key: cord-0820674-tsootrxz authors: nan title: Full Issue PDF date: 2020-05-31 journal: JACC: Basic to Translational Science DOI: 10.1016/s2452-302x(20)30205-9 sha: 46732d42cca2be682c8a6b28236e0f47f5b23376 doc_id: 820674 cord_uid: tsootrxz nan the corresponding author may electronically sign the copyright form; however, ALL AUTHORS ARE REQUIRED TO ELECTRONICALLY SIGN A RELATIONSHIP WITH INDUSTRY FORM. Once completed, a PDF version of the form is e-mailed to the author. Authors can access and confirm receipt of forms by logging into their account online. Each author will be alerted if his/her form has not been completed by the deadline. Only authors appearing on the final title page will be sent a form. YOU CANNOT ADD AUTHORS AFTER ACCEPTANCE OR ON PROOFS. After a paper is sent to the publisher, the links to the electronic forms will no longer be active. In this case, authors will be sent links to download hard copy forms that they may mail or fax to the JACC: Basic to Translational Science office. Studies should be in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines. Human studies must be performed with the subjects' written informed consent. Authors must provide the details of this procedure and indicate that the institutional committee on human research has approved the study protocol. If radiation is used in a research procedure, the radiation exposure must be specified in the Methods. Clinical trials should be registered. Studies on patients or volunteers require ethics committee approval and informed consent which should be documented in your paper. Patients have a right to privacy. Therefore, identifying information, including patients' images, names, initials, or hospital numbers, should not be included in videos, recordings, written descriptions, photographs, and pedigrees unless the information is essential for scientific purposes and you have obtained written informed consent for publication in print and electronic form from the patient (or parent, guardian or next of kin where applicable). If such consent is made subject to any conditions, the editorial office must be made aware of all such conditions. Written consents must be provided to the editorial office on request. Even where consent has been given, identifying details should be omitted if they are not essential. If identifying characteristics are altered to protect anonymity, such as in genetic pedigrees, authors should provide assurance that alterations do not distort scientific meaning and editors should so note. If such consent has not been obtained, personal details of patients included in any part of the paper and in any supplementary materials (including all illustrations and videos) must be removed before submission. Animal investigation must conform to the "Position of the American Heart Association on Research Animal Use," adopted by the AHA on November 11, 1984 . If equivalent guidelines are used, they should be indicated. The The corresponding author should be specified in the cover letter. All editorial communications will be sent to this author. The corresponding author will be whom we contact for submission queries. To add or remove any authors after acceptance of their paper, all listed authors at the time of acceptance need to provide written approval to the JACC Journals' editorial office prior to the scheduling and publication of the paper. JACC: Basic to Translational Science is not restricted to page length, however the Editors prefer that manuscripts not exceed 5,500 words (including references and figure legends). Note that if you are asked to revise your paper an alternate word limit may be specified by the Editors. Illustrations and tables should be limited to those necessary to highlight key data. Please provide gender-specific data, when appropriate, in describing outcomes of epidemiologic analyses or clinical trials; or specifically state that no gender- First Look" server will be free to upload and download. Authors may post a preprint of their manuscript during the journal submission process and in advance of manuscript decision. This service is not a Updated April 2020 requirement to submit to the Journal and has no bearing on the peer review process. Authors who wish to opt in and have their paper considered for posting should answer "Yes" in the Preprint Deposition section of the submission site. Please note that agreeing to post a manuscript to SSRN does not guarantee it will be posted. Only manuscripts sent out for peer review (at the editors' discretion) will be posted to SSRN. Papers that are accepted for publication will remain on the "JACC: Basic to Translational Science First Look" server indefinitely, whereas papers that are ultimately rejected will be archived on a different site on the SSRN preprint server. The following information should be noted for these paper types: STATE-OF-THE-ART PAPERS. The Editors will consider both invited and volunteered review articles. Such manuscripts must adhere to preferred length guidelines of no more than 5,000 words and require an unstructured abstract, a central illustration and a list of 3 to 4 brief bullet points (15 words or fewer for each bullet, or 85 characters for each bullet) that highlight the main message of the review. The first bullet should provide the translational/clinical context or background that establishes the relevance or need for this review. The second bullet should speak to the main message and focus of the review, including any recommendations made by the authors. The final bullet should summarize where the field needs to move forward from this point. Authors should detail in their cover letters how their submission differs from existing reviews on the subject. The acute inflammatory response is a critical mechanism for host defense, whereas the resolution of inflammation is equally important for tissue homeostasis by delimiting the destructive effects of chronic inflammation. This review will discuss the role of the activation of the G-protein coupled formyl peptide receptor 2 (ALX/FPR2) in terms of regulating the resolution of inflammation following tissue injury, and will specifically focus on the role of lipid mediators in activating the ALX/FPR2 receptor. Additional studies will be required to clarify whether activation of the ALX/FPR2 receptor can be used therapeutically to prevent chronic inflammation, scar tissue formation following acute tissue injury. LEADING EDGE TRANSLATIONAL SCIENCE articles are discrete, highly significant, innovative or novel findings reported in a shorter format of 3,500 words or fewer in length. Editors will review for interest within seven (7) days of submission. These may be invited or volunteered manuscripts. TRANSLATIONAL PERSPECTIVES. Although usually invited, succinct opinion pieces relevant to a specific aspect of translational medicine will also be considered for JACC: Basic to Translational Science. They should not exceed 2,500 words and should have no more than a total of 2 figures and tables than 5 references. Table. A title page is required with a unique title of 15 words or less that does not include the title of the original research paper. Replies will generally be solicited by the Editors. Include the full title (no more than 15 words, hyphenated words count as a single word and single terms [e.g., de novo, in vivo, etc.] count as a single word), authors' names (including full first name and middle initial and degrees), total word count, and a brief title of no more than 15 words. List the departments and institutions with which the authors are affiliated, and indicate the specific affiliations if the work is generated from more than one institution (use superscript letters a, b, c, d , and so on). Also provide infor- ACCF has adopted this format for its competency and training statements, career milestones, lifelong learning, and educational programs. The ACCF also has developed tools to assist physicians in assessing, enhancing, and documenting these competencies (www.acc.org/Lifelong-Learning-and-MOC/Resources/Competencies). Authors are asked to consider the clinical implications of their report and identify applications in one or more of these competency domains that could be used by clinician readers to enhance their competency as professional caregivers. This applies not only to physicians in training, but to the sustained commitment to education and continuous improvement across the span of their professional careers. gov/about/about.html). Authors are asked to place their work in the context of the scientific continuum, by identifying impediments and challenges requiring further investigation and anticipating next steps and directions for future research. All original research papers should develop at least 1 visual abstract drawing or figure (that may be a simple/rough hand-drawn figure) , which summarizes the entire manuscript or at least a major section of the manuscript. Our inhouse medical illustrators will create the final printable versions of these figures in consultation with the authors and the editors. The purpose of these illustrations is to provide a snapshot of your paper in a single visual, conceptual manner. This illustration must be accompanied by a legend. Acknowledgments or appendices should be concise. Signed letters of permission from all individuals listed in the acknowledgments must be submitted to JACC: Basic to Translational Science. Identify references in the text by Arabic numerals in parentheses on the line. The reference list should be typed double-spaced on pages separate from the text. The references should be numbered consecutively in the order in which they are mentioned in the text. Do not cite personal communications, manuscripts in preparation, or other unpublished data in the references; however, these may be included in the text in parentheses. Do not cite abstracts that are older than 2 years. Identify abstracts by the abbreviation "abstr" in parentheses. If letters to the editor are cited, identify them with the word "letter" in parentheses. Use Index Medicus (National Library of Medicine) abbreviations for journal titles. It is important to note that when citing an article from the JACC: Basic to Translational Science, the correct citation format is J Am Coll Cardiol Basic Trans Science. Use the following style and punctuation for references: Periodical. If the ahead-of-print date is known, provide as in example below. Decimals, lines, and other details must be strong enough for reproduction. Designate special features with arrows. All symbols, arrows, and lettering on halftone illustrations must contrast with the background. Tables Tables should be typed double-spaced on Inclusion of videos in the published paper is at the discretion of the Editors. only. The Journal office will not accept any other file formats. The feasibility of rapid genetic testing in patients undergoing percutaneous coronary intervention (PCI) and the comparison of the pharmacodynamic effects of prasugrel versus ticagrelor among carriers of cytochrome P450 2C19 loss-of-function alleles treated with PCI has been poorly explored. Rapid genetic testing using the Spartan assay was shown to be feasible and provides results in a timely fashion in a real-world setting of patients undergoing coronary angiography (n ¼ 781). Among patients (n ¼ 223, 28 (1) . Although clopidogrel is the most commonly used P2Y 12 inhibitor, its pharmacodynamic (PD) effects are nonuniform, and patients with high on-treatment platelet reactivity (HPR) are at increased thrombotic risk (2) (3) (4) (5) (6) . Such PD variability is in part attributed to genetic polymorphisms of the cytochrome P450 (CYP) 2C19 enzyme, a key modulator of clopidogrel metabolism (7) (8) (9) (10) . In particular, carriers of loss-of-function (LOF) alleles of the CYP2C19 gene are associated with reduced generation of clopidogrel's active metabolite, diminished platelet inhibition, and increased rates of thrombotic events (7) (8) (9) (10) (11) (12) (13) . Consequently, drug-regulating authorities have issued a boxed warning on the reduced efficacy of clopidogrel among CYP2C19 LOF carriers and suggest that alternative P2Y 12 -inhibiting therapies (i.e., prasugrel or ticagrelor) be used in these individuals (14, 15) . However, in clinical practice, implementing a strategy of genotype-guided selection of oral P2Y 12 inhibitor has been limited by turnaround times of test results (16) (17) (18) . Prasugrel and ticagrelor are characterized by more potent platelet inhibitory effects and greater efficacy in reducing thrombotic complications, albeit at the expense of increased bleeding, compared with clopidogrel (19) (20) (21) . Post hoc analyses of large-scale investigations have not shown any interaction between CYP2C19 LOF polymorphisms and the clinical effects of prasugrel and ticagrelor (22) (23) (24) (25) . However, prasugrel and ticagrelor differ considerably regarding their pharmacokinetic properties, and studies assessing the comparative PD effects between prasugrel and ticagrelor have yielded conflicting findings, with earlier investigations suggesting ticagrelor to have enhanced and less variable P2Y 12 inhibitory effects with lower rates of HPR compared with prasugrel (19, 26) . Of note, although ticagrelor is a direct-acting P2Y 12 inhibitor, prasugrel is a prodrug that needs to be metabolized by CYP enzymes to generate an active metabolite to exert its effects (19) . Hence, it had been suggested that genetic polymorphisms regulating CYP enzyme activity could have contributed to these findings (26) . Although subsequent studies have failed to demonstrate greater P2Y 12 inhibitory effects of ticagrelor over prasugrel, or for these effects to be potentially modulated by CYP2C19 genetic status (19, 22, 23, 27) , to date there are no studies that have prospectively compared these agents specifically among CYP2C19 LOF carriers. The aim of this investigation was to assess the feasibility of implementing a rapid bedside CYP2C19 genetic testing assay in real-world clinical practice of not (28) (29) (30) . with valid data would allow for the 95% confidence interval (CI) to stay within 40 PRU with an 85% power and alpha ¼ 0.025 (27, 32) . Considering up to a 25% rate of invalid results due to hemolysis or drop-out, we planned to randomize up to a total of 80 patients to ensure complete data for analysis. Noninferiority was assessed using a 95% CI of the difference in mean PRU between the 2 groups. The 40 PRU noninferiority margin was defined according to previously published studies (33) . Exploratory endpoints included assessment of PD differences between prasugrel and ticagrelor at 30 Comparisons between categorical variables were performed using chi-square test or Fisher exact test. Missing data were not imputed. An analysis of variance method with a general linear model, with treatment as the main effect, was used to evaluate the primary noninferiority endpoint as well as all superiority between-group comparisons at each time point. Least squares mean differences in PRU between groups and the corresponding 2-sided 95% CI for the difference was obtained based on the analysis of variance model and used to assess noninferiority. The p values are used to report superiority testing, and Between March 2014 and September 2018, a total of 781 consecutive patients scheduled for left heart catheterization with the intent to undergo PCI were genotyped. Of these, 222 (28.5%) patients were carriers of at least 1 LOF: 9% were homozygotes (*2/*2, n ¼ 20) and 91% were heterozygotes (*1/*2, n ¼ 189; *1/*3, n ¼ 1; *2/*17, n ¼ 32). Of the cohort of CYP2C19 LOF carriers, 157 patients did not meet criteria to be randomized. Thus, a total 65 patients underwent PCI and were randomized to either prasugrel (n ¼ 32) or ticagrelor (n ¼ 33). These patients represented the PD population of the study ( Figure 2 ). Baseline characteristics of the PD population are summarized in Table 1 . CYP2C19 LOF carriers who were not randomized were more likely to be female and less likely to have ACS compared with those who were randomized (Supplemental Table 1 ). In the PD population, 8 patients (12%) were homozygotes for *2/*2, and 57 (88%) were heterozygotes (*1/*2: 78.5%; *1/*3: 1.5%; *2/*17: 8%). Fifty-one (78.5%) and 14 (21.5%) patients were on aspirin or DAPT before randomization, respectively. No ischemic or Bleeding Academic Research Consortium type 2 to 5 bleeding events were observed; 3 patients (9%) receiving ticagrelor experienced dyspnea, which led to drug discontinuation in 1 patient, versus none of those receiving prasugrel; 1 patient receiving prasugrel had a stroke; 2 patients had chest pain during follow-up that did not require any intervention (prasugrel, n ¼ 1; ticagrelor, n ¼ 1). PHARMACODYNAMIC RESULTS. At baseline, PRU levels were similar between groups. A significant reduction in PRU was observed as early as 30 min The implementation of genotype-guided selection of P2Y 12 -inhibiting therapy in patients undergoing PCI has been limited in real-world clinical practice by the availability of assays able to provide results of CYP2C19 genotypes in a timely fashion (16) (17) (18) . Patients most commonly undergo ad hoc PCI immediately following diagnostic angiography, which further emphasizes the importance of having readily available genotyping results. Earlier small-scale investigations have suggested the clinical utility of genotype-guided selection of oral P2Y 12 inhibitors in patients undergoing PCI (34) (35) (36) (37) . However, some of these were conducted using genotyping approaches that would require several days, making results unavailable until after hospital discharge (34, 35) . This has important implications. First, switching antiplatelet treatment after hospital discharge is of limited practicality; second, the early post-PCI period is when the risk for thrombotic complication is Although CYP enzymes are involved in prasugrel metabolism, which could potentially affect its PD effects, the contribution of CYP2C19 is minimal, as also supported by the very high levels of platelet inhibition achieved with prasugrel in our study (44) . Moreover, our investigation confirms results of prior studies on the prompt and enhanced platelet inhibitory effects associated with escalation from clopidogrel to prasugrel or ticagrelor, leading to a reduction in HPR rates when a loading dose is used (27, 38) . 24-h PRU absolute difference and 2-sided 95% confidence interval between prasugrel and ticagrelor. Tinted area indicates zone of noninferiority (NI). The dotted line represents the prespecified limit of noninferiority of þ40. Franchi et al. our study showed no differences in platelet reactivity between prasugrel and ticagrelor among CYP2C19 LOF carriers undergoing PCI during the entire study time-course, assessing the effects of both the loading and maintenance doses of these agents. These observations may have practical and cost implications, given that prasugrel is now available in a generic formulation in many countries, making it an attractive treatment option, including among physicians who elect an alternative agent to clopidogrel based on results of genetic testing. TRANSLATIONAL OUTLOOK: Our current investigation demonstrating no differences in PD effects between prasugrel and ticagrelor in this subset of patients, which is in line with prior investigations from our group assessing the comparative PD effects between these agents not stratified according to CYP2C19 genotype, support that recent trial findings showing significantly reduced ischemic events with prasugrel over ticagrelor cannot be attributed to differential levels of P2Y 12 inhibition. However, our study was not designed to assess the clinical outcomes of a rapid genotype-guided strategy in patients undergoing PCI. Moreover, it was not designed to compare the safety and efficacy of prasugrel versus ticagrelor in CYP2C19 LOF carriers, which would also warrant further investigation in large-scale clinical trials. Cardiac fibrosis is a pathological process associated with various forms of heart failure. This study identified latent transforming growth factor-b binding protein 2, cartilage oligomeric matrix protein, and cartilage intermediate layer protein 1 as potential biomarkers for cardiac fibrosis. All 3 encoded proteins showed increased expression in fibroblasts after transforming growth factor-b stimulation in vitro and localized specifically to fibrotic regions in vivo. Of the 3, only the full-length cartilage intermediate layer protein 1 showed a significant decrease in circulating levels in patients with heart failure compared with healthy volunteers. Further studies on these 3 proteins will lead to a better understanding of their biomarker potential for cardiac fibrosis. After transferring the gel onto a polyvinylidene fluoride membrane, detection of CILP was conducted by incubating the membrane with primary antibody followed by secondary antibody conjugated with horseradish peroxidase (Supplemental Table 2 ). The signal was developed using the Pierce ECL Western Blotting Substrate (Thermo Fisher Scientific). STATISTICAL ANALYSIS. Continuous data are presented using the mean AE SEM and comparisons between groups were performed using Student's t-test. A p value < 0.05 was considered statistically significant, and data were analyzed using GraphPad Prism 6 (San Diego, California). After TAC, many genes were differentially expressed in CFBs ( Figure 1A , Supplemental Table 3 ). Specifically, CFBs from mice that had undergone TAC showed higher expression of various genes associated with fibrosis ( Figure 1B ). From these, we selected genes that encoded for secreted proteins and then further filtered the list to those that were novel in the context of heart failure and had previously reported roles in ECM formation and remodeling. We identified Ltbp2, Comp, and Cilp as potential candidate biomarkers. These results were further validated by reverse transcription-quantitative PCR ( Figure 1C ). The TGF-b signaling pathway is a major component of injury response in CFBs (14) . Treatment of fibro- Acta2 ¼ a-smooth muscle actin; Angptl4 ¼ angiopoietin-like 4; Col5a2 (1a1, 1a2, 2a1,3a1, 4a2, 5a1) ¼ collagen type V (I, II, III, IV) a-2 (a-1); Ctgf ¼ connective tissue sham hearts, which exhibited no fibrosis ( Figure 3A ). Immunofluorescence staining showed minimal expression of the 3 proteins in sham hearts. In TAC hearts, Ltbp2, Comp, and Cilp expression appeared to colocalize with discoidin domain-containing receptor 2 (Ddr2), a marker for fibroblasts (19) , and a-smooth muscle actin (20) within the fibrotic regions of the myocardium in TAC hearts ( Figure 3B ). Table 4 ). We observed no significant differences in the circulating levels of LTBP2 (22) or COMP ( Figure 6A ). The expression of these proteins by CFBs in response COMP is another ECM protein that is mainly studied in the context of tendons and cartilage (27) . up-regulation of CILP in CFBs but the potential for CILP to be a potential biomarker for fibrosis had not been previously explored (24, 39) . The CILP gene encodes for a precursor protein containing a furin cleavage site. The precursor is first synthesized and processed by furin proteases intracellularly prior to being secreted (23) . The Nterminal fragment has been shown to directly interact with TGF-b, suppressing TGF-b signaling in CFb, whereas the C-terminal fragment is homologous to a porcine nucleotide pyrophosphohydrolase, which has been reported to have limited enzymatic activity (23, 40) . In contrast to the 2 fragments, the functional role of full-length CILP protein has not been well studied. The full-length Cilp has been shown to inhibit TGF-b signaling, similarly to the Nterminal fragment, most likely due to the common thrombospondin-1 domain, which has been shown to bind to TGF-b (24) . However, further studies to determine any functional differences between the N-terminal fragment and the full-length CILP are required. Our data specifically demonstrate that circulating levels of the full-length CILP are attenuated in patients with heart failure but show an abundance of expression in the fibrotic myocardium. A possible mechanism for this paradox is that fulllength CILP is sequestered to the ECM by its binding to TGF-b, therefore reducing circulating levels. Studies have reported that while injury induces increased expression of TGFb in the myocardium of patients with heart failure (41), circulating TGFb is reduced (42, 43) . Due to the inhibitory role of fulllength CILP in TGF-b signaling, it is possible that increased levels of CILP may reside in the ECM and promote a negative feedback mechanism to suppress CFB activation (24, 44 (5) hypothesized, that these proteins are indeed highly induced and secreted, but instead of being released into the blood vessels, they bind to ECM components and reside within the heart, thus making them unavailable as blood-based biomarkers. However, CILP seemed to be a promising candidate as a biomarker for cardiac fibrosis because it was significantly up-regulated in cardiac fibroblasts (7, 8) , This study used both human samples and iPSC-CMs to evaluate the effects of hypoxia on CM proliferation. The degree of hypoxia and the manner in which O 2 decreases both contribute to the cell cycle activity of post-natal human CMs. From the perspective of CM proliferation and protection, it has been unclear why moderate hypoxia (SaO 2 :75% to 85%) is targeted by many children's medical centers when children with CHD are being transported. A target was provided that can be used for antioxidant DNA damage to protect the proliferation of post-natal human CMs. This study used human heart samples and human induced pluripotent stem cellÀcardiomyocytes (iPSC-CMs) to assess how SaO 2 affects human CM cell cycle activities. The results showed that there were significantly more cell cycle markers in the moderate hypoxia group (SaO 2 : 75% to 85%) than in the other 2 groups (SaO 2 <75% or >85%). In iPSC-CMs 15% and 10% oxygen (O 2 ) treatment increased cell cycle markers, whereas 5% and rapid represents a more optimal scenario. This is also why many children's centers aim to supply moderate levels of SaO 2 during transportation (13) . When O 2 levels increase, mitochondrial oxidative phosphorylation increases accordingly. This phenomenon facilitates increased free radical production, causing increased DNA damage (14, 15) . increased DNA damage (16, 17) . Current evidence suggests that DNA damage is a critical factor in the suppression of CM proliferation (12, 18) . We speculated that dramatic increases or decreases in postnatal O 2 contribute to an increase in mitochondrial content, thereby activating the DNA damage response and causing permanent cell cycle arrest in CMs. Yes-associated protein 1 (YAP1) is closely related to the regulation of CM proliferation (19) (20) (21) . For Table S3 ). The only factor that significantly differed among the groups was SaO 2 (p < 0.001; n ¼ 10). In clinical practice, patients were divided into 3 groups according to SaO 2 levels: >85% was defined as mild hypoxia (group A); 75% to 85% was defined as moderate hypoxia (group B); and <75% was defined as severe hypoxia (group C) (13). Ten patients from each group were analyzed to test our hypothesis that To confirm these results, we also performed qPCR to detect the mRNA levels of Ki67, cyclin D2, and aurora B. As shown in Figures 1G patients (28, 29) . Furthermore, newer, more promising drugs have not been subjected to randomized clinical trials in pediatric patients (30, 31) . Because prevention is better than therapy, there is increasing awareness of the importance of protecting the young human heart. Therefore, new therapeutic paradigms for pediatric heart failure are now under investigation (32) . This study is the first to focus on the relationship between CM proliferation and heart protection in children. We are hopeful that this research will provide a platform from which the potential pediatric heart failure therapies may be further investigated. When considering the effects of hypoxia, the role of hypoxia-inducible factor 1 alpha must be considered. As expected, higher expression of hypoxia-inducible factor 1 alpha was found in the severe hypoxia group (Supplemental Figure S1 ); however, it has not been positively correlated with CM proliferation rate. The role of hypoxia-inducible factor-1 alpha in the regulation of CMs proliferation is complex. Paradis et al. (11) showed that when neonatal rat hearts were exposed to hypoxia in vivo, there was a significant increase in hypoxiainducible factor-1 alpha protein but CMs proliferation was inhibited. Their results showed that in this process, endothelin-1 might be the major responsive factor. In contrast, Kimura et al. (39) showed that stabilization of hypoxia-inducible factor-1 alpha was Ye et al. Ye et al. This study assessed the regional changes in myocardial geometry, microstructure, mechanical behavior, and properties that occur in response to progressive left ventricular pressure overload (LVPO) in a large animal model. Using an index of local biomechanical function at early onset of LVPO allowed for prediction of the magnitude of left ventricular chamber stiffness (Kc) and left atrial area at LVPO late timepoints. Our study found that LV myocardial collagen content alone was insufficient to identify mechanisms for LV myocardial stiffness with progression to heart failure with preserved ejection fraction (HFpEF). Serial assessment of hypertrophy with stable EF but with evidence for impaired diastolic function that was consistent with the clinical phenotype of HFpEF (22) . The central hypothesis of this study was that LV myocardial remodeling in response to progressive LVPO is characterized by an increase in LV myocardial collagen content and a change in collagen fiber microstructure, which together will affect both regional LV myocardial mechanical properties and LV chamber stiffness. To test this hypothesis, we developed and deployed novel and innovative approaches based on noninvasive imaging to assess LV regional diastolic function together with advanced optical analysis of LV myocardial collagen microstructure. We used ob- were then computed as: where Dt is the relative time in the cardiac cycle. LV REGIONAL LV MYOCARDIAL WALL STRESS. We modified a thick-walled ellipsoidal model proposed by Janz (42) to compute regional LV myocardial wall stress in the circumferential and longitudinal directions. The regional circumferential LV myocardial wall stress ðs C Þ was computed as: where r is the inner radius, t is the regional wall thickness, and P is LV pressure. For the purposes of this study, LV pressure was assumed to equal zero at the onset of diastole. An estimated value at end-diastole (described in the following) regional longitudinal LV myocardial wall stress ðs L Þ was computed as: where F is the angle between the normal vector from the endocardium at the region of interest and the axis of revolution in the truncated ellipsoid model. Obtained values for regional LV myocardial wall stress and segmental myocardial strain at the onset of diastole and at end-diastole enabled calculation of regional LV diastolic myocardial stiffness in both the circumferential and longitudinal directions. The slope of the line between these 2 points in the stressstrain plane, developed in the defined anatomical regions, was used to compute the regional LV diastolic myocardial stiffness (k MR ) as: where s ED and ε D0 are the regional end-diastolic LV myocardial wall stress and LV segmental myocardial strain at the onset of diastole, respectively (39) . sure, a surrogate for P ED , was measured using conventional methods (43) . Data were used to identify an expression for noninvasive estimation of LV enddiastolic pressure, specifically P ED ¼ 1:88e 0:16ðLA areaÞ (r 2 ¼ 0.91), which was subsequently applied across the study groups. This pressure estimation was used to compute a noninvasive measure of LV chamber stiffness (K Ã C ) as follows (39): After data acquisition was complete, the digitized LV pressure and dimension data were aligned using the R-wave of the simultaneously recorded electrocardiogram from each modality. The aligned data for the steady-state and caval occlusion cardiac cycles were then used to compute the regional LV myocardial stiffness constants (k MR ) and LV chamber stiffness (K C ), respectively (45, 46) . In addition, data were processed to compute classic indexes of LV systolic function and LV diastolic function using established methods (47) (48) (49) . SHG IMAGING. LV myocardial collagen microstructure was analyzed in subset of the referent control Thus, with LVPO, significant LV hypertrophy and LA dilation occurred over and above that of normal growth. As expected, LV peak systolic pressure was increased at 4 and 5 weeks post-LVPO ( Table 1) . Additional indexes of LV pump function (LVEF shown in Figure 2B ), such as stroke work and LV pressure development (þdP/dt), either increased or remained unchanged from the referent control values ( Table 1) . Load-independent indexes of LV function such as pre-load recruitable stroke work (PRSW) and endsystolic elastance followed a similar pattern ( Table 1) . LV end-diastolic pressure was increased from referent control values at 4 and 5 weeks post-LVPO ( Table 1 ) and paralleled the relative magnitude in LA area at these timepoints ( Figure 2D) Torres et al. where K Ã C;pred: is the predicted percent increase in chamber Abbreviations as in Figure 1 . Other abbreviation as in Figure 1 . Torres et al. HFpEF is a specific HF phenotype that afflicts millions of patients annually, although specific and effective therapeutic strategies have not been forthcoming (1, 2, 61) . This issue is also compounded by the fact that the indexes of LV function that contribute to the development and progression of HFpEF require specific measures of LV myocardial diastolic performance (20, 21) . The present study addressed these issues by Although past clinical studies suggested that HFpEF is accompanied by a reduction in LV global longitudinal myocardial strain, the present study (along with others) observed modest, if any, early changes in regional or global myocardial strain and diastolic strain rate (27, 29, 62, (66) (67) (68) . In addition to LV regional strain measurements, the present study examined several indexes of LV systolic function. Overall, these measurements, such as EF and stroke work, were either preserved or modestly changed with progressive LVPO. Load-independent measures of LV function, such as PRSW and end-systolic elastance, followed a similar trend. Thus, using multiple approaches, this model of LVPO was shown to not to be associated with a compromise in LV pump function or systolic performance. The relative increase in load-independent indexes of LV function, such as PRSW, were likely due to the increased LV mass, and as such, increased mass of contractile units. The present study also identified that LV myocardial collagen fiber realignment occurred as a function of time with LVPO, which further supported the concept that the microarchitecture of the assembled collagen fibers with LVPO was abnormal. However, it must be recognized that past studies with LVPO identified significant shifts in myocyte cytoarchitecture, such as titin, which were associated with changes in LV myocardial stiffness properties (83) . Although examined only at the transcriptional level, the present study identified that titin mRNA was The present study, using STE, provided a serial method for assessing regional LV myocardial stiffness, but future work will be required to examine Krebs-Henseleit solution containing (in mM) 118 NaCl, 4. Hearts from ex vivo studies were sliced longitudinally, halfway between the anterior and posterior sides. One-half of the heart was preserved in 10% formalin and stained with Masson's trichrome to visualize collagen deposition. WESTERN BLOTTING. Hearts from ex vivo studies were sliced longitudinally, halfway between the anterior and posterior sides. LV tissue from one-half Oxytocin Network Improves Cardiac Function in HF Pressure overload-induced HF was initiated in another group of animals using a TAC procedure to initiate progression to HF (11) . In TAC animals, the photostimulated release of OXT, as detected by OXTsensitive CHO cells, was significantly diminished at 6 and 10 weeks post-TAC ( Figures 1B and 1C) . Oxytocin Network Improves Cardiac Function in HF Figure 3C ). The survival rate in TAC animals 16 weeks post-TAC was 50% and was significantly increased to 66% and 70%, respectively, in the earlyand late-treatment animals ( Figure 3C ). Contractility and relaxation were measured as the maximum and minimum values of the first derivative of the LVDP waveform, respectively, to assess inotropy and lusitropy, as we have previously described (16) . TAC significantly impaired LVDP, and PVN OXT treatment attenuated this dysfunction ( Figure 4A) . Similarly, cardiac contractility and relaxation ( Figures 4B and 4C) were significantly compromised in TAC compared with Sham animals; however, Shamand PVN-treated animals did not vary significantly. Parasympathetic activity to the heart originates in the brainstem and acts to reduce heart rate (18) HIGHLIGHTS SARS-CoV-2, the virus that causes COVID-19, is a novel CoV that infects humans by binding to ACE2, which degrades angiotensin II, and hence plays a critical role in modulating the renin angiotensin system (RAS). The emerging epidemiology of COVID-19 suggests that patients with cardiovascular risk factors, including older age, cardiovascular disease, or cancer may be more susceptible to infection and suffer from worse clinical outcomes. Because of the limited understanding with respect to the interaction of RAS inhibitors and SARS-CoV-2 infectivity, we endorse current society recommendations to continue RAS antagonists for clinical indications for which these agents are known to be beneficial. Treatments for COVID-19 that are undergoing clinical trials range from therapies that block the entry of SARS-CoV-2 into host cells, to repurposed antiviral therapies such as protease inhibitors and nucleoside analogs that block viral replication by inhibiting viral RNA-dependent RNA polymerase. The coronavirus disease-2019 (COVID-19) pandemic has resulted in a proliferation of clinical trials designed to slow the spread of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Many therapeutic agents that are being used to treat patients with COVID-19 are repurposed treatments for influenza, Ebola, or for malaria that were developed decades ago and are unlikely to be familiar to the cardiovascular and cardio-oncology communities. Here, the authors provide a foundation for cardiovascular and cardio-oncology physicians on the front line providing care to patients with COVID-19, so that they may better understand the emerging cardiovascular epidemiology and the biological rationale for the breadth of information that is emerging, we will not discuss the role of vaccines. The current impact of the novel CoV, SARS-CoV-2 is unquantifiable. Patients with cancer who were recently treated with chemotherapy or surgery were also more likely to suffer from clinically severe adverse events. However, there is a critical need for additional studies to validate these early observations. CoVs represent a large family of hundreds of envel- (16, 17) and is composed of a short intracellular tail, a transmembrane anchor, and a large ectodomain that consists of a receptor binding S1 subunit and a membrane-fusing S2 subunit (16) . Given that far more is known with respect to the virology of SARS-CoV than of SARS-CoV-2, and given that these 2 CoVs appear to have some overlapping biology and clinical presentations, we will discuss these 2 viruses together, with an emphasis on the most recent studies that have revealed unique biological aspects of SARS-CoV-2. We will review viral attachment, entry, and replication of SARS-CoV and SARS-CoV-2 in host cells. This discussion will be integrated with a review of the ongoing clinical trials that target these different aspects of the biology of SARS-CoV-2 (see Tables 1 to 5) . receptors (19) . ACE, however, has not been implicated in the entry of human CoVs into cells. ACE2 is highly expressed in the mouth, tongue, and types I and II alveolar epithelial cells in the lungs. Table 1) . Relevant to this discussion, the ACE inhibitors in clinical use do not directly affect ACE2 activity (27) . The biological significance of circulating sACE2 is not known. Of note, sACE2 retains its ability to bind the S protein of SARS-CoV and was shown to prevent entry of SARS-CoV into cells in vitro (28) . Thus, sACE2 may act as a decoy receptor that prevents SARS-CoV-2 from binding to ACE2 on the cell surface. APN01 is a human recombinant sACE2 that has been shown to block the early stages of SARS-CoV-2 infections in cell culture and human tissue organoid cultures (29) . APN01 has already undergone safety and tolerability testing in a phase II trial of healthy volunteers (NCT00886353), but at the time of this writing is not being tested clinically in patients with COVID-19. The recognition that many patients with COVID-19 have underlying medical conditions that are treated with ACE inhibitors and AT1 receptor antagonists (30) , coupled with the knowledge that higher urinary ACE2 levels have been observed in patients treated with AT1 receptor antagonists (26) , has given rise to the concern that pharmacologic up-regulation of analog that exhibits broad antiviral activity. Remdesivir is a prodrug that is metabolized to its active form Interestingly, the protease activity of the CoV receptors, ACE2, DPP4, and APN, does not seem necessary for membrane fusion (14) . infection, are all known to employ ACE2 as a receptor (3, 4, 16, 17) . Given the functions of ACE2 in the car- Another relevant feature of the Ace2 gene expression is its encoding on the X chromosome, which may account for possible sex differences observed in the epidemiology of COVID-19 (25) . In animal models of acute respiratory distress syndrome (ARDS), due to chemical pneumonitis, overwhelming sepsis, endotoxemia, or influenza, Ace2 KO mice have more severe acute lung injury (ALI) relative to their wild-type counterparts as evaluated histologically and by measures of elastance (26) (27) (28) . The phenotype of increased elastance was rescued by administration of recombinant human ACE2, which affirms a causal link between Ace2 deficiency and a more profound state of ALI (26, 28) . Additionally, the administration of losartan, an angiotensin II type 1 receptor (AT 1 R) blocker mitigated the exacerbating effects of SARS-CoV S protein in an animal model of ARDS (29) . Losartan also abrogated the severity of ALI due to influenza in mice (27, 28) . In regard to the counter-regulatory properties of ACE1 and ACE2, the effects of Ace2 deficiency appear to be rescued by Ace1 deficiency in mice. For example, Ace2 KO mice demonstrated more severe ALI than did Ace2 KO ;Ace1 þ/mice, with further reduction in severity observed in Ace2 KO ;Ace1 -/mice (26) . This dose-responsiveness also implies causation. Comparable effects were seen with myocardial dysfunction, as Ace2 KO ;Ace1 þ/and Ace2 KO ;Ace1 -/mice had no evidence of the contractile deficit observed in Ace2 KO mice (30) . Of note, however, in each of the previous cases, the animal models were constitutive knockout systems (rather than lineage-specific or inducible knockout (48) . ARDS tends to occur w1 to 2 weeks into illness and is often precipitous and protracted (51, 53, 57) . For these reasons, and to avoid risk of provider infection with emergent intubation, professional societies recommend early intubation in the event of respiratory decline (41) . Intubation was required in 10% to 33% in the various Chinese series; however, rates of high-flow nasal cannula and noninvasive mechanical ventilation also were high (35, (51) (52) (53) (58) . R e n a l i n j u r y . Estimates vary as to the incidence of AKI in COVID-19, ranging between 0.5% and 15% (35, 48, 52, 53, 56, 59) . Among hospitalized patients, the rates of proteinuria (43.9%) and hematuria (26.7%) appear to be even higher (59) . AKI occurs in the first few days after admission in patients with baseline chronic kidney disease, and after 7 to 10 days in patients with normal baseline renal function (59) . Mechanisms of renal injury have been hypothesized to include both acute tubular necrosis, direct cytotoxic effects of the virus itself, and immune-mediated damage (59) . L i v e r i n j u r y . Transaminitis is common, with an incidence of 21% to 37%, and as high as 48% to 62% of patients who are critically ill or who do not survive (35, 48, 53 The reported rate of cardiac injury varies between studies, from 7% to 28% of hospitalized patients, a number that is likely partially dependent on the definition used and the severity of cases at the hospital from which the data were drawn (52) (53) (54) 56) . Notably, patients with evidence of cardiac injury tend to be older, with more comorbidities, including baseline hypertension, diabetes, coronary heart disease, and heart failure (54, 56) . Across all studies, cardiac injury is associated with worse outcomes, including ICU admission and death (52) (53) (54) 56) . Based on serial assessment of troponin, researchers in China reported that the median time to the development of acute cardiac injury was 15 (IQR: 10 to 17) days after illness onset, occurring after the development of ARDS (53) . Of note, early cardiac injury has been reported, even in the absence of respiratory symptoms (60) . In a case series by Shi et al. (56) , the mortality rate for those hospitalized with subsequent evidence of cardiac injury was significantly higher than for those without cardiac injury (51.2% vs. 4.5%; p < 0.001) and, along with ARDS, was an independent predictor of death. The magnitude of troponin elevation correlates modestly with the degree of high-sensitivity CRP (hsCRP) elevation (54) . Dynamic increases in troponin were associated with a higher mortality rate (54, 61) . Importantly, the mechanism of cardiac injury may be multifactorial, including demand ischemia, toxicity from direct viral injury, stress, inflammation, microvascular dysfunction, or plaque rupture, as discussed subsequently (Central Illustration). Heart failure, cardiogenic shock, and myocarditis. Heart failure and myocardial dysfunction have been described in COVID-19 (53, 55, 58, 60, 63) . In a case se- 95% CI: 1.9 to 9.5; and OR: 7.9; 95% CI: 3.7 to 16.7, respectively) (56) . However, it should be noted that both of these complications tend to occur in older individuals (56, 73) . (96) . However, there is historical precedent for an association between infection and an elevated risk of ACS. Epidemiologic studies have shown that hospitalization for pneumonia is associated with a higher risk for atherosclerotic events (97) . Influenza infection has been well studied and shown to have a temporal association with cardiovascular complications and ACS (98, 99) . Annual vaccination against seasonal influenza was associated with a 36% lower rate of major adverse cardiovascular events in a metaanalysis of clinical trials evaluating this question (98) . Therefore, viral infection is associated with an increased risk for coronary events and prevention with a reduction in this risk. Therefore, it is plausible that ACS will also be an important cause of acute cardiac injury in patients with COVID-19. Accordingly, international societies have devised pathways and protocols to effectively treat COVID-19 patients with ACS, including appropriate and timely use of resources to ensure the best outcome for the patient while also maintaining provider safety (100) . patients, an entity that confers poorer prognosis (108) (109) (110) . The mechanism of such myocardial injury is thought to be related to a mismatch between oxygen supply and demand, without acute atherothrombotic plaque disruption, and consistent with a diagnosis of type 2 MI (101, 111) . Indeed, patients who suffer from type 2 MI compared with type 1 MI have higher mortality rates, which may in part be explained by a higher burden of acute and chronic comorbid conditions in the type 2 MI population (112) . Furthermore, type 2 MI on the background of coronary artery disease (CAD) has a worse prognosis than those patients without CAD. Given the age and comorbidity profile of patients hospitalized with severe COVID-19, it is reasonable to assume that this population has a higher risk of underlying nonobstructive CAD; therefore, the presence of type 2 MI in this population is likely a marker of and contributor to the poor outcomes of COVID-19 patients with troponin elevations (56) . Prior studies have shown that cardiomyopathy in sepsis is partially mediated by inflammatory cytokines such as TNF-a, IL-6, IL-1b, interferon gamma, and IL-2 (73) . Recombinant TNF-a resulted in an early and sustained left ventricular systolic dysfunction in canines (118) . Cultured rat cardiomyocytes demonstrated reduced contractility when exposed to IL-6 (119). The mechanism may be through modulation of calcium-channel activity with resultant myocardial dysfunction (120) (121) (122) . Additionally, nitric oxide is believed to be a mediator of myocardial depression in hyperinflammatory states such as sepsis. Seminal studies found that medium from lipopolysaccharideactivated macrophages suppressed myocyte contractility, a finding reversed with the nitric oxide synthase inhibitor L-N-monomethyl arginine (123) . The most widely applied agent in this class against SARS-CoV-2 has been remdesivir (126) . Remdesivir functions as a chain terminator of RNA replication, initially designed for use against Ebola (125) . Addition of remdesivir to the growing RNA strand by RdRp blocks the incorporation of additional nucleotides, thereby halting genome replication (127, 128 Another nucleotide analog for the disruption of RdRp-dependent viral replication is favipiravir, which has investigational approval in several countries (129, 130) . Additional agents that are under study include emtricitabine or tenofovir and ribavirin (129, 131) . Although the results of this trial were met with disappointment, this negative study should not forestall trials and drug development of protease inhibitors as a therapeutic class, given that this drug was not specifically designed for SARS-CoV-2 (129). Indeed, the development of inhibitors specific to SARS-CoV-2 main protease is underway. A class of agents identified using structure-based drug design, a-ketonamide inhibitors, has demonstrated in vitro efficacy and favorable pharmacokinetics (133) . Other candidate protease inhibitors for SARS-CoV-2 include danoprevir, a drug originally intended for hepatitis C virus therapy (134) . In order for the viral genome to gain access to cellular machinery for replication, a membrane fusion event must occur between the viral and endosomal membranes, which are noncovalently bound by the interaction between the S protein and ACE2. The exact mechanism of membrane fusion is unknown but appears to be dependent on endosomal maturation and a membrane-bound host protease, TMPRSS2 (7) . It is unclear whether differences in the S proteins of SARS-CoV-1 and SARS-CoV-2 may limit the effectiveness of antibodies cloned from patients convalescent to SARS-CoV-1 (9) . Synthetic antibodies represent an exciting, novel therapeutic avenue. One strategy being explored is to fuse ACE2 to fragment crystallizable region immunoglobulin G, with the hypothesis that this synthetic antibody would serve as a decoy receptor, preventing cellular binding of the virion (144). In a similar vein, studies are ongoing of decoy proteins that are designed to act as viral "sinks." There is preliminary success with this strategy using soluble human ACE2 (34) (Central Illustration). ANTI-INFLAMMATORY THERAPY. Advanced stages of COVID-19 have been likened to cytokine storm syndromes with nonspecific widespread immune activation (115) . Elevated levels of inflammatory biomarkers, such as IL-6 and hsCRP, identify patients at high risk of progressing to severe disease and death (53) . Immunomodulatory and anti-inflammatory therapy have been used, despite limited data, in patients with evidence of hyperinflammation in an effort to curb pathologic immune activation. A z i t h r o m y c i n . Azithromycin, a macrolide antibiotic, has long been touted for its anti-inflammatory effect and has been used as adjunctive therapy in treatment of community acquired pneumonia and chronic obstructive pulmonary disease exacerbations (148) . Limited data suggest that adjunctive azithromycin in moderate-to-severe ARDS is associated with improved outcomes (149) . A small nonrandomized study showed that combination azithromycin and HCQ was associated with more effective SARS-CoV-2 clearance in COVID-19 patients compared with either monotherapy with HCQ or standard of care; however, numerous limitations of this study render the data uninterpretable (141) . shock from a non-COVID-19 etiology). A random system (e.g., lottery) should be used to break "ties" in cases with a similar estimated prognosis, rather than a first come, first serve approach. Importantly, many advocate that an independent triage physician make the determination to remove the burden from the bedside health care team. The triage physician may be supported, as necessary, by a triage committee, comprising experts in the area of ethics and relevant medical fields. Areas of controversy include whether there should be priority allowed for health care providers. Some ethicists argue that they should not be prioritized as that are unlikely to recovery in a time frame that would allow them to continue their professional responsibilities (164) . Others argue that granting priority recognizes the assumption of risk and also encourages ongoing participation in patient care (161) . Along the same line, an argument has also been made to prioritize research participation (161) . The optimal tool for prognostication also remains elusive. The SOFA score has been suggested as quantitative assessment of acute illness severity; however, there is a recognition that this tool may not be well calibrated to all populations and could lead to inaccurate assessments of prognosis (166, 167) . The Heart in COVID-19 Primary Target This diagram depicts how inflammatory infectious processes in remote locations including the lungs can produce systemic effects that can promote atherothrombotic events and myocardial ischemia and also evoke "echoes" within the plaque itself that can predispose toward plaque disruption or acute progression of the disease. Reproduced with permission from Libby et al. (5) . Not all rises in this biomarker of cardiac injury will Since the COVID-19 outbreak, there has been an urgent need for effective treatments. A wide spectrum of disease severity has been described, ranging from asymptomatic, to mildly symptomatic, to severe symptomatic requiring hospitalization, to respiratory failure from acute respiratory distress syndrome. Furthermore, it has been widely reported that the prevalence of the disease is almost 3 times higher in male patients. Overall, this evidence suggests that the prognosis appears to be more condi- The pathogenesis of cardiac fibrosis Fibrosis in heart disease: understanding the role of transforming growth factor-beta in cardiomyopathy, valvular disease and arrhythmia Cardiac fibrosis: the fibroblast awakens Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease Cardiac fibrosis: potential therapeutic targets The detection of myocardial fibrosis: an opportunity to reduce cardiovascular risk in patients with diabetes mellitus? Circ Cardiovasc The dynamic role of cardiac fibroblasts in development and disease Developmental heterogeneity of cardiac fibroblasts does not predict pathological proliferation and activation Latent TGF-bbinding proteins Cartilage oligomeric matrix protein and its binding partners in the cartilage extracellular matrix: interaction, regulation and role in chondrogenesis A novel cartilage protein (Cilp) present in the mid-zone of human articular cartilage increases with age Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Publicationready Volcano Plots With Enhanced Colouring and Labeling. R Package Version 120 TGFb: the master regulator of fibrosis TGF-beta 1 stimulates cultured human fibroblasts to proliferate and produce tissue-like fibroplasia: a fibronectin matrixdependent event Origin of cardiac fibroblasts and the role of periostin Small animal models of heart failure: development of novel therapies, past and present Organization of fibroblasts in the heart 20-year survival of children born with congenital anomalies: a population-based study The incidence of congenital heart disease Congenital heart disease: the original heart failure syndrome The low triiodothyronine syndrome: a strong predictor of low cardiac output and death in patients undergoing coronary artery bypass grafting Cardiomyocytes in young infants with congenital heart disease: a three-month window of proliferation Decreased Yes-associated protein-1 (YAP1) expression in pediatric hearts with ventricular septal defects Heart disease and stroke statistics'2017 update: a report from the American Heart Association Systolic and diastolic heart failure in the community Diastolic and systolic heart failure: different stages or distinct phenotypes of the heart failure syndrome? New concepts in diastolic dysfunction and diastolic heart failure: part II. Causal mechanisms and treatment In vivo assessment of regional mechanics postmyocardial infarction: a focus on the road ahead Structure and mechanics of healing myocardial infarcts Stress-modulated growth, residual stress, and vascular heterogeneity Perspectives on biological growth and remodeling Stress-driven collagen fiber remodeling in arterial walls Biomechanics of growth, remodeling, and morphogenesis Stress, strain, growth, and remodeling of living organisms Utilizing NT-proBNP for Eligibility and Enrichment in Trials in HFpEF, HFmrEF, and HFrEF Microtubule depolymerization normalizes in vivo myocardial contractile function in dogs with Imaging and impact of myocardial fibrosis in aortic stenosis Regulation of coronary blood flow in health and ischemic heart disease Diversity of oxytocin neurones: beyond magno-and parvocellular cell types? Oxytocin specifically enhances valence-dependent parasympathetic responses Oxytocin increases autonomic cardiac control: moderation by loneliness Benefits of oxytocin administration in obstructive sleep apnea Heart disease and stroke statistics: 2016 update Defective cardiac parasympathetic control in patients with heart disease Autonomic pathophysiology in heart failure patients: sympathetic-cholinergic interrelations Vagus nerve stimulation: a new approach to reduce heart failure Time course of sympathovagal imbalance and left ventricular dysfunction in conscious dogs with heart failure Respiratory-related heart rate variability in progressive experimental heart failure ventricular hypertrophy-induced heart failure Oxytocin neuron activation prevents hypertension that occurs with chronic intermittent hypoxia/hypercapnia in rats Functional response of the isolated, perfused normoxic heart to pyruvate dehydrogenase activation by dichloroacetate and pyruvate Physiological response of cardiac tissue to bisphenol A: alterations in ventricular pressure and contractility Visualization of oxytocin release that mediates paired pulse facilitation in hypothalamic pathways to brainstem autonomic neurons The prognostic value of heart rate recovery in patients with coronary artery disease: a systematic review and meta-analysis Neurotransmitter control of sinoatrial pacemaker frequency in isolated rat atria and in intact rabbits Vagal modulation of epicardial coronary artery size in dogs: a two-dimensional intravascular ultrasound study Acetylcholine causes coronary vasodilation in dogs and baboons Parasympathetic vagal control of cardiac function Optogenetic approaches to characterize the long-range synaptic pathways from the hypothalamus to brain stem autonomic nuclei Structural remodeling in hypertensive heart disease and the role of hormones Development of cardiac failure by coronary small vessel disease in hypertensive heart disease? Cardiac excitation-contraction coupling Beta 1-and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure Sympathetic activation in heart failure and its treatment with beta-blockade Muscarinic regulation of cardiac ion channels Vasoactive intestinal peptide: cardiovascular effects The sympathetic/parasympathetic imbalance in heart failure with reduced ejection fraction Activation of oxytocin neurons improves cardiac function in a pressure overload model of heart failure Neural regulation of endocrine and autonomic stress responses Chronic activation of hypothalamic oxytocin neurons improves cardiac function during left ventricular hypertrophy-induced heart failure Oxytocin increases autonomic cardiac control: moderation by loneliness Understanding the relationship between heart failure and osteoporosis-related fractures The Covid-19 Tracker for the China Medical Treatment Expert Group for COVID-19. Clinical characteristics of coronavirus disease 2019 in China Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China The novel coronavirus disease The heart in COVID19: primary target or secondary bystander? Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19) Pathological findings of COVID-19 associated with acute respiratory distress syndrome Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis Donor heart selection during the COVID-19 pandemic: a case study Dilemma of organ donation in transplantation and the COVID-19 pandemic Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China Emerging coronaviruses: genome structure, replication, and pathogenesis Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation One protein to rule them all: modulation of cell surface receptors and molecules by HIV Nef Neurohormonal activation in heart failure with reduced ejection fraction Contractile responses of isolated adult rat and rabbit cardiac myocytes to isoproterenol and calcium Angiotensin-converting enzyme 2 protects from severe acute lung failure A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor ADAM-17: the enzyme that does it all Proteolytic activation of the SARScoronavirus spike protein: cutting enzymes at the cutting edge of antiviral research Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical grade human ACE2 Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Reninangiotensin-aldosterone system inhibitors in patients with Covid-19 HFSA/ACC/ AHA Statement Addresses concerns Re: Using RAAS Antagonists in COVID-19. Latest in Cardiology How viruses invade cells Simultaneous treatment Aprotinin and similar protease inhibitors as drugs against influenza Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Drugs that may cause or exacerbate heart failure: a scientific statement from the American Heart Association WHO launches a global megatrial of the four most promising coronavirus treatments Amiodarone and metabolite MDEA inhibit Ebola virus infection by interfering with the viral entry process Amiodarone alters late endosomes and inhibits SARS coronavirus infection at a post-endosomal level ACE2: from vasopeptidase to SARS virus receptor Coronaviruses: an overview of their replication and pathogenesis Broadspectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses Discovering drugs to treat coronavirus disease 2019 (COVID-19) A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19 Treatment of SARS with human interferons The antiviral effect of interferon-beta against SARS-coronavirus is not mediated by MxA protein Pegylated interferon-alpha protects type 1 pneumocytes against SARS coronavirus infection in macaques for the MIRACLE Trial Group. Treatment of Middle East respiratory syndrome with a combination of lopinavir-ritonavir and interferon-beta1b (MIRA-CLE trial): study protocol for a randomized controlled trial COVID-19: consider cytokine storm syndromes and immunosuppression Interleukin-6 in COVID-9: a systematic review and meta-analysis Chimeric antigen receptor T-cell therapy-assessment and management of toxicities CAR T cell therapy-related cardiovascular outcomes and management: systemic disease or direct cardiotoxicity? American Society for Blood and Marrow Transplantation Pharmacy Special Interest Group survey on chimeric antigen receptor T cell therapy administrative, logistic, and toxicity management practices in the United States Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury Coronaviruses: an overview of their replication and pathogenesis A novel coronavirus from patients with pneumonia in China Origin and evolution of pathogenic coronaviruses A pneumonia outbreak associated with a new coronavirus of probable bat origin A new coronavirus associated with human respiratory disease in China Identification and characterization of severe acute respiratory syndrome coronavirus replicase proteins SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor The spike protein of SARS-CoV-a target for vaccine and therapeutic development Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2 Structural basis of receptor recognition by SARS-CoV-2 The M, E, and N structural proteins of the severe acute respiratory syndrome coronavirus are required for efficient assembly, trafficking, and release of virus-like particles Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein Membrane ectopeptidases targeted by human coronaviruses Expression, purification, and characterization of SARS coronavirus RNA polymerase Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus Replication-dependent downregulation of cellular angiotensin-converting enzyme 2 protein expression by human coronavirus NL63 Reninangiotensin-aldosterone system inhibitors in patients with Covid-19 Coronavirus disease 2019 (COVID-19) and cardiovascular disease Does the angiotensin-converting enzyme (ACE)/ACE2 balance contribute to the fate of angiotensin peptides in programmed hypertension? Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease The emerging role of ACE2 in physiology and disease Hydrolysis of biological peptides by human angiotensinconverting enzyme-related carboxypeptidase Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis A novel coronavirus outbreak of global health concern Angiotensinconverting enzyme 2 protects from severe acute lung failure Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury Angiotensin-converting enzyme 2 is an essential regulator of heart function Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2) Angiotensin-converting enzyme 2 inhibits lung injury induced by respiratory syncytial virus A pilot clinical trial of recombinant human angiotensinconverting enzyme 2 in acute respiratory distress syndrome Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2 Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1 Public health responses to COVID-19 outbreaks on cruise ships -worldwide Detection of SARS-CoV-2 in different types of clinical specimens Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19) Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2) The coronavirus pandemic in five powerful charts Presymptomatic transmission of SARS-CoV-2 -Singapore Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention Severe outcomes among patients with coronavirus disease 2019 (COVID-19) -United States Defining the epidemiology of Covid-19 -studies needed Clinical characteristics of coronavirus disease 2019 in China The incubation period of coronavirus disease from publicly reported confirmed cases: estimation and application Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington State Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Kidney disease is associated with in-hospital death of patients with COVID-19 Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19) Atherogenic diets enhance endotoxinstimulated interleukin-1 and tumor necrosis factor gene expression in rabbit aortae The cardiovascular manifestations of influenza: a systematic review Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study Pulmonary pathology of severe acute respiratory syndrome in Toronto Clinical pathology of critical patient with novel coronavirus pneumonia (COVID-19). Preprints COVID-19 and coagulopathy: frequently asked questions Likelihood of survival of coronavirus disease 2019 Estimates of the severity of coronavirus disease 2019: a model-based analysis Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy Disparities in age-specific morbidity and mortality from SARS-CoV-2 in China and the Republic of Korea Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro myocardial cell depression induced by human septic shock serum SARScoronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases The clinical pathology of severe acute respiratory syndrome (SARS): a report from China Virus-induced systemic vasculitides: new therapeutic approaches Vasculitides secondary to infections Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia The coagulopathy of acute sepsis Activation of coagulation after administration of tumor necrosis factor to normal subjects Activation of coagulation by administration of recombinant factor VIIa elicits interleukin 6 (IL-6) and IL-8 release in healthy human subjects The in vivo kinetics of tissue factor messenger RNA expression during human endotoxemia: relationship with activation of coagulation Bidirectional relation between inflammation and coagulation The protein C pathway and sepsis The tissue factor and plasminogen activator inhibitor type-1 response in pediatric sepsis-induced multiple organ failure Platelets and the innate immune system: mechanisms of bacterial-induced platelet activation Platelet function in septic multiple organ dysfunction syndrome Time course of platelet counts in critically ill patients Thrombocytopenia in sepsis: a predictor of mortality in the intensive care unit Stress cardiomyopathy diagnosis and treatment: JACC State-of-the-Art Review ST-segment elevation in patients with Covid-19 -a case series Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analysis Acute myocardial infarction after laboratoryconfirmed influenza infection Catheterization laboratory considerations during the coronavirus (COVID-19) pandemic: from ACC's Interventional Council and SCAI Inflammation, immunity, and infection in atherothrombosis: JACC Review Topic of the Week Antiinflammatory therapy with canakinumab for atherosclerotic disease Inflammation in atherosclerosis Pneumonia, thrombosis and vascular disease Pathogen recognition and inflammatory signaling in innate immune defenses Inflammasome activation and IL-1beta and IL-18 processing during infection Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link Prognostic impact of myocardial injury related to various cardiac and noncardiac conditions Elevated cardiac troponin measurements in critically ill patients Clinical characteristics and outcomes of patients with myocardial infarction, myocardial injury, and nonelevated troponins Longterm outcomes in patients with type 2 myocardial infarction and myocardial injury Dysregulation of immune response in patients with COVID-19 in Wuhan, China Chimeric antigen receptor-modified T cells for acute lymphoid leukemia COVID-19: consider cytokine storm syndromes and immunosuppression COVID-19 Illness in Native and Immunosuppressed States: A Clinical-Therapeutic Staging Proposal Cytokine release syndrome with chimeric antigen receptor T cell therapy Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock Effects of TNFalpha on [Ca2þ]i and contractility in isolated adult rabbit ventricular myocytes TNF alpha receptor expression in rat cardiac myocytes: TNF alpha inhibition of L-type Ca2þ current and Ca2þ transients Dysregulation of intracellular calcium transporters in animal models of sepsis-induced cardiomyopathy Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophageconditioned medium The role of mitochondria in sepsis-induced cardiomyopathy A randomized, controlled trial of Ebola virus disease therapeutics First case of 2019 novel coronavirus in the United States The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV Coronavirus puts drug repurposing on the fast track Discovering drugs to treat coronavirus disease 2019 (COVID-19) COVID-19: an update on the Epidemiological, Clinical, Preventive and Therapeutic Evidence and Guidelines of Integrative Chinese-Western Medicine for the Management of A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19 Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors First clinical study using HCV protease inhibitor danoprevir to treat naive and experienced COVID-19 patients The anti-HIV-1 activity of chloroquine Anti-HIV effects of chloroquine: mechanisms of inhibition and spectrum of activity Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion Endosome maturation, transport and functions Chloroquine is a potent inhibitor of SARS coronavirus infection and spread Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial A SARS-CoV-2-human protein-protein interaction map reveals drug targets and potential drugrepurposing Treatment of 5 critically ill patients with COVID-19 with convalescent plasma Potent neutralization of 2019 novel coronavirus by recombinant ACE2-Ig Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome The immunomodulatory effects of macrolides-a systematic review of the underlying mechanisms Adjunctive therapy with azithromycin for moderate and severe acute respiratory distress syndrome: a retrospective, propensity score-matching analysis of prospectively collected data at a single center Baricitinib as potential treatment for 2019-nCoV acute respiratory disease Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury Simvastatin decreases lipopolysaccharideinduced pulmonary inflammation in healthy volunteers Simvastatin in the acute respiratory distress syndrome Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial The effect of rosuvastatin on incident pneumonia: results from the JUPITER trial SARS vaccine development Mucosal immunisation of African green monkeys (Cercopithecus aethiops) with an attenuated parainfluenza virus expressing the SARS coronavirus spike protein for the prevention of SARS From SARS to MERS, thrusting coronaviruses into the spotlight The outbreak of SARS-CoV-2 pneumonia calls for viral vaccines Developments in viral vector-based vaccines Fair allocation of scarce medical resources in the time of Covid-19 Clinical ethics recommendations for the allocation of intensive care treatments, in exceptional, resource-limited circumstances Committee on Guidance for Establishing Crisis Standards of Care for Use in Disaster Situations; Institute of Medicine. Crisis Standards of Care: A Systems Framework for Catastrophic Disaster Response Ethical considerations: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement The toughest triage -allocating ventilators in a pandemic Sequential organ failure assessment in H1N1 pandemic planning An assessment of the validity of SOFA score based triage in H1N1 critically ill patients during an influenza pandemic Coronavirus fulminant myocarditis treated with glucocorticoid and human immunoglobulin Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19) COVID-19 for the cardiologist: a state-of-the-art review of the virology, clinical epidemiology, cardiac and other clinical manifestations and potential therapeutic strategies Roles of infectious agents in atherosclerosis and restenosis: an assessment of the evidence and need for future research Inflammation, immunity, and infection in atherothrombosis: JACC Review Topic of the Week Leukocytes link local and systemic inflammation in ischemic cardiovascular disease Bat coronaviruses and experimental infection of bats, the Philippines Dampened NLRP3-mediated inflammation in bats and implications for a special viral reservoir host Mechanism of NLRP3 inflammasome activation Imbalance between interleukin-1b and interleukin-1 receptor antagonist in epicardial adipose tissue is associated with non ST-segment elevation acute coronary syndrome Inhibitory effects of toll-like receptor 4, NLRP3 inflammasome, and interleukin-1b on white adipocyte browning Primitive Early Eocene bat from Wyoming and the evolution of flight and echolocation Airplane tracking documents the fastest flight speeds recorded for bats Enhanced autophagy contributes to reduced viral infection in black flying fox cells The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' in-