolarization were measured in a sheep model using the IKr inhibitor dofetilide to induce QT prolongation and arrhythmia. Ca2+ transients, Ca2+ waves and SR Ca2+ content were measured in isolated ventricular myocytes. PDE5 inhibition was achieved using acute application of sildenafil and protein kinase G (PKG) was inhibited with KT5823. PDE5 inhibition reduced beat-to-beat variability of repolarization and suppressed after-depolarizations, premature ventricular complexes, and torsade de pointes in vivo. In single cells, dofetilide-induced DADs and triggered action potentials were suppressed by PDE5 inhibition. PDE5 inhibition decreased Ca2+ wave frequency in all cells and abolished waves in 12/22 cells. A decrease in SR Ca2+ uptake, increased trans-sarcolemmal Ca2+ efflux and reduced trans-sarcolemmal Ca2+ influx led to a reduction of SR Ca2+ content, and Ca2+ wave abolition. These effects were dependent on PKG activation. Conclusions: PDE5 inhibition acutely suppresses triggered ventricular arrhythmias in vivo and cellular data suggests this occurs via suppression of cellular Ca2+ waves. These novel anti-arrhythmic properties of PDE5 inhibition are mediated by a reduction of SR Ca2+ content and are PKG-dependent.




Circ Res: 11 Jul 2021; epub ahead of print
Hutchings DC, Pearman CM, Madders GW, Woods LS, ... Dibb KM, Trafford AW
Circ Res: 11 Jul 2021; epub ahead of print | PMID: 34247494
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Abstract

Disrupted Resolution Mechanisms Favor Altered Phagocyte Responses in Covid-19.

Koenis DS, Beegun I, Jouvene C, Aguirre GA, ... Pfeffer P, Dalli J
Rationale: Resolution mechanisms are central in both the maintenance of homeostasis and the return to catabasis following tissue injury and/or infections. Amongst the pro-resolving mediators, the essential fatty acid-derived specialized pro-resolving lipid mediators (SPM) govern immune responses to limit disease severity. Notably, little is known about the relationship between the expression and activity of SPM pathways, circulating phagocyte function and disease severity in patients infected with novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leading to coronavirus disease 2019 (COVID-19). Objective: Herein, we investigated the link between circulating SPM concentrations and phagocyte activation status and function in COVID-19 patients (n=39) compared to healthy (n=12) and post-COVID-19 (n=8) volunteers.Methods and Results:Lipid mediator profiling demonstrated that plasma SPM concentrations were upregulated in patients with mild COVID-19 and are downregulated in those with severe disease. SPM concentrations were correlated with both circulating phagocyte activation status and function. Perturbations in plasma SPM concentrations and phagocyte activation were retained after the resolution of COVID-19 clinical symptoms. Treatment of patients with dexamethasone upregulated both the expression of SPM biosynthetic enzymes in circulating phagocytes and plasma concentration of these mediators. Furthermore, incubation of phagocytes from COVID-19 patients with SPM rectified their phenotype and function. This included a downregulation in the expression of activation markers, a decrease in the Tissue Factor and inflammatory cytokine expression, and an upregulation of bacterial phagocytosis.Conclusions: The present findings suggest that downregulation of systemic SPM concentrations is linked with both increased disease severity and dysregulated phagocyte function. They also identify the upregulation of these mediators by dexamethasone as a potential mechanism in host protective activities elicited by this drug in COVID-19 patients. Taken together, our findings elucidate a role for altered resolution mechanisms in the disruption of phagocyte responses and the propagation of systemic inflammation in COVID-19.



Circ Res: 08 Jul 2021; epub ahead of print
Koenis DS, Beegun I, Jouvene C, Aguirre GA, ... Pfeffer P, Dalli J
Circ Res: 08 Jul 2021; epub ahead of print | PMID: 34238021
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Abstract

Loss of Hepatic Angiotensinogen Attenuates Sepsis-Induced Myocardial Dysfunction.

Rong J, Tao X, Lin Y, Zheng H, ... Xu Y, Wang J
Rationale: The renin-angiotensin system (RAS) is a complex regulatory network that maintains normal physiological functions. The role of the RAS in sepsis-induced myocardial dysfunction (SIMD) is poorly defined. Angiotensinogen (AGT) is the unique precursor of the RAS and gives rise to all angiotensin peptides. The effects and mechanisms of AGT in development of SIMD have not been defined. Objective: To determine a role of AGT in SIMD and investigate the underlying mechanisms.
Methods and results:
Either intraperitoneal injection of lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) significantly enhanced AGT abundances in liver, heart, and plasma. Deficiency of hepatocyte-derived AGT (hepAGT), rather than cardiomyocyte-derived AGT (carAGT), alleviated septic cardiac dysfunction in mice and prolonged survival time. Further investigations revealed that the effects of hepAGT on SIMD were partially associated with augmented angiotensin II (AngII) production in circulation. In addition, hepAGT was internalized by LDL receptor-related protein 1 (LRP1) in cardiac fibroblasts (CF), and subsequently activated NLRP3 inflammasome via an AngII-independent pathway, ultimately promoting SIMD by suppressing Sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) abundances in cardiomyocytes (CM). Conclusions: HepAGT promoted SIMD via both AngII-dependent and AngII-independent pathways. We identified a liver-heart axis by which AGT regulated development of SIMD. Our study may provide a potential novel therapeutic target for SIMD.




Circ Res: 08 Jul 2021; epub ahead of print
Rong J, Tao X, Lin Y, Zheng H, ... Xu Y, Wang J
Circ Res: 08 Jul 2021; epub ahead of print | PMID: 34238019
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Abstract

Glucose Derivative Induced Vasculopathy in Children on Chronic Peritoneal Dialysis.

Bartosova M, Zhang C, Schaefer B, Herzog R, ... Kratochwill K, Schmitt CP
Rationale
Patients with chronic kidney disease (CKD) have an exceedingly high cardiovascular risk; which further increases in patients on peritoneal dialysis (PD). The pathophysiological role of reactive metabolites accumulating in CKD such as glucose degradation products (GDP) is uncertain.
Objective
Delineating the impact of GDP present in PD fluids in accelerated vasculopathy development in patients with CKD.
Methods and results
Omental and parietal peritoneal tissues were obtained from 107 children with CKD prior to dialysis, and 90 children on chronic PD with PD fluids containing very low or high concentrations of GDP. Omental arterioles, protected from local PD fluid exposure by surrounding fat, were microdissected for multi-omics analyses. High-GDP exposed omental arterioles exhibited three-fold higher advanced glycation endproduct concentrations and upregulated genes involved in cell death/apoptosis and suppressed genes related to cell viability/survival, cytoskeleton organization and immune response biofunctions. Vasculopathy associated canonical pathways concordantly regulated on gene- and protein level with high-GDP exposure included cell death/proliferation, apoptosis, cytoskeleton organization, metabolism and detoxification, cell junction signaling, and immune response. Parietal peritoneal arterioles of patients exposed to high-GDP fluids exhibited lumen narrowing compared to patients with CKD5 and patients on low-GDP PD, intima thickness was increased. Protein quantification verified increased proapoptotic activity and cytoskeleton disintegration, single-molecule-localization microscopy demonstrated arteriolar endothelial zonula occludens-1 (ZO-1) disruption. Absolute and per endoluminal surface length, arteriolar endothelial cell counts inversely correlated with GDP exposure, caspase-3, TGF-ß induced pSMAD2/3, interleukin-6, ZO-1 abundance and lumen narrowing. In vitro, 3,4-dideoxyglucosone-3-ene reduced lamin-A/C and membrane ZO-1 assembly, increased pSMAD2/3, and ionic and 4- and 10kDa permeability of arterial endothelial cells.
Conclusions
Our findings indicate a fundamental role of GDP in PD associated vasculopathy, exerted by endothelial cell junction and cytoskeleton disruption, and induction of apoptosis. They should redirect the focus of research and intervention on targeting reactive metabolite overload in CKD and PD.



Circ Res: 07 Jul 2021; epub ahead of print
Bartosova M, Zhang C, Schaefer B, Herzog R, ... Kratochwill K, Schmitt CP
Circ Res: 07 Jul 2021; epub ahead of print | PMID: 34233458
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Abstract

Electronic and Tobacco Cigarettes Alter Polyunsaturated Fatty Acids and Oxidative Biomarkers.

Gupta R, Lin Y, Luna K, Logue A, ... Middlekauff HR, Araujo JA
Rationale: Chronic electronic cigarette (EC) users exhibit a higher susceptibility of low-density lipoprotein (LDL) to undergo oxidation as compared to non-user controls. However, there is a paucity of data regarding EC effects on lipid peroxidation in the blood and their relationship to cardiovascular risk. Objective: To test the hypothesis that chronic (≥1 year) EC use exerts intermediate effects on plasma lipid peroxidation and/or antioxidant defense compared to chronic tobacco cigarette (TC) smoking.
Methods and results:
We enrolled EC-users (n=32), TC-smokers (n=29) and non-users (n=45), with mean ages of 28.3, 27.8 and 27.4 years, respectively. Plasma concentrations of free polyunsaturated fatty acids and oxidized metabolites were assessed by mass spectrometry. Total antioxidant capacity (TAC), concentrations of glutathione, bilirubin, heme oxygenase-1 (HO-1), and functional activity of paraoxonase1 (PON1) were determined by colorimetric and enzymatic assays. Multivariable analysis was performed using classification models for segregating participants based on biomarker profiles. Plasma arachidonic acid (AA) concentration was higher in TC-smokers but lower in EC-users, together with linoleic acid (LA) concentration, as compared to TC-smokers and non-users (p<0.05). Oxidized LA metabolites (9- and 13-hydroxyoctadecadienoic acid (HODE)) were lower in EC-users and TC-smokers as compared to non-users (p<0.001). Consistently, TAC and bilirubin were elevated in EC-users and TC-smokers as compared to non-users (p<0.05). Of interest, plasma HO-1 concentration was higher in TC-smokers as compared to non-users (p=0.01) with intermediate levels in EC-users. Multivariable analysis identified 5 biomarkers (13-HODE, LA, 9-HODE, 12-hydroxyeicosatetraenoic acid (HETE), AA) that discriminated EC-users from TC-smokers and non-users with an accuracy of 73.4%.Conclusions: Chronic use of EC induces common (i.e. lower 9- and/or 13-HODEs and higher TAC and bilirubin) as well as differential effects (i.e. altered AA and LA concentrations) to those induced by TC, along with intermediate plasma HO-1 concentration, suggesting that EC, likewise TC smoke, could impact cardiovascular risk.




Circ Res: 29 Jun 2021; epub ahead of print
Gupta R, Lin Y, Luna K, Logue A, ... Middlekauff HR, Araujo JA
Circ Res: 29 Jun 2021; epub ahead of print | PMID: 34187173
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Abstract

ANXA7 Regulates Platelet Lipid Metabolism and Ca Release in Arterial Thrombosis.

Manke MC, Geue S, Coman C, Peng B, ... Ahrends R, Borst O
Rationale: Platelet activation after contact to subendothelial collagen leads to acute arterial thrombosis. Annexin A7 (ANXA7) is a phospholipid-binding protein participating in the regulation of intracellular Ca2+ and exocytosis. Objective: The present study aimed to determine the role of ANXA7 in platelet Ca2+ signaling and lipid metabolism during platelet activation in arterial thrombosis using the ANXA7 inhibitor ABO and gene-targeted mice lacking Anxa7 (Anxa7-/-).
Methods and results:
ANXA7 is strongly expressed in platelets. Functionally, luminescence aggregometry revealed significantly abrogated aggregation and secretion of ABO-treated or Anxa7-/- platelets when compared with untreated or Anxa7+/+ platelets after activation with collagen or the GPVI-specific agonist collagen-related peptide (CRP). Furthermore, while both thrombus formation on collagen-coated surfaces under high arterial shear rates in ABO-treated or Anxa7-deficient whole blood, and thrombotic vascular occlusion after FeCl3-induced injury in vivo in Anxa7-/- bone marrow chimeric mice were significantly diminished, no prolongation of bleeding time was observed in ABO-treated or Anxa7-/- mice. Fura-2-AM spectrofluorimetry unraveled a blunted [Ca2+]i increase in ABO-treated or Anxa7-/- platelets after GPVI stimulation. Due to an abolished PLCy2 phosphorylation, Anxa7-/- platelets displayed abrogated intracellular Ca2+ mobilization following CRP-dependent platelet activation. Quantitative lipidomics analysis further revealed that ANXA7 critically affects platelet oxylipin metabolism following GPVI-dependent platelet activation. Anxa7-/- platelets showed a significantly reduced generation of several bioactive metabolites, particularly TxA2 and 12(S)-HETE. Finally, defective PLCy2 phosphorylation and blunted [Ca2+]i increase in Anxa7-/- platelets could be rescued by exogenous addition of 12(S)-HETE, indicating that ANXA7 is a critical regulator of the platelet 12-lipoxygenase in GPVI-dependent platelet Ca2+ signaling during arterial thrombosis. Conclusions:The present study unravels ANXA7 as a regulator of oxylipin metabolism and Ca2+-dependent platelet activation downstream of GPVI. ANXA7 plays an important role in platelet signaling during arterial thrombosis and thus may reflect a promising target for novel antiplatelet strategies.




Circ Res: 27 Jun 2021; epub ahead of print
Manke MC, Geue S, Coman C, Peng B, ... Ahrends R, Borst O
Circ Res: 27 Jun 2021; epub ahead of print | PMID: 34176316
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Abstract

Coronary Disease Association with ADAMTS7 is due to Protease Activity.

Mizoguchi T, MacDonald BT, Bhandary B, Popp NR, ... Kathiresan S, Ellinor PT
Rationale: Despite contemporary therapy, coronary artery disease (CAD) remains a leading cause of mortality. Genetic variants at ADAMTS7 have been associated with CAD and the loss of ADAMTS7 is protective for atherosclerosis. ADAMTS7 (a disintegrin and metalloproteinase with thrombospondin motifs 7) is a secreted metalloproteinase and complex proteoglycan, yet the mechanism linking ADAMTS7 to CAD risk remains unresolved. Objective: To investigate the role of ADAMTS7 catalytic function in vascular smooth muscle cellular migration and during atherosclerosis.
Methods and results:
We established a new purification strategy for full-length mouse ADAMTS7 and demonstrated the loss of activity in the catalytic mutant form of ADAMTS7. To test if the enzymatic activity of ADAMTS7 mediates atherosclerosis, we generated a catalytically inactive mutant mouse allele and compared it to the Adamts7 knockout. Using two models of atherosclerosis, we found that reducing either ADAMTS7 dosage or catalytic function decreased the burden of atherosclerosis. We demonstrate impaired vascular smooth muscle migration in both Adamts7 catalytic mutant and null cells using a lateral migration wound healing assay. Expression of the wild-type allele rescued the migration phenotype in Adamts7 null cells while expression of the catalytic mutant protein did not. We then characterized a human ADAMTS7 coding variant rs3825807 (Ser214Pro) associated with reduced CAD risk. This variant had a hypomorphic effect on ADAMTS7 secretion and migration of vascular smooth muscle cells (VSMC), findings consistent with our mouse studies. Conclusions: We demonstrated that loss of ADAMTS7 catalytic function protects against atherosclerosis via phenotype switch of VSMCs and that the atherosclerosis protective effects could be mediated by a loss-of-function coding variant associated with CAD risk. In aggregate, we provide compelling evidence that dosage of ADAMTS7 and catalytic function are responsible for the atherosclerotic phenotype, suggesting that the catalytic domain would be an attractive therapeutic target for CAD.




Circ Res: 27 Jun 2021; epub ahead of print
Mizoguchi T, MacDonald BT, Bhandary B, Popp NR, ... Kathiresan S, Ellinor PT
Circ Res: 27 Jun 2021; epub ahead of print | PMID: 34176299
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Abstract

Preclinical Models of Cancer Therapy-Associated Cardiovascular Toxicity: A Scientific Statement From the American Heart Association.

Asnani A, Moslehi JJ, Adhikari BB, Baik AH, ... American Heart Association Council on Basic Cardiovascular Sciences; Cardio-Oncology Science Subcommittee of Council on Genomic and Precision Medicine and Council on Clinical Cardiology; Council on Peripheral Vascular Disease; and Council on Arteriosclerosis, Thrombosis and Vascular Biology
Although cardiovascular toxicity from traditional chemotherapies has been well recognized for decades, the recent explosion of effective novel targeted cancer therapies with cardiovascular sequelae has driven the emergence of cardio-oncology as a new clinical and research field. Cardiovascular toxicity associated with cancer therapy can manifest as a broad range of potentially life-threatening complications, including heart failure, arrhythmia, myocarditis, and vascular events. Beyond toxicology, the intersection of cancer and heart disease has blossomed to include discovery of genetic and environmental risk factors that predispose to both. There is a pressing need to understand the underlying molecular mechanisms of cardiovascular toxicity to improve outcomes in patients with cancer. Preclinical cardiovascular models, ranging from cellular assays to large animals, serve as the foundation for mechanistic studies, with the ultimate goal of identifying biologically sound biomarkers and cardioprotective therapies that allow the optimal use of cancer treatments while minimizing toxicities. Given that novel cancer therapies target specific pathways integral to normal cardiovascular homeostasis, a better mechanistic understanding of toxicity may provide insights into fundamental pathways that lead to cardiovascular disease when dysregulated. The goal of this scientific statement is to summarize the strengths and weaknesses of preclinical models of cancer therapy-associated cardiovascular toxicity, to highlight overlapping mechanisms driving cancer and cardiovascular disease, and to discuss opportunities to leverage cardio-oncology models to address important mechanistic questions relevant to all patients with cardiovascular disease, including those with and without cancer.



Circ Res: 24 Jun 2021; 129:e21-e34
Asnani A, Moslehi JJ, Adhikari BB, Baik AH, ... American Heart Association Council on Basic Cardiovascular Sciences; Cardio-Oncology Science Subcommittee of Council on Genomic and Precision Medicine and Council on Clinical Cardiology; Council on Peripheral Vascular Disease; and Council on Arteriosclerosis, Thrombosis and Vascular Biology
Circ Res: 24 Jun 2021; 129:e21-e34 | PMID: 33934611
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Abstract

Cerebrovascular Anomalies: Perspectives From Immunology and Cerebrospinal Fluid Flow.

Rustenhoven J, Tanumihardja C, Kipnis J
Appropriate vascular function is essential for the maintenance of central nervous system homeostasis and is achieved through virtue of the blood-brain barrier; a specialized structure consisting of endothelial, mural, and astrocytic interactions. While appropriate blood-brain barrier function is typically achieved, the central nervous system vasculature is not infallible and cerebrovascular anomalies, a collective terminology for diverse vascular lesions, are present in meningeal and cerebral vasculature supplying and draining the brain. These conditions, including aneurysmal formation and rupture, arteriovenous malformations, dural arteriovenous fistulas, and cerebral cavernous malformations, and their associated neurological sequelae, are typically managed with neurosurgical or pharmacological approaches. However, increasing evidence implicates interacting roles for inflammatory responses and disrupted central nervous system fluid flow with respect to vascular perturbations. Here, we discuss cerebrovascular anomalies from an immunologic angle and fluid flow perspective. We describe immune contributions, both common and distinct, to the formation and progression of diverse cerebrovascular anomalies. Next, we summarize how cerebrovascular anomalies precipitate diverse neurological sequelae, including seizures, hydrocephalus, and cognitive effects and possible contributions through the recently identified lymphatic and glymphatic systems. Finally, we speculate on and provide testable hypotheses for novel nonsurgical therapeutic approaches for alleviating neurological impairments arising from cerebrovascular anomalies, with a particular emphasis on the normalization of fluid flow and alleviation of inflammation through manipulations of the lymphatic and glymphatic central nervous system clearance pathways.



Circ Res: 24 Jun 2021; 129:174-194
Rustenhoven J, Tanumihardja C, Kipnis J
Circ Res: 24 Jun 2021; 129:174-194 | PMID: 34166075
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Abstract

Lymphatic Malformations: Genetics, Mechanisms and Therapeutic Strategies.

Mäkinen T, Boon LM, Vikkula M, Alitalo K
Lymphatic vessels maintain tissue fluid homeostasis by returning to blood circulation interstitial fluid that has extravasated from the blood capillaries. They provide a trafficking route for cells of the immune system, thus critically contributing to immune surveillance. Developmental or functional defects in the lymphatic vessels, their obstruction or damage, lead to accumulation of fluid in tissues, resulting in lymphedema. Here we discuss developmental lymphatic anomalies called lymphatic malformations and complex lymphatic anomalies that manifest as localized or multifocal lesions of the lymphatic vasculature, respectively. They are rare diseases that are caused mostly by somatic mutations and can present with variable symptoms based upon the size and location of the lesions composed of fluid-filled cisterns or channels. Substantial progress has been made recently in understanding the molecular basis of their pathogenesis through the identification of their genetic causes, combined with the elucidation of the underlying mechanisms in animal disease models and patient-derived lymphatic endothelial cells. Most of the solitary somatic mutations that cause lymphatic malformations and complex lymphatic anomalies occur in genes that encode components of oncogenic growth factor signal transduction pathways. This has led to successful repurposing of some targeted cancer therapeutics to the treatment of lymphatic malformations and complex lymphatic anomalies. Apart from the mutations that act as lymphatic endothelial cell-autonomous drivers of these anomalies, current evidence points to superimposed paracrine mechanisms that critically contribute to disease pathogenesis and thus provide additional targets for therapeutic intervention. Here, we review these advances and discuss new treatment strategies that are based on the recently identified molecular pathways.



Circ Res: 24 Jun 2021; 129:136-154
Mäkinen T, Boon LM, Vikkula M, Alitalo K
Circ Res: 24 Jun 2021; 129:136-154 | PMID: 34166072
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Abstract

Genetic Basis and Therapies for Vascular Anomalies.

Queisser A, Seront E, Boon LM, Vikkula M
Vascular and lymphatic malformations represent a challenge for clinicians. The identification of inherited and somatic mutations in important signaling pathways, including the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin), RAS (rat sarcoma)/RAF (rapidly accelerated fibrosarcoma)/MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinases), HGF (hepatocyte growth factor)/c-Met (hepatocyte growth factor receptor), and VEGF (vascular endothelial growth factor) A/VEGFR (vascular endothelial growth factor receptor) 2 cascades has led to the evaluation of tailored strategies with preexisting cancer drugs that interfere with these signaling pathways. The era of theranostics has started for the treatment of vascular anomalies. Registration: URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2015-001703-32.



Circ Res: 24 Jun 2021; 129:155-173
Queisser A, Seront E, Boon LM, Vikkula M
Circ Res: 24 Jun 2021; 129:155-173 | PMID: 34166070
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Abstract

Vascular and Lymphatic Malformations: Perspectives From Human and Vertebrate Studies.

Janardhan HP, Saheera S, Jung R, Trivedi CM
Vascular malformations, affecting ≈1% to 1.5% of the population, comprise a spectrum of developmental patterning defects of capillaries, arteries, veins, and/or lymphatics. The majority of vascular malformations occur sporadically; however, inherited malformations exist as a part of complex congenital diseases. The malformations, ranging from birthmarks to life-threatening conditions, are present at birth, but may reveal signs and symptoms-including pain, bleeding, disfigurement, and functional defects of vital organs-in infancy, childhood, or adulthood. Vascular malformations often exhibit recurrent patterns at affected sites due to the lack of curative treatments. This review series provides a state-of-the-art assessment of vascular malformation research at basic, clinical, genetic, and translational levels.



Circ Res: 24 Jun 2021; 129:131-135
Janardhan HP, Saheera S, Jung R, Trivedi CM
Circ Res: 24 Jun 2021; 129:131-135 | PMID: 34166069
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Abstract

Smooth Muscle Overexpression of PGC1α Attenuates Atherosclerosis in Rabbits.

Wei Z, Chong H, Jiang Q, Tang Y, ... Zhang CY, Jiang X
Rationale: Targeting vascular smooth muscle cell (VSMC) phenotypic switching is a promising therapeutic approach for atherosclerosis (AS). Dysregulation of PGC1α, a key regulator of cellular energy metabolism, has been implicated in the pathogenesis of AS, yet its role in AS remains controversial. Objective: The current study aimed to determine whether and how PGC1α in VSMCs regulates AS progression.
Methods and results:
We generated transgenic (Tg) rabbits with SMC-specific PGC1α overexpression and showed that these rabbits developed significantly less aortic AS than their non-Tg littermates after high-cholesterol diet (HCD) feeding, while total plasma cholesterol levels were similar. As indicated by the restored expression of VSMC differentiation marker genes, the HCD-induced phenotypic switching in the aortic media was largely reversed in Tg rabbits, accompanied by decreased levels of synthetic phenotype genes, proinflammatory cytokines, adhesion molecules, macrophage infiltration, matrix metalloproteinases (MMPs), reactive oxygen species (ROS) production and senescence. Ex vivo studies further showed that VSMC-specific PGC1α overexpression markedly suppressed the promotive effect of HCD feeding on the association of serum response factor (SRF) with ELK1, a ternary complex factor (TCF) that acts as a myogenic repressor in VSMCs, thereby preserving the VSMC contractile phenotype. Furthermore, knockdown of PGC1α remarkably increased extracellular signal-regulated kinase (ERK)1/2-ELK-1 signaling, which promoted phenotypic switching and proliferation of cultured rabbit VSMCs. In addition, we showed that PGC1α can regulate EGFR-ERK1/2 MAP kinase signaling via modulating PPARγ activity in RVSMCs. Finally, we showed that these beneficial results of SMC-specific PGC1α overexpression can be extrapolated from rabbits to human VSMCs and clinical settings. Conclusions: We demonstrated a critical role of PGC1α in maintaining the contractile phenotype of VSMCs and highlighted the therapeutic potential of PGC1α for AS.




Circ Res: 23 Jun 2021; epub ahead of print
Wei Z, Chong H, Jiang Q, Tang Y, ... Zhang CY, Jiang X
Circ Res: 23 Jun 2021; epub ahead of print | PMID: 34162227
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Impact:
Abstract

Unveiling Complexity and Multipotentiality of Early Heart Fields.

Zhang Q, Carlin D, Zhu F, Cattaneo P, ... Bloomekatz J, Chi NC
Rationale: Extraembryonic tissues, including the yolk sac and placenta, and the heart within the embryo, work to provide crucial nutrients to the embryo. The association of congenital heart defects (CHDs) with extraembryonic tissue defects further supports the potential developmental relationship between the heart and extraembryonic tissues. Although the development of early cardiac lineages has been well-studied, the developmental relationship between cardiac lineages, including epicardium, and extraembryonic mesoderm remains to be defined. Objective: To explore the developmental relationships between cardiac and extraembryonic lineages.
Methods and results:
Through high-resolution single cell and genetic lineage/clonal analyses, we show an unsuspected clonal relationship between extraembryonic mesoderm and cardiac lineages. Single-cell transcriptomics and trajectory analyses uncovered two mesodermal progenitor sources contributing to left ventricle cardiomyocytes, one embryonic and the other with an extraembryonic gene expression signature. Additional lineage-tracing studies revealed that the extraembryonic-related progenitors reside at the embryonic-extraembryonic interface in gastrulating embryos, and produce distinct cell types forming the pericardium, septum transversum, epicardium, dorsolateral regions of the left ventricle and atrioventricular canal myocardium, and extraembryonic mesoderm. Clonal analyses demonstrated that these progenitors are multipotent, giving rise to not only cardiomyocytes and serosal mesothelial cell types but also, remarkably, extraembryonic mesoderm. Conclusions: Overall, our results reveal the location of previously unknown multipotent cardiovascular progenitors at the embryonic-extraembryonic interface, and define the earliest embryonic origins of serosal mesothelial lineages, including the epicardium, which contributes fibroblasts and vascular support cells to the heart. The shared lineage relationship between embryonic cardiovascular lineages and extraembryonic mesoderm revealed by our studies underscores an underappreciated blurring of boundaries between embryonic and extraembryonic mesoderm. Our findings suggest unexpected underpinnings of the association between congenital heart disease and placental insufficiency anomalies, and the potential utility of extraembryonic cells for generating cardiovascular cell types for heart repair.




Circ Res: 23 Jun 2021; epub ahead of print
Zhang Q, Carlin D, Zhu F, Cattaneo P, ... Bloomekatz J, Chi NC
Circ Res: 23 Jun 2021; epub ahead of print | PMID: 34162224
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Impact:
Abstract

KLF2 Mediates the Suppressive Effect of Laminar Flow on Vascular Calcification by Inhibiting Endothelial BMP/SMAD1/5 Signaling.

Huang J, Pu Y, Zhang H, Xie L, ... Huang Y, Luo JY
Rationale: Vascular calcification in arterial intima is closely associated with atherosclerosis. Endothelial cells (ECs) sense blood flow and respond to the mechanical cues generated by different flow patterns. Laminar flow (LF) induces an anti-atherosclerotic EC phenotype whereas disturbed flow (DF) exerts an atheroprone effect. However, the contribution of blood flow to calcification in atherosclerotic arteries remains to be evaluated. Objective: We aim to investigate whether blood flow plays a determinant role in the distribution of vascular calcification and the underlying mechanisms involved.
Methods and results:
Computed tomography angiography analysis of human coronary arteries (n = 48) shows that calcification preferentially develops at flow perturbated sites. Similar phenomenon was observed in calcified human aortic valves and mouse arteries. Nonuniform shear stress produced in Y-shaped slide simulating live conditions in branched arteries promotes calcification in human umbilical vein ECs (HUVECs). The expression of Krüppel-like Factor 2 (KLF2), a transcription factor inducible by LF, is reduced in ECs of calcified human aortic valves and in endothelial calcification model, suggesting that KLF2 downregulation is likely involved in intimal calcification. Indeed, KLF2 silencing induces endothelial-to-mesenchymal transition and accelerates osteo-induction in both human aortic ECs and HUVECs. EC-specific KLF2 knockdown promotes whereas AAV9-mediated EC-KLF2 overexpression ameliorates vascular calcification in ApoE-/- mice. Global mRNA profiling in HUVECs reveals that KLF2 inhibits BMP/SMAD1/5 pathway which is critical in vascular calcification. Furthermore, KLF2 mediates LF-induced inhibition of the BMP/SMAD1/5 pathway. By contrast, DF-induced activation of BMP/SMAD1/5 pathway is suppressed by KLF2 overexpression. Mechanistically, KLF2 binds to the promoters of BMP4, BMPER and SMAD1 to directly regulate their expression in ECs. Conclusions: Vascular calcification prefers to occur at branched or bifurcated areas of vasculature. LF inhibits vascular calcification through KLF2-mediated inhibition of endothelial BMP/SMAD1/5 signaling. Targeting KLF2 may represent a novel therapeutic approach against vascular calcification.




Circ Res: 22 Jun 2021; epub ahead of print
Huang J, Pu Y, Zhang H, Xie L, ... Huang Y, Luo JY
Circ Res: 22 Jun 2021; epub ahead of print | PMID: 34157851
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Impact:
Abstract

Impaired Binding to Junctophilin2 and Nanostructural Alteration in CPVT Mutation.

Yin L, Zahradnikova A, Rizzetto R, Boncompagni S, ... Benitah JP, Gomez AM
Rationale: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare disease, manifested by syncope or sudden death in children or young adults under stress conditions. Mutations in the Ca2+ release channel/ryanodine receptor (RyR2) gene account for about 60% of the identified mutations. Recently, we found and described a mutation in RyR2 N-terminal domain, RyR2R420Q. Objective: To determine the arrhythmogenic mechanisms of this mutation.
Methods and results:
Ventricular tachycardias under stress conditions were observed in both CPVT patients and KI mice. During action potential recording (by patch-clamp in KI mouse cardiomyocytes and by microelectrodes in mutant hiPSC-CM) we observed an increased occurrence of delayed after-depolarizations (DADs) under isoproterenol stimulation, associated with increased Ca2+ waves during confocal Ca2+ recording in both mouse and human RyR2R420Q cardiomyocytes. In addition, Ca2+-induced Ca2+-release, as well as a rough indicator of fractional Ca2+ release, were higher and Ca2+ sparks longer in the RyR2R420Q expressing cells. At the ultrastructural nanodomain level, we observed smaller RyR2 clusters and widened junctional sarcoplasmic reticulum (jSR) measured by g-STED super-resolution and electronic microscopy, respectively. The increase in jSR width might be due to the impairment of RyR2R420Q binding to junctophilin-2, as there were less junctophilin-2 co-immunoprecipitated with RyR2R420Q. At the single current level, the RyR2R420Q channel dwells longer in the open state at low [Ca2+]i, but there is predominance of a subconductance state. The latter might be correlated with an enhanced interaction between the N-terminus and the core solenoid, a RyR2 inter-domain association that has not been previously implicated in the pathogenesis of arrhythmias and sudden cardiac death. Conclusions: The RyR2R420Q CPVT mutation modifies the interdomain interaction of the channel and weaken its association with junctophillin-2. These defects may underlie both nanoscale disarrangement of the dyad and channel dysfunction.




Circ Res: 10 Jun 2021; epub ahead of print
Yin L, Zahradnikova A, Rizzetto R, Boncompagni S, ... Benitah JP, Gomez AM
Circ Res: 10 Jun 2021; epub ahead of print | PMID: 34111951
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Impact:
Abstract

Leveraging Machine Learning and Artificial Intelligence to Improve Peripheral Artery Disease Detection, Treatment, and Outcomes.

Flores AM, Demsas F, Leeper NJ, Ross EG
Peripheral artery disease is an atherosclerotic disorder which, when present, portends poor patient outcomes. Low diagnosis rates perpetuate poor management, leading to limb loss and excess rates of cardiovascular morbidity and death. Machine learning algorithms and artificially intelligent systems have shown great promise in application to many areas in health care, such as accurately detecting disease, predicting patient outcomes, and automating image interpretation. Although the application of these technologies to peripheral artery disease are in their infancy, their promises are tremendous. In this review, we provide an introduction to important concepts in the fields of machine learning and artificial intelligence, detail the current state of how these technologies have been applied to peripheral artery disease, and discuss potential areas for future care enhancement with advanced analytics.



Circ Res: 10 Jun 2021; 128:1833-1850
Flores AM, Demsas F, Leeper NJ, Ross EG
Circ Res: 10 Jun 2021; 128:1833-1850 | PMID: 34110911
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Impact:
Abstract

Contemporary Medical Management of Peripheral Artery Disease.

Bonaca MP, Hamburg NM, Creager MA
Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis. Modifiable risk factors including cigarette smoking, dyslipidemia, diabetes, poor diet quality, obesity, and physical inactivity, along with underlying genetic factors contribute to lower extremity atherosclerosis. Patients with PAD often have coexistent coronary or cerebrovascular disease, and increased likelihood of major adverse cardiovascular events, including myocardial infarction, stroke and cardiovascular death. Patients with PAD often have reduced walking capacity and are at risk of acute and chronic critical limb ischemia leading to major adverse limb events, such as peripheral revascularization or amputation. The presence of polyvascular disease identifies the highest risk patient group for major adverse cardiovascular events, and patients with prior critical limb ischemia, prior lower extremity revascularization, or amputation have a heightened risk of major adverse limb events. Medical therapies have demonstrated efficacy in reducing the risk of major adverse cardiovascular events and major adverse limb events, and improving function in patients with PAD by modulating key disease determining pathways including inflammation, vascular dysfunction, and metabolic disturbances. Treatment with guideline-recommended therapies, including smoking cessation, lipid lowering drugs, optimal glucose control, and antithrombotic medications lowers the incidence of major adverse cardiovascular events and major adverse limb events. Exercise training and cilostazol improve walking capacity. The heterogeneity of risk profile in patients with PAD supports a personalized approach, with consideration of treatment intensification in those at high risk of adverse events. This review highlights the medical therapies currently available to improve outcomes in patients with PAD.



Circ Res: 10 Jun 2021; 128:1868-1884
Bonaca MP, Hamburg NM, Creager MA
Circ Res: 10 Jun 2021; 128:1868-1884 | PMID: 34110910
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Impact:
Abstract

Inflammation, Infection and Venous Thromboembolism.

Colling ME, Tourdot BE, Kanthi Y
The association between inflammation, infection, and venous thrombosis has long been recognized; yet, only in the last decades have we begun to understand the mechanisms through which the immune and coagulation systems interact and reciprocally regulate one another. These interconnected networks mount an effective response to injury and pathogen invasion, but if unregulated can result in pathological thrombosis and organ damage. Neutrophils, monocytes, and platelets interact with each other and the endothelium in host defense and also play critical roles in the formation of venous thromboembolism. This knowledge has advanced our understanding of both human physiology and pathophysiology, as well as identified mechanisms of anticoagulant resistance and novel therapeutic targets for the prevention and treatment of thrombosis. In this review, we discuss the contributions of inflammation and infection to venous thromboembolism.



Circ Res: 10 Jun 2021; 128:2017-2036
Colling ME, Tourdot BE, Kanthi Y
Circ Res: 10 Jun 2021; 128:2017-2036 | PMID: 34110909
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Impact:
Abstract

Vascular Impact of Cancer Therapies: The Case of BTK (Bruton Tyrosine Kinase) Inhibitors.

Fleming MR, Xiao L, Jackson KD, Beckman JA, Barac A, Moslehi JJ
Novel targeted cancer therapies have revolutionized oncology therapies, but these treatments can have cardiovascular complications, which include heterogeneous cardiac, metabolic, and vascular sequelae. Vascular side effects have emerged as important considerations in both cancer patients undergoing active treatment and cancer survivors. Here, we provide an overview of vascular effects of cancer therapies, focusing on small-molecule kinase inhibitors and specifically inhibitors of BTK (Bruton tyrosine kinase), which have revolutionized treatment and prognosis for B-cell malignancies. Cardiovascular side effects of BTK inhibitors include atrial fibrillation, increased risk of bleeding, and hypertension, with the former 2 especially providing a treatment challenge for the clinician. Cardiovascular complications of small-molecule kinase inhibitors can occur through either on-target (targeting intended target kinase) or off-target kinase inhibition. We will review these concepts and focus on the case of BTK inhibitors, highlight the emerging data suggesting an off-target effect that may provide insights into development of arrhythmias, specifically atrial fibrillation. We believe that cardiac and vascular sequelae of novel targeted cancer therapies can provide insights into human cardiovascular biology.



Circ Res: 10 Jun 2021; 128:1973-1987
Fleming MR, Xiao L, Jackson KD, Beckman JA, Barac A, Moslehi JJ
Circ Res: 10 Jun 2021; 128:1973-1987 | PMID: 34110908
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Impact:
Abstract

Epidemiology of Peripheral Artery Disease and Polyvascular Disease.

Aday AW, Matsushita K
Atherosclerotic lower extremity peripheral artery disease (PAD) is increasingly recognized as an important cause of cardiovascular morbidity and mortality that affects >230 million people worldwide. Traditional cardiovascular risk factors, including advanced age, smoking, and diabetes, are strongly linked to an increase risk of PAD. Although PAD has been historically underappreciated compared with coronary artery disease and stroke, greater attention on PAD in recent years has led to important new epidemiological insights in the areas of thrombosis, inflammation, dyslipidemia, and microvascular disease. In addition, the concept of polyvascular disease, or clinically evident atherosclerosis in multiple arterial beds, is increasingly identified as a particularly malignant cardiovascular disease worthy of special clinical attention and further study. It is noteworthy that PAD may increase the risk of adverse outcomes in similar or even greater magnitude than coronary disease or stroke. In this review, we highlight important new advances in the epidemiology of PAD with a particular focus on polyvascular disease, emerging biomarkers, and differential risk pathways for PAD compared with other atherosclerotic diseases.



Circ Res: 10 Jun 2021; 128:1818-1832
Aday AW, Matsushita K
Circ Res: 10 Jun 2021; 128:1818-1832 | PMID: 34110907
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Impact:
Abstract

Genetic Determinants of Peripheral Artery Disease.

Klarin D, Tsao PS, Damrauer SM
Peripheral artery disease-atherosclerosis of the abdominal aorta and lower extremity vascular bed-is a complex disease with both environmental and genetic determinants. Unmitigated disease is associated with major functional decline and can lead to chronic limb-threatening ischemia, amputation, and increased mortality. Over the last 10 years, major advances have been made in identifying the genetic basis of this common, complex disease. In this review, we provide an overview of the primary types of genetic analyses performed for peripheral artery disease, including heritability and linkage studies, and more recently biobank-based genome-wide association studies. Looking forward, we highlight areas of future study including efforts to identify causal peripheral artery disease genes, rare variant and structural variant analyses using whole-exome and whole-genome sequencing data, and the need to include individuals of diverse genetic ancestries.



Circ Res: 10 Jun 2021; 128:1805-1817
Klarin D, Tsao PS, Damrauer SM
Circ Res: 10 Jun 2021; 128:1805-1817 | PMID: 34110906
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Impact:
Abstract

Advances in Lymphedema.

Rockson SG
Lymphedema is a common, complex, and inexplicably underappreciated human disease. Despite a history of relative neglect by health care providers and by governmental health care agencies, the last decade has seen an explosive growth of insights into, and approaches to, the problem of human lymphedema. The current review highlights the significant advances that have occurred in the investigative and clinical approaches to lymphedema, particularly over the last decade. This review summarizes the progress that has been attained in the realms of genetics, lymphatic imaging, and lymphatic surgery. Newer molecular insights are explored, along with their relationship to future molecular therapeutics. Growing insights into the relationships among lymphedema, obesity, and other comorbidities are important to consider in current and future responses to patients with lymphedema.



Circ Res: 10 Jun 2021; 128:2003-2016
Rockson SG
Circ Res: 10 Jun 2021; 128:2003-2016 | PMID: 34110905
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Impact:
Abstract

Advances in Revascularization for Peripheral Artery Disease: Revascularization in PAD.

Beckman JA, Schneider PA, Conte MS
Effective revascularization of the patient with peripheral artery disease is about more than the procedure. The approach to the patient with symptom-limiting intermittent claudication or limb-threatening ischemia begins with understanding the population at risk and variation in clinical presentation. The urgency of revascularization varies significantly by presentation; from patients with intermittent claudication who should undergo structured exercise rehabilitation before revascularization (if needed) to those with acute limb ischemia, a medical emergency, who require revascularization within hours. Recent years have seen the rapid development of new tools including wires, catheters, drug-eluting technology, specialized balloons, and biomimetic stents. Open surgical bypass remains an important option for those with advanced disease. The strategy and techniques employed vary by clinical presentation, lesion location, and lesion severity. There is limited level 1 evidence to guide practice, but factors that determine technical success and anatomic durability are largely understood and incorporated into decision-making. Following revascularization, medical therapy to reduce adverse limb outcomes and a surveillance plan should be put in place. There are many hurdles to overcome to improve the efficacy of lower extremity revascularization, such as restenosis, calcification, microvascular disease, silent embolization, and tools for perfusion assessment. This review highlights the current state of revascularization in peripheral artery disease with an eye toward technologies at the cusp, which may significantly impact current practice.



Circ Res: 10 Jun 2021; 128:1885-1912
Beckman JA, Schneider PA, Conte MS
Circ Res: 10 Jun 2021; 128:1885-1912 | PMID: 34110904
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Impact:
Abstract

Walking Exercise Therapy Effects on Lower Extremity Skeletal Muscle in Peripheral Artery Disease.

McDermott MM, Dayanidhi S, Kosmac K, Saini S, ... Sufit R, Ferrucci L
Walking exercise is the most effective noninvasive therapy that improves walking ability in peripheral artery disease (PAD). Biologic mechanisms by which exercise improves walking in PAD are unclear. This review summarizes evidence regarding effects of walking exercise on lower extremity skeletal muscle in PAD. In older people without PAD, aerobic exercise improves mitochondrial activity, muscle mass, capillary density, and insulin sensitivity in skeletal muscle. However, walking exercise increases lower extremity ischemia in people with PAD, and therefore, mechanisms by which this exercise improves walking may differ between people with and without PAD. Compared with people without PAD, gastrocnemius muscle in people with PAD has greater mitochondrial impairment, increased reactive oxygen species, and increased fibrosis. In multiple small trials, walking exercise therapy did not consistently improve mitochondrial activity in people with PAD. In one 12-week randomized trial of people with PAD randomized to supervised exercise or control, supervised treadmill exercise increased treadmill walking time from 9.3 to 15.1 minutes, but simultaneously increased the proportion of angular muscle fibers, consistent with muscle denervation (from 7.6% to 15.6%), while angular myofibers did not change in the control group (from 9.1% to 9.1%). These findings suggest an adaptive response to exercise in PAD that includes denervation and reinnervation, an adaptive process observed in skeletal muscle of people without PAD during aging. Small studies have not shown significant effects of exercise on increased capillary density in lower extremity skeletal muscle of participants with PAD, and there are no data showing that exercise improves microcirculatory delivery of oxygen and nutrients in patients with PAD. However, the effects of supervised exercise on increased plasma nitrite abundance after a treadmill walking test in people with PAD may be associated with improved lower extremity skeletal muscle perfusion and may contribute to improved walking performance in response to exercise in people with PAD. Randomized trials with serial, comprehensive measures of muscle biology, and physiology are needed to clarify mechanisms by which walking exercise interventions improve mobility in PAD.



Circ Res: 10 Jun 2021; 128:1851-1867
McDermott MM, Dayanidhi S, Kosmac K, Saini S, ... Sufit R, Ferrucci L
Circ Res: 10 Jun 2021; 128:1851-1867 | PMID: 34110902
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Impact:
Abstract

Racial and Ethnic Disparities in Peripheral Artery Disease.

Hackler EL, Hamburg NM, White Solaru KT
Peripheral artery disease is an obstructive, atherosclerotic disease of the lower extremities causing significant morbidity and mortality. Black Americans are disproportionately affected by this disease while they are also less likely to be diagnosed and promptly treated. The consequences of this disparity can be grim as Black Americans bear the burden of lower extremity amputation resulting from severe peripheral artery disease. The risk factors of peripheral artery disease and how they differentially affect certain groups are discussed in addition to a review of pharmacological and nonpharmacological treatment modalities. The purpose of this review is to highlight health care inequities and provide a review and resource of available recommendations for clinical management of all patients with peripheral artery disease.



Circ Res: 10 Jun 2021; 128:1913-1926
Hackler EL, Hamburg NM, White Solaru KT
Circ Res: 10 Jun 2021; 128:1913-1926 | PMID: 34110901
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Impact:
Abstract

Bench-to-Bedside in Vascular Medicine: Optimizing the Translational Pipeline for Patients With Peripheral Artery Disease.

Alsaigh T, Di Bartolo BA, Mulangala J, Figtree GA, Leeper NJ
Peripheral arterial disease is a growing worldwide problem with a wide spectrum of clinical severity and is projected to consume >$21 billion per year in the United States alone. While vascular researchers have brought several therapies to the clinic in recent years, few of these approaches have leveraged advances in high-throughput discovery screens, novel translational models, or innovative trial designs. In the following review, we discuss recent advances in unbiased genomics and broader omics technology platforms, along with preclinical vascular models designed to enhance our understanding of disease pathobiology and prioritize targets for additional investigation. Furthermore, we summarize novel approaches to clinical studies in subjects with claudication and ischemic ulceration, with an emphasis on streamlining and accelerating bench-to-bedside translation. By providing a framework designed to enhance each aspect of future clinical development programs, we hope to enrich the pipeline of therapies that may prevent loss of life and limb for those with peripheral arterial disease.



Circ Res: 10 Jun 2021; 128:1927-1943
Alsaigh T, Di Bartolo BA, Mulangala J, Figtree GA, Leeper NJ
Circ Res: 10 Jun 2021; 128:1927-1943 | PMID: 34110900
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Impact:
Abstract

New Directions in Therapeutic Angiogenesis and Arteriogenesis in Peripheral Arterial Disease.

Annex BH, Cooke JP
The prevalence of peripheral arterial disease (PAD) in the United States exceeds 10 million people, and PAD is a significant cause of morbidity and mortality across the globe. PAD is typically caused by atherosclerotic obstructions in the large arteries to the leg(s). The most common clinical consequences of PAD include pain on walking (claudication), impaired functional capacity, pain at rest, and loss of tissue integrity in the distal limbs that may lead to lower extremity amputation. Patients with PAD also have higher than expected rates of myocardial infarction, stroke, and cardiovascular death. Despite advances in surgical and endovascular procedures, revascularization procedures may be suboptimal in relieving symptoms, and some patients with PAD cannot be treated because of comorbid conditions. In some cases, relieving obstructive disease in the large conduit arteries does not assure complete limb salvage because of severe microvascular disease. Despite several decades of investigational efforts, medical therapies to improve perfusion to the distal limb are of limited benefit. Whereas recent studies of anticoagulant (eg, rivaroxaban) and intensive lipid lowering (such as PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitors) have reduced major cardiovascular and limb events in PAD populations, chronic ischemia of the limb remains largely resistant to medical therapy. Experimental approaches to improve limb outcomes have included the administration of angiogenic cytokines (either as recombinant protein or as gene therapy) as well as cell therapy. Although early angiogenesis and cell therapy studies were promising, these studies lacked sufficient control groups and larger randomized clinical trials have yet to achieve significant benefit. This review will focus on what has been learned to advance medical revascularization for PAD and how that information might lead to novel approaches for therapeutic angiogenesis and arteriogenesis for PAD.



Circ Res: 10 Jun 2021; 128:1944-1957
Annex BH, Cooke JP
Circ Res: 10 Jun 2021; 128:1944-1957 | PMID: 34110899
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Impact:
Abstract

FMD and SCAD: Sex-Biased Arterial Diseases With Clinical and Genetic Pleiotropy.

Kim ESH, Saw J, Kadian-Dodov D, Wood M, Ganesh SK
Multifocal fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection are both sex-biased diseases disproportionately affecting women over men in a 9:1 ratio. Traditionally known in the context of renovascular hypertension, recent advances in knowledge about FMD have demonstrated that FMD is a systemic arteriopathy presenting as arterial stenosis, aneurysm, and dissection in virtually any arterial bed. FMD is also characterized by major cardiovascular presentations including hypertension, stroke, and myocardial infarction. Similar to FMD, spontaneous coronary artery dissection is associated with a high prevalence of extracoronary vascular abnormalities, including FMD, aneurysm, and extracoronary dissection, and recent studies have also found genetic associations between the two diseases. This review will summarize the relationship between FMD and spontaneous coronary artery dissection with a focus on common clinical associations, histopathologic mechanisms, genetic susceptibilities, and the biology of these diseases. The current status of disease models and critical future research directions will also be addressed.



Circ Res: 10 Jun 2021; 128:1958-1972
Kim ESH, Saw J, Kadian-Dodov D, Wood M, Ganesh SK
Circ Res: 10 Jun 2021; 128:1958-1972 | PMID: 34110898
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Impact:
Abstract

Epidemiology and Genetics of Venous Thromboembolism and Chronic Venous Disease.

Baylis RA, Smith NL, Klarin D, Fukaya E
Venous disease is a term that broadly covers both venous thromboembolic disease and chronic venous disease. The basic pathophysiology of venous thromboembolism and chronic venous disease differ as venous thromboembolism results from an imbalance of hemostasis and thrombosis while chronic venous disease occurs in the setting of tissue damage because of prolonged venous hypertension. Both diseases are common and account for significant mortality and morbidity, respectively, and collectively make up a large health care burden. Despite both diseases having well-characterized environmental components, it has been known for decades that family history is an important risk factor, implicating a genetic element to a patient\'s risk. Our understanding of the pathogenesis of these diseases has greatly benefited from an expansion of population genetic studies from pioneering familial studies to large genome-wide association studies; we now have multiple risk loci for each venous disease. In this review, we will highlight the current state of knowledge on the epidemiology and genetics of venous thromboembolism and chronic venous disease and directions for future research.



Circ Res: 10 Jun 2021; 128:1988-2002
Baylis RA, Smith NL, Klarin D, Fukaya E
Circ Res: 10 Jun 2021; 128:1988-2002 | PMID: 34110897
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Impact:
Abstract

Activation of Autophagic Flux Blunts Cardiac Ischemia/Reperfusion Injury.

Xie M, Cho GW, Kong Y, Li DL, ... Gillette TG, Hill JA
Rationale: Reperfusion injury accounts for up to half of myocardial infarct size, and meaningful clinical therapies targeting it do not exist. We have reported previously that autophagy is reduced during reperfusion and that HDAC inhibition enhances cardiomyocyte autophagy and blunts ischemia/reperfusion (I/R) injury when administered at the time of reperfusion. However, whether inducing autophagy per se, as opposed to other effects triggered by HDAC inhibition, is sufficent to protect against reperfusion injury is not clear. Objective: We set out to test whether augmentation of autophagy using a specific autophagy-inducing peptide, Tat-Beclin, protects the myocardium through reduction of reactive oxygen species (ROS) during reperfusion injury.
Methods and results:
Eight to twelve-week-old, wild-type, C57BL6 mice and drug-inducible cardiomyocyte-specific ATG7 knockout mice (to test the dependency on autophagy) were randomized into two groups: exposed to a control Tat-Scrambled (TS) peptide or a Tat-Beclin (TB) peptide. Each group was subjected to I/R surgery (45min coronary ligation, 24h reperfusion). Infarct size, systolic function, autophagic flux, and ROS were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were exposed to TB during simulated ischemia/reperfusion injury. ATG7 knockdown by siRNA in NRVMs was used to evaluate the role of autophagy. TB treatment at reperfusion reduced infarct size by 20% (absolute reduction; 50% relative reduction) and improved contractile function. Improvement correlated with increased autophagic flux in the border zone with less oxidative stress. ATG7 KO mice did not manifest TB-promoted cardioprotection during I/R. In NRVMs subjected to I/R, TB reduced cell death by 41% and reduced I/R-induced ROS generation. Conversely, ATG7 knockdown in NRVMs abolished these beneficial effects of TB on cell death and ROS reduction. Conclusions: Induction of autophagy at the time of reperfusion is sufficient to mitigate myocardial reperfusion injury by reducing ROS and cell death. Maintenance of appropriate autophagic flux may emerge as a viable clinical therapy to reduce reperfusion injury in acute myocardial infarction.




Circ Res: 10 Jun 2021; epub ahead of print
Xie M, Cho GW, Kong Y, Li DL, ... Gillette TG, Hill JA
Circ Res: 10 Jun 2021; epub ahead of print | PMID: 34111934
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Impact:
Abstract

A Variant Noncoding Region Regulates Prrx1 and Predisposes to Atrial Arrhythmias.

Bosada FM, Rivaud MR, Uhm JS, Verheule S, ... Christoffels VM, Boukens BJ
Rationale: Atrial Fibrillation (AF) is the most common cardiac arrhythmia diagnosed in clinical practice. Genome-wide association studies have identified AF-associated common variants across 100+ genomic loci, but the mechanism underlying the impact of these variant loci on AF susceptibility in vivo has remained largely undefined. One such variant region, highly associated with AF, is found at 1q24, close to PRRX1, encoding the Paired Related Homeobox 1 transcription factor. Objective: To identify the mechanistic link between the variant region at 1q24 and AF predisposition.
Methods and results:
The mouse orthologue of the noncoding variant genomic region (R1A) at 1q24 was deleted using CRISPR genome editing. Among the genes sharing the topologically associated domain with the deleted R1A region (Kifap3, Prrx1, Fmo2, Prrc2c), only the broadly expressed gene Prrx1 was downregulated in mutants, and only in cardiomyocytes. Expression and epigenetic profiling revealed that a cardiomyocyte lineage-specific gene program (Mhrt, Myh6, Rbm20, Tnnt2, Ttn, Ckm) was upregulated in R1A-/- atrial cardiomyocytes, and that Mef2 binding motifs were significantly enriched at differentially accessible chromatin sites. Consistently, Prrx1 suppressed Mef2-activated enhancer activity in HL-1 cells. Mice heterozygous or homozygous for the R1A deletion were susceptible to atrial arrhythmia induction, had atrial conduction slowing and more irregular RR intervals. Isolated R1A-/- mouse left atrial cardiomyocytes showed lower action potential upstroke velocities and sodium current, as well as increased systolic and diastolic calcium concentrations compared to controls. Conclusions: The noncoding AF variant region at 1q24 modulates Prrx1 expression in cardiomyocytes. Cardiomyocyte-specific reduction of Prrx1 expression upon deletion of the noncoding region leads to a profound induction of a cardiac lineage-specific gene program and to propensity for AF. These data indicate that AF-associated variants in humans may exert AF predisposition through reduced PRRX1 expression in cardiomyocytes.




Circ Res: 06 Jun 2021; epub ahead of print
Bosada FM, Rivaud MR, Uhm JS, Verheule S, ... Christoffels VM, Boukens BJ
Circ Res: 06 Jun 2021; epub ahead of print | PMID: 34092116
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Impact:
Abstract

Targeting the Microtubule EB1-CLASP2 Complex Modulates Na1.5 at Intercalated Discs.

Marchal GA, Jouni M, Chiang DY, Pérez-Hernández Duran M, ... Portero V, Remme CA
Rationale: Loss-of-function of the cardiac sodium channel NaV1.5 causes conduction slowing and arrhythmias. NaV1.5 is differentially distributed within subcellular domains of cardiomyocytes, with sodium current (INa) being enriched at the intercalated discs (ID). Various pathophysiological conditions associated with lethal arrhythmias display ID-specific INa reduction, but the mechanisms underlying microdomain-specific targeting of NaV1.5 remain largely unknown. Objective: To investigate the role of the microtubule (MT) plus-end tracking proteins end binding protein 1 (EB1) and CLIP-associated protein 2 (CLASP2) in mediating NaV1.5 trafficking and subcellular distribution in cardiomyocytes.
Methods and results:
EB1 overexpression in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) resulted in enhanced whole-cell INa, increased action potential (AP) upstroke velocity (Vmax), and enhanced NaV1.5 localization at the plasma membrane as detected by multi-color stochastic optical reconstruction microscopy (STORM). Fluorescence recovery after photobleaching (FRAP) experiments in HEK293A cells demonstrated that EB1 overexpression promoted NaV1.5 forward trafficking. Knockout of MAPRE1 in hiPSC-CMs led to reduced whole-cell INa, decreased Vmax and AP duration (APD) prolongation. Similarly, acute knockout of the MAPRE1 homolog in zebrafish (mapre1b) resulted in decreased ventricular conduction velocity and Vmax as well as increased APD. STORM imaging and macropatch INa measurements showed that subacute treatment (2-3 hours) with SB216763 (SB2), a GSK3β inhibitor known to modulate CLASP2-EB1 interaction, reduced GSK3β localization and increased NaV1.5 and INa preferentially at the ID region of wild type murine ventricular cardiomyocytes. By contrast, SB2 did not affect whole cell INa or NaV1.5 localization in cardiomyocytes from Clasp2-deficient mice, uncovering the crucial role of CLASP2 in SB2-mediated modulation of NaV1.5 at the ID. Conclusions: Our findings demonstrate the modulatory effect of the MT plus-end tracking protein EB1 on NaV1.5 trafficking and function, and identify the EB1-CLASP2 complex as a target for preferential modulation of INa within the ID region of cardiomyocytes.




Circ Res: 06 Jun 2021; epub ahead of print
Marchal GA, Jouni M, Chiang DY, Pérez-Hernández Duran M, ... Portero V, Remme CA
Circ Res: 06 Jun 2021; epub ahead of print | PMID: 34092082
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Abstract

Myofibroblast Deficiency of LSD1 Alleviates TAC-Induced Heart Failure.

Huo JL, Jiao L, An Q, Chen X, ... Wang C, Zhao W
Rationale: Histone lysine specific demethylase 1 (LSD1) is an important epigenetic anti-tumor drug target, whose inhibitors are currently in phase Ⅰ/Ⅱ clinical trials. However, the potential side effects of LSD1 inhibition in the progress of cardiac remodeling to heart failure remain to be investigated. Objective: To evaluate the roles of myofibroblast- or cardiomyocyte-specific LSD1 deficiency in pressure overload-induced cardiac remodeling.
Methods and results:
Adult mouse cardiac fibroblasts (CFs),neonatal rat cardiac myocytes (NRCMs) and fibroblasts (NRCFs) were isolated, respectively. The myofibroblast-specific and cardiomyocyte-specific LSD1 inducible knockout mice were then generated. We found that LSD1 was increased not only in human DCM (dilated cardiomyopathy) hearts, but also in wild type mouse heart homogenates and isolated CFs, following 20 weeks of transverse aortic constriction (TAC). The upregulation of LSD1 was also observed in Ang II-treated NRCFs, which was reversed by LSD1 silence or its activity inhibition by ORY-1001. These findings suggested a potential involvement of LSD1 in cardiac remodeling. Importantly, myofibroblast-specific LSD1 inducible knockout in vivo significantly alleviated systolic dysfunction, cardiac hypertrophy and fibrosis, following 6 and 20 weeks of TAC. Mechanistically, through RNA-sequencing and the following western blot analysis, we found that loss of LSD1 in Ang II-induced myofibroblasts not only inhibited the intracellular upregulation of transforming growth factor β1 (TGFβ1), its downstream effectors Smad2/3 phosphorylation, as well as the phosphorylation of p38, ERK1/2 and JNK, but also reduced the supernatant TGFβ1 secretion, which then decreased myocyte hypertrophy in the indirect co-culture model. On the other hand, cardiomyocyte-specific LSD1 inducible knockout in vivo triggered the reprogramming of fetal genes, mild cardiac hypertrophy and dysfunction under both basal and stressed conditions. Conclusions: Our findings, for the first time, implicate that myofibroblast-specific LSD1 deletion attenuates TAC-induced cardiac remodeling and improves heart function, suggesting that LSD1 is a potential therapeutic target for late stage heart failure.




Circ Res: 02 Jun 2021; epub ahead of print
Huo JL, Jiao L, An Q, Chen X, ... Wang C, Zhao W
Circ Res: 02 Jun 2021; epub ahead of print | PMID: 34078090
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Impact:
Abstract

Molecular Imaging of Inflammation and Fibrosis in Pressure Overload Heart Failure.

Glasenapp A, Derlin K, Gutberlet M, Hess A, ... Bengel FM, Thackeray JT
Rationale: Tissue inflammation and subsequent fibrosis contribute to ventricle remodelling after ischemic injury, and have emerged as viable therapeutic targets. Comparatively little is understood about the dynamics of inflammation and fibrosis in non-ischemic heart failure, which is challenging to interrogate longitudinally. Objective: To investigate the interplay between ventricle loading conditions, tissue inflammation, and progressive fibrosis using non-invasive multimodality molecular imaging to characterize these processes in pressure overload heart failure.
Methods and results:
We evaluated cardiac inflammation using positron emission tomography radiotracer 68Ga-pentixafor which binds to chemokine CXC-motif receptor 4 (CXCR4). Over the first 7d after transverse aortic constriction (TAC), CXCR4 imaging identified diffuse elevated myocardial inflammation throughout the left ventricle (+34%, p<0.001), returning to sham levels over 6 weeks after surgery. This transient signal colocalized to local enrichment of CD68 macrophages, as confirmed by autoradiography and immunostaining. Magnetic resonance imaging demonstrated a parallel prolongation of myocardial T1 relaxation time in TAC mice, persisting from 8d to 6 weeks after surgery (+22%, p=0.003). The persistent imaging signal correlated to increased tissue fibrosis on histology. Molecular imaging at 1 week after surgery correlated independently with the change in ventricle geometry over the subsequent 3 weeks (CXCR4, rpartial=0.670, p=0.024; T1, rpartial=0.689, p=0.019). Alleviation of ventricle pressure by mechanical unloading restored not only cardiac function and geometry, but also attenuated global inflammation and normalized T1 relaxation time. This finding demonstrates the capacity to monitor therapeutic intervention by serial molecular imaging. Conclusions: Inflammation and fibrosis are implicated in the early response to pressure overload, and may be sensitively monitored by multimodality imaging. Such multimodality molecular imaging approaches may guide novel therapeutic approaches in non-ischemic heart failure.




Circ Res: 01 Jun 2021; epub ahead of print
Glasenapp A, Derlin K, Gutberlet M, Hess A, ... Bengel FM, Thackeray JT
Circ Res: 01 Jun 2021; epub ahead of print | PMID: 34074134
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Abstract

Mechanisms of Cardiovascular Toxicities Associated With Immunotherapies.

Baik AH, Oluwole OO, Johnson DB, Shah N, ... Tsai KK, Moslehi JJ
Immune-based therapies have revolutionized cancer treatments. Cardiovascular sequelae from these treatments, however, have emerged as critical complications, representing new challenges in cardio-oncology. Immune therapies include a broad range of novel drugs, from antibodies and other biologics, including immune checkpoint inhibitors and bispecific T-cell engagers, to cell-based therapies, such as chimeric-antigen receptor T-cell therapies. The recognition of immunotherapy-associated cardiovascular side effects has also catapulted new research questions revolving around the interactions between the immune and cardiovascular systems, and the signaling cascades affected by T cell activation, cytokine release, and immune system dysregulation. Here, we review the specific mechanisms of immune activation from immunotherapies and the resulting cardiovascular toxicities associated with immune activation and excess cytokine production.



Circ Res: 27 May 2021; 128:1780-1801
Baik AH, Oluwole OO, Johnson DB, Shah N, ... Tsai KK, Moslehi JJ
Circ Res: 27 May 2021; 128:1780-1801 | PMID: 33934609
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Impact:
Abstract

Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease.

Ridker PM, Rane M
IL (interleukin)-6 is a pivotal cytokine of innate immunity, which enacts a broad set of physiological functions traditionally associated with host defense, immune cell regulation, proliferation, and differentiation. Following recognition of innate immune pathways leading from the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome to IL-1 to IL-6 and on to the hepatically derived clinical biomarker CRP (C-reactive protein), an expanding literature has led to understanding of the proatherogenic role for IL-6 in cardiovascular disease and thus the potential for IL-6 inhibition as a novel method for vascular protection. In this review, we provide an overview of the mechanisms by which IL-6 signaling occurs and how that impacts upon pharmacological inhibition; describe murine models of IL-6 and atherogenesis; summarize human epidemiological data outlining the utility of IL-6 as a biomarker of vascular risk; outline genetic data suggesting a causal role for IL-6 in systemic atherothrombosis and aneurysm formation; and then detail the potential role of IL-6 inhibition in stable coronary disease, acute coronary syndromes, heart failure, and the atherothrombotic complications associated with chronic kidney disease and end-stage renal failure. Finally, we review anti-inflammatory and antithrombotic findings for ziltivekimab, a novel IL-6 ligand inhibitor being developed specifically for use in atherosclerotic disease and poised to be tested formally in a large-scale cardiovascular outcomes trial focused on individuals with chronic kidney disease and elevated levels of CRP, a population at high residual atherothrombotic risk, high residual inflammatory risk, and considerable unmet clinical need.



Circ Res: 27 May 2021; 128:1728-1746
Ridker PM, Rane M
Circ Res: 27 May 2021; 128:1728-1746 | PMID: 33998272
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Abstract

Immune Cells and Immunotherapy for Cardiac Injury and Repair.

Rurik JG, Aghajanian H, Epstein JA
Cardiac injury remains a major cause of morbidity and mortality worldwide. Despite significant advances, a full understanding of why the heart fails to fully recover function after acute injury, and why progressive heart failure frequently ensues, remains elusive. No therapeutics, short of heart transplantation, have emerged to reliably halt or reverse the inexorable progression of heart failure in the majority of patients once it has become clinically evident. To date, most pharmacological interventions have focused on modifying hemodynamics (reducing afterload, controlling blood pressure and blood volume) or on modifying cardiac myocyte function. However, important contributions of the immune system to normal cardiac function and the response to injury have recently emerged as exciting areas of investigation. Therapeutic interventions aimed at harnessing the power of immune cells hold promise for new treatment avenues for cardiac disease. Here, we review the immune response to heart injury, its contribution to cardiac fibrosis, and the potential of immune modifying therapies to affect cardiac repair.



Circ Res: 27 May 2021; 128:1766-1779
Rurik JG, Aghajanian H, Epstein JA
Circ Res: 27 May 2021; 128:1766-1779 | PMID: 34043424
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Abstract

Nonalcoholic Fatty Liver Disease: An Emerging Driver of Cardiac Arrhythmia.

Chen Z, Liu J, Zhou F, Li H, ... Cai J, Li H
Cardiac arrhythmias and the resulting sudden cardiac death are significant cardiovascular complications that continue to impose a heavy burden on patients and society. An emerging body of evidence indicates that nonalcoholic fatty liver disease (NAFLD) is closely associated with the risk of cardiac arrhythmias, independent of other conventional cardiometabolic comorbidities. Although most studies focus on the relationship between NAFLD and atrial fibrillation, associations with ventricular arrhythmias and cardiac conduction defects have also been reported. Mechanistic investigations suggest that a number of NAFLD-related pathophysiological alterations may potentially elicit structural, electrical, and autonomic remodeling in the heart, contributing to arrhythmogenic substrates in the heart. NAFLD is now the most common liver and metabolic disease in the world. However, the upsurge in the prevalence of NAFLD as an emerging risk factor for cardiac arrhythmias has received little attention. In this review, we summarize the clinical evidence and putative pathophysiological mechanisms for the emerging roles of NAFLD in cardiac arrhythmias, with the purpose of highlighting the notion that NAFLD may serve as an independent risk factor and a potential driving force in the development and progression of cardiac arrhythmias.



Circ Res: 27 May 2021; 128:1747-1765
Chen Z, Liu J, Zhou F, Li H, ... Cai J, Li H
Circ Res: 27 May 2021; 128:1747-1765 | PMID: 34043417
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Impact:
Abstract

GSDMD-Mediated Cardiomyocyte Pyroptosis Promotes Myocardial I/R Injury.

Shi H, Gao Y, Dong Z, Yang J, ... Sun A, Ge J
Rationale: Pyroptosis is a morphologically and mechanistically distinct form of cell death and is characterized by gasdermin D (GSDMD) or gasdermin E (GSDME)-mediated necrosis with excessive inflammatory factor release. Cardiomyocyte necrosis and inflammation play key roles in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury. However, whether cardiomyocytes undergo pyroptosis and the underlying mechanism in myocardial I/R injury remain unclear. Objective: We aimed to investigate the role of pyroptosis in myocardial I/R injury.
Methods and results:
In vivo and in vitro experiments were used to investigate pyroptosis of cardiomyocyte and the associated mechanisms during I/R injury. Wild-type (WT), Myh6-Cre and cardiomyocyte-specific GSDMD-deficient (GSDMD-CKO) male mice were subjected to I/R. Human peripheral blood samples were collected from STEMI (acute ST-segment-elevation myocardial infarction) patients or control patients at 0, 1 and 24 h after PCI (percutaneous coronary intervention) in our department. The serum levels of GSDMD were measured by ELISA. H/R (hypoxia/reoxygenation) induced cardiomyocyte pyroptosis and the release of mature IL-18 but not IL-1β, which mechanistically resulted from GSDMD cleavage by caspase-11 in cardiomyocytes. Furthermore, GSDMD gene deletion blocked H/R-induced cardiomyocyte pyroptosis and IL-18 release. GSDMD and its pyroptosis-inducing N-terminal fragment (GSDMD-N) were upregulated in myocardial tissues after I/R injury. Immunofluorescence analysis showed that GSDMD was mainly localized in cardiomyocytes. GSDMD deficiency in cardiomyocytes significantly reduced the I/R-induced myocardial infarct size. Moreover, increased GSDMD serum levels were detected in patients exhibiting I/R injury 1 h after PCI for STEMI. Conclusions: Our results show that GSDMD-mediated cardiomyocyte pyroptosis is a key event during myocardial I/R injury and that the caspase-11/GSDMD pathway may be essential to this process. Additionally, GSDMD inhibition significantly reduces cardiomyocyte pyroptosis and I/R-induced myocardial injury.




Circ Res: 20 May 2021; epub ahead of print
Shi H, Gao Y, Dong Z, Yang J, ... Sun A, Ge J
Circ Res: 20 May 2021; epub ahead of print | PMID: 34015941
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Impact:
Abstract

Epidemiology of Heart Failure: A Contemporary Perspective.

Roger VL
Designated as an emerging epidemic in 1997, heart failure (HF) remains a major clinical and public health problem. This review focuses on the most recent studies identified by searching the Medline database for publications with the subject headings HF, epidemiology, prevalence, incidence, trends between 2010 and present. Publications relevant to epidemiology and population sciences were retained for discussion in this review after reviewing abstracts for relevance to these topics. Studies of the epidemiology of HF over the past decade have improved our understanding of the HF syndrome and of its complexity. Data suggest that the incidence of HF is mostly flat or declining but that the burden of mortality and hospitalization remains mostly unabated despite significant ongoing efforts to treat and manage HF. The evolution of the case mix of HF continues to be characterized by an increasing proportion of cases with preserved ejection fraction, for which established effective treatments are mostly lacking. Major disparities in the occurrence, presentation, and outcome of HF persist particularly among younger Black men and women. These disturbing trends reflect the complexity of the HF syndrome, the insufficient mechanistic understanding of its various manifestations and presentations and the challenges of its management as a chronic disease, often integrated within a context of aging and multimorbidity. Emerging risk factors including omics science offer the promise of discovering new mechanistic pathways that lead to HF. Holistic management approaches must recognize HF as a syndemic and foster the implementation of multidisciplinary approaches to address major contributors to the persisting burden of HF including multimorbidity, aging, and social determinants of health.



Circ Res: 13 May 2021; 128:1421-1434
Roger VL
Circ Res: 13 May 2021; 128:1421-1434 | PMID: 33983838
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Impact:
Abstract

Pathophysiology and Therapeutic Approaches to Acute Decompensated Heart Failure.

Njoroge JN, Teerlink JR
Acute decompensated heart failure (ADHF) is one of the leading admission diagnoses worldwide, yet it is an entity with incompletely understood pathophysiology and limited therapeutic options. Patients admitted for ADHF have high in-hospital morbidity and mortality, as well as frequent rehospitalizations and subsequent cardiovascular death. This devastating clinical course is partly due to suboptimal medical management of ADHF with persistent congestion upon hospital discharge and inadequate predischarge initiation of life-saving guideline-directed therapies. While new drugs for the treatment of chronic HF continue to be approved, there has been no new therapy approved for ADHF in decades. This review will focus on the current limited understanding of ADHF pathophysiology, possible therapeutic targets, and current limitations in expanding available therapies in light of the unmet need among these high-risk patients.



Circ Res: 13 May 2021; 128:1468-1486
Njoroge JN, Teerlink JR
Circ Res: 13 May 2021; 128:1468-1486 | PMID: 33983837
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Impact:
Abstract

Cardiac Energy Metabolism in Heart Failure.

Lopaschuk GD, Karwi QG, Tian R, Wende AR, Abel ED
Alterations in cardiac energy metabolism contribute to the severity of heart failure. However, the energy metabolic changes that occur in heart failure are complex and are dependent not only on the severity and type of heart failure present but also on the co-existence of common comorbidities such as obesity and type 2 diabetes. The failing heart faces an energy deficit, primarily because of a decrease in mitochondrial oxidative capacity. This is partly compensated for by an increase in ATP production from glycolysis. The relative contribution of the different fuels for mitochondrial ATP production also changes, including a decrease in glucose and amino acid oxidation, and an increase in ketone oxidation. The oxidation of fatty acids by the heart increases or decreases, depending on the type of heart failure. For instance, in heart failure associated with diabetes and obesity, myocardial fatty acid oxidation increases, while in heart failure associated with hypertension or ischemia, myocardial fatty acid oxidation decreases. Combined, these energy metabolic changes result in the failing heart becoming less efficient (ie, a decrease in cardiac work/O2 consumed). The alterations in both glycolysis and mitochondrial oxidative metabolism in the failing heart are due to both transcriptional changes in key enzymes involved in these metabolic pathways, as well as alterations in NAD redox state (NAD+ and nicotinamide adenine dinucleotide levels) and metabolite signaling that contribute to posttranslational epigenetic changes in the control of expression of genes encoding energy metabolic enzymes. Alterations in the fate of glucose, beyond flux through glycolysis or glucose oxidation, also contribute to the pathology of heart failure. Of importance, pharmacological targeting of the energy metabolic pathways has emerged as a novel therapeutic approach to improving cardiac efficiency, decreasing the energy deficit and improving cardiac function in the failing heart.



Circ Res: 13 May 2021; 128:1487-1513
Lopaschuk GD, Karwi QG, Tian R, Wende AR, Abel ED
Circ Res: 13 May 2021; 128:1487-1513 | PMID: 33983836
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Impact:
Abstract

Pathophysiology and Therapeutic Approaches to Cardiac Amyloidosis.

Griffin JM, Rosenblum H, Maurer MS
Often considered a rare disease, cardiac amyloidosis is increasingly recognized by practicing clinicians. The increased rate of diagnosis is in part due the aging of the population and increasing incidence and prevalence of cardiac amyloidosis with advancing age, as well as the advent of noninvasive methods using nuclear scintigraphy to diagnose transthyretin cardiac amyloidosis due to either variant or wild type transthyretin without a biopsy. Perhaps the most important driver of the increased awareness is the elucidation of the biologic mechanisms underlying the pathogenesis of cardiac amyloidosis which have led to the development of several effective therapies with differing mechanisms of actions. In this review, the mechanisms underlying the pathogenesis of cardiac amyloidosis due to light chain (AL) or transthyretin (ATTR) amyloidosis are delineated as well as the rapidly evolving therapeutic landscape that has emerged from a better pathophysiologic understanding of disease development.



Circ Res: 13 May 2021; 128:1554-1575
Griffin JM, Rosenblum H, Maurer MS
Circ Res: 13 May 2021; 128:1554-1575 | PMID: 33983835
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Impact:
Abstract

The Complex and Diverse Genetic Architecture of Dilated Cardiomyopathy.

Hershberger RE, Cowan J, Jordan E, Kinnamon DD
Our insight into the diverse and complex nature of dilated cardiomyopathy (DCM) genetic architecture continues to evolve rapidly. The foundations of DCM genetics rest on marked locus and allelic heterogeneity. While DCM exhibits a Mendelian, monogenic architecture in some families, preliminary data from our studies and others suggests that at least 20% to 30% of DCM may have an oligogenic basis, meaning that multiple rare variants from different, unlinked loci, determine the DCM phenotype. It is also likely that low-frequency and common genetic variation contribute to DCM complexity, but neither has been examined within a rare variant context. Other types of genetic variation are also likely relevant for DCM, along with gene-by-environment interaction, now established for alcohol- and chemotherapy-related DCM. Collectively, this suggests that the genetic architecture of DCM is broader in scope and more complex than previously understood. All of this elevates the impact of DCM genetics research, as greater insight into the causes of DCM can lead to interventions to mitigate or even prevent it and thus avoid the morbid and mortal scourge of human heart failure.



Circ Res: 13 May 2021; 128:1514-1532
Hershberger RE, Cowan J, Jordan E, Kinnamon DD
Circ Res: 13 May 2021; 128:1514-1532 | PMID: 33983834
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Impact:
Abstract

Heart Failure With Targeted Cancer Therapies: Mechanisms and Cardioprotection.

Hahn VS, Zhang KW, Sun L, Narayan V, Lenihan DJ, Ky B
Oncology has seen growing use of newly developed targeted therapies. Although this has resulted in dramatic improvements in progression-free and overall survival, challenges in the management of toxicities related to longer-term treatment of these therapies have also become evident. Although a targeted approach often exploits the differences between cancer cells and noncancer cells, overlap in signaling pathways necessary for the maintenance of function and survival in multiple cell types has resulted in systemic toxicities. In particular, cardiovascular toxicities are of important concern. In this review, we highlight several targeted therapies commonly used across a variety of cancer types, including HER2 (human epidermal growth factor receptor 2)+ targeted therapies, tyrosine kinase inhibitors, immune checkpoint inhibitors, proteasome inhibitors, androgen deprivation therapies, and MEK (mitogen-activated protein kinase kinase)/BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors. We present the oncological indications, heart failure incidence, hypothesized mechanisms of cardiotoxicity, and potential mechanistic rationale for specific cardioprotective strategies.



Circ Res: 13 May 2021; 128:1576-1593
Hahn VS, Zhang KW, Sun L, Narayan V, Lenihan DJ, Ky B
Circ Res: 13 May 2021; 128:1576-1593 | PMID: 33983833
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Impact:
Abstract

Mechanisms and Models in Heart Failure: A Translational Approach.

Mann DL, Felker GM
Despite multiple attempts to develop a unifying hypothesis that explains the pathophysiology of heart failure with a reduced ejection fraction (HFrEF), no single conceptual model has withstood the test of time. In the present review, we discuss how the results of recent successful phase III clinical development programs in HFrEF are built upon existing conceptual models for drug development. We will also discuss where recent successes in clinical trials do not fit existing models to identify areas where further refinement of current paradigms may be needed. To provide the necessary structure for this review, we will begin with a brief overview of the pathophysiology of HFrEF, followed by an overview of the current conceptual models for HFrEF, and end with an analysis of the scientific rationale and clinical development programs for 4 new therapeutic classes of drugs that have improved clinical outcomes in HFrEF. The 4 new therapeutic classes discussed are ARNIs, SGLT2 (sodium-glucose cotransporter 2) inhibitors, soluble guanylate cyclase stimulators, and myosin activators. With the exception of SGLT2 inhibitors, each of these therapeutic advances was informed by the insights provided by existing conceptual models of heart failure. Although the quest to determine the mechanism of action of SGLT2 inhibitors is ongoing, this therapeutic class of drugs may represent the most important advance in cardiovascular therapeutics of recent decades and may lead to rethinking or expanding our current conceptual models for HFrEF.



Circ Res: 13 May 2021; 128:1435-1450
Mann DL, Felker GM
Circ Res: 13 May 2021; 128:1435-1450 | PMID: 33983832
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Impact:
Abstract

From Systemic Inflammation to Myocardial Fibrosis: The Heart Failure With Preserved Ejection Fraction Paradigm Revisited.

Paulus WJ, Zile MR
In accordance with the comorbidity-inflammation paradigm, comorbidities and especially metabolic comorbidities are presumed to drive development and severity of heart failure with preserved ejection fraction through a cascade of events ranging from systemic inflammation to myocardial fibrosis. Recently, novel experimental and clinical evidence emerged, which strengthens the validity of the inflammatory/profibrotic paradigm. This evidence consists among others of (1) myocardial infiltration by immunocompetent cells not only because of an obesity-induced metabolic load but also because of an arterial hypertension-induced hemodynamic load. The latter is sensed by components of the extracellular matrix like basal laminin, which also interact with cardiomyocyte titin; (2) expression in cardiomyocytes of inducible nitric oxide synthase because of circulating proinflammatory cytokines. This results in myocardial accumulation of degraded proteins because of a failing unfolded protein response; (3) definition by machine learning algorithms of phenogroups of patients with heart failure with preserved ejection fraction with a distinct inflammatory/profibrotic signature; (4) direct coupling in mediation analysis between comorbidities, inflammatory biomarkers, and deranged myocardial structure/function with endothelial expression of adhesion molecules already apparent in early preclinical heart failure with preserved ejection fraction (HF stage A, B). This new evidence paves the road for future heart failure with preserved ejection fraction treatments such as biologicals directed against inflammatory cytokines, stimulation of protein ubiquitylation with phosphodiesterase 1 inhibitors, correction of titin stiffness through natriuretic peptide-particulate guanylyl cyclase-PDE9 (phosphodiesterase 9) signaling and molecular/cellular regulatory mechanisms that control myocardial fibrosis.



Circ Res: 13 May 2021; 128:1451-1467
Paulus WJ, Zile MR
Circ Res: 13 May 2021; 128:1451-1467 | PMID: 33983831
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Impact:
Abstract

Molecular Genetic Basis of Hypertrophic Cardiomyopathy.

Marian AJ
Hypertrophic cardiomyopathy (HCM) is a genetic disease of the myocardium characterized by a hypertrophic left ventricle with a preserved or increased ejection fraction. Cardiac hypertrophy is often asymmetrical, which is associated with left ventricular outflow tract obstruction. Myocyte hypertrophy, disarray, and myocardial fibrosis constitute the histological features of HCM. HCM is a relatively benign disease but an important cause of sudden cardiac death in the young and heart failure in the elderly. Pathogenic variants (PVs) in genes encoding protein constituents of the sarcomeres are the main causes of HCM. PVs exhibit a gradient of effect sizes, as reflected in their penetrance and variable phenotypic expression of HCM. MYH7 and MYBPC3, encoding β-myosin heavy chain and myosin binding protein C, respectively, are the two most common causal genes and responsible for ≈40% of all HCM cases but a higher percentage of HCM in large families. PVs in genes encoding protein components of the thin filaments are responsible for ≈5% of the HCM cases. Whereas pathogenicity of the genetic variants in large families has been firmly established, ascertainment causality of the PVs in small families and sporadic cases is challenging. In the latter category, PVs are best considered as probabilistic determinants of HCM. Deciphering the genetic basis of HCM has enabled routine genetic testing and has partially elucidated the underpinning mechanism of HCM as increased number of the myosin molecules that are strongly bound to actin. The discoveries have led to the development of mavacamten that targets binding of the myosin molecule to actin filaments and imparts beneficial clinical effects. In the coming years, the yield of the genetic testing is expected to be improved and the so-called missing causal gene be identified. The advances are also expected to enable development of additional specific therapies and editing of the mutations in HCM.



Circ Res: 13 May 2021; 128:1533-1553
Marian AJ
Circ Res: 13 May 2021; 128:1533-1553 | PMID: 33983830
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Impact:
Abstract

Reverse Remodeling With Left Ventricular Assist Devices.

Burkhoff D, Topkara VK, Sayer G, Uriel N
This review provides a comprehensive overview of the past 25+ years of research into the development of left ventricular assist device (LVAD) to improve clinical outcomes in patients with severe end-stage heart failure and basic insights gained into the biology of heart failure gleaned from studies of hearts and myocardium of patients undergoing LVAD support. Clinical aspects of contemporary LVAD therapy, including evolving device technology, overall mortality, and complications, are reviewed. We explain the hemodynamic effects of LVAD support and how these lead to ventricular unloading. This includes a detailed review of the structural, cellular, and molecular aspects of LVAD-associated reverse remodeling. Synergisms between LVAD support and medical therapies for heart failure related to reverse remodeling, remission, and recovery are discussed within the context of both clinical outcomes and fundamental effects on myocardial biology. The incidence, clinical implications and factors most likely to be associated with improved ventricular function and remission of the heart failure are reviewed. Finally, we discuss recognized impediments to achieving myocardial recovery in the vast majority of LVAD-supported hearts and their implications for future research aimed at improving the overall rates of recovery.



Circ Res: 13 May 2021; 128:1594-1612
Burkhoff D, Topkara VK, Sayer G, Uriel N
Circ Res: 13 May 2021; 128:1594-1612 | PMID: 33983828
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Abstract

Genetic and Developmental Contributors to Aortic Stenosis.

Dutta P, James JF, Kazik H, Lincoln J
Aortic stenosis (AS) remains one of the most common forms of valve disease, with significant impact on patient survival. The disease is characterized by left ventricular outflow obstruction and encompasses a series of stenotic lesions starting from the left ventricular outflow tract to the descending aorta. Obstructions may be subvalvar, valvar, or supravalvar and can be present at birth (congenital) or acquired later in life. Bicuspid aortic valve, whereby the aortic valve forms with two instead of three cusps, is the most common cause of AS in younger patients due to primary anatomic narrowing of the valve. In addition, the secondary onset of premature calcification, likely induced by altered hemodynamics, further obstructs left ventricular outflow in bicuspid aortic valve patients. In adults, degenerative AS involves progressive calcification of an anatomically normal, tricuspid aortic valve and is attributed to lifelong exposure to multifactoral risk factors and physiological wear-and-tear that negatively impacts valve structure-function relationships. AS continues to be the most frequent valvular disease that requires intervention, and aortic valve replacement is the standard treatment for patients with severe or symptomatic AS. While the positive impacts of surgical interventions are well documented, the financial burden, the potential need for repeated procedures, and operative risks are substantial. In addition, the clinical management of asymptomatic patients remains controversial. Therefore, there is a critical need to develop alternative approaches to prevent the progression of left ventricular outflow obstruction, especially in valvar lesions. This review summarizes our current understandings of AS cause; beginning with developmental origins of congenital valve disease, and leading into the multifactorial nature of AS in the adult population.



Circ Res: 29 Apr 2021; 128:1330-1343
Dutta P, James JF, Kazik H, Lincoln J
Circ Res: 29 Apr 2021; 128:1330-1343 | PMID: 33914609
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Abstract

Multi-Omics Approaches to Define Calcific Aortic Valve Disease Pathogenesis.

Blaser MC, Kraler S, Lüscher TF, Aikawa E
Calcific aortic valve disease sits at the confluence of multiple world-wide epidemics of aging, obesity, diabetes, and renal dysfunction, and its prevalence is expected to nearly triple over the next 3 decades. This is of particularly dire clinical relevance, as calcific aortic valve disease can progress rapidly to aortic stenosis, heart failure, and eventually premature death. Unlike in atherosclerosis, and despite the heavy clinical toll, to date, no pharmacotherapy has proven effective to halt calcific aortic valve disease progression, with invasive and costly aortic valve replacement representing the only treatment option currently available. This substantial gap in care is largely because of our still-limited understanding of both normal aortic valve biology and the key regulatory mechanisms that drive disease initiation and progression. Drug discovery is further hampered by the inherent intricacy of the valvular microenvironment: a unique anatomic structure, a complex mixture of dynamic biomechanical forces, and diverse and multipotent cell populations collectively contributing to this currently intractable problem. One promising and rapidly evolving tactic is the application of multiomics approaches to fully define disease pathogenesis. Herein, we summarize the application of (epi)genomics, transcriptomics, proteomics, and metabolomics to the study of valvular heart disease. We also discuss recent forays toward the omics-based characterization of valvular (patho)biology at single-cell resolution; these efforts promise to shed new light on cellular heterogeneity in healthy and diseased valvular tissues and represent the potential to efficaciously target and treat key cell subpopulations. Last, we discuss systems biology- and network medicine-based strategies to extract meaning, mechanisms, and prioritized drug targets from multiomics datasets.



Circ Res: 29 Apr 2021; 128:1371-1397
Blaser MC, Kraler S, Lüscher TF, Aikawa E
Circ Res: 29 Apr 2021; 128:1371-1397 | PMID: 33914608
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Abstract

Current Therapeutic Options in Aortic Stenosis.

Boskovski MT, Gleason TG
Aortic stenosis is the most common valvular disease requiring valve replacement. Valve replacement therapies have undergone progressive evolution since the 1960s. Over the last 20 years, transcatheter aortic valve replacement has radically transformed the care of aortic stenosis, such that it is now the treatment of choice for many, particularly elderly, patients. This review provides an overview of the pathophysiology, presentation, diagnosis, indications for intervention, and current therapeutic options for aortic stenosis.



Circ Res: 29 Apr 2021; 128:1398-1417
Boskovski MT, Gleason TG
Circ Res: 29 Apr 2021; 128:1398-1417 | PMID: 33914604
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Abstract

Inflammatory and Biomechanical Drivers of Endothelial-Interstitial Interactions in Calcific Aortic Valve Disease.

Driscoll K, Cruz AD, Butcher JT
Calcific aortic valve disease is dramatically increasing in global burden, yet no therapy exists outside of prosthetic replacement. The increasing proportion of younger and more active patients mandates alternative therapies. Studies suggest a window of opportunity for biologically based diagnostics and therapeutics to alleviate or delay calcific aortic valve disease progression. Advancement, however, has been hampered by limited understanding of the complex mechanisms driving calcific aortic valve disease initiation and progression towards clinically relevant interventions.



Circ Res: 29 Apr 2021; 128:1344-1370
Driscoll K, Cruz AD, Butcher JT
Circ Res: 29 Apr 2021; 128:1344-1370 | PMID: 33914601
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This program is still in alpha version.