Long COVID-19: A Primer for Cardiovascular Health Professionals, on Behalf of the CCS Rapid Response Team.

It is now widely recognized that COVID-19 illness can be associated with significant intermediate and potentially longer-term physical limitations. The term, "long COVID-19" is used to define any patient with persistent symptoms after acute COVID-19 infection (ie, after 4 weeks). It is postulated that cardiac injury might be linked to symptoms that persist after resolution of acute infection, as part of this syndrome. The Canadian Cardiovascular Society Rapid Response Team has generated this document to provide guidance to health care providers on the optimal management of patients with suspected cardiac complications of long COVID-19.

Cardiovascular Care Delivery During the Second Wave of COVID-19 in Canada.

Hospitals and ambulatory facilities significantly reduced cardiac care delivery in response to the first wave of the COVID-19 pandemic. The deferral of elective cardiovascular procedures led to a marked reduction in health care delivery with a significant impact on optimal cardiovascular care. International and Canadian data have reported dramatically increased wait times for diagnostic tests and cardiovascular procedures, as well as associated increased cardiovascular morbidity and mortality. In the wake of the demonstrated ability to rapidly create critical care and hospital ward capacity, we advocate a different approach during the second and possible subsequent COVID-19 pandemic waves. We suggest an approach, informed by local data and experience, that balances the need for an expected rise in demand for health care resources to ensure appropriate COVID-19 surge capacity with continued delivery of essential cardiovascular care. Incorporating cardiovascular care leaders into pandemic planning and operations will help health care systems minimise cardiac care delivery disruptions while maintaining critical care and hospital ward surge capacity and continuing measures to reduce transmission risk in health care settings. Specific recommendations targeting the main pillars of cardiovascular care are presented: ambulatory, inpatient, procedural, diagnostic, surgical, and rehabilitation.

Guiding Cardiac Care During the COVID-19 Pandemic: How Ethics Shapes Our Health System Response.

The COVID-19 pandemic has raised ethical questions for the cardiovascular leader and practitioner. Attention has been redirected from a system that focuses on individual patient benefit toward one that focuses on protecting society as a whole. Challenging resource allocation questions highlight the need for a clearly articulated ethics framework that integrates principled decision making into how different cardiovascular care services are prioritized. A practical application of the principles of harm minimisation, fairness, proportionality, respect, reciprocity, flexibility, and procedural justice is provided, and a model for prioritisation of the restoration of cardiovascular services is outlined. The prioritisation model may be used to determine how and when cardiovascular services should be continued or restored. There should be a focus on an iterative and responsive approach to broader health care system needs, such as other disease groups and local outbreaks.

Cardiac Rehabilitation During the COVID-19 Era: Guidance on Implementing Virtual Care.

Cardiac rehabilitation programs across Canada have suspended in-person services as a result of large-scale physical distancing recommendations designed to flatten the COVID-19 pandemic curve. Virtual cardiac rehabilitation (VCR) offers an alternate mechanism of care delivery, capable of providing similar patient outcomes and safety profiles compared with centre-based programs. To minimize care gaps, all centres should consider developing and implementing a VCR program. The process of this rapid implementation, however, can be daunting. Centres should initially focus on the collation, utilization, and repurposing of existing resources, equipment, and technology. Once established, programs should then focus on ensuring that quality indicators are met and care processes are protocolized. This should be followed by the development of sustainable VCR solutions to account for care gaps that existed before COVID-19, and to improve cardiac rehabilitation delivery, moving forward. This article reviews the potential challenges and obstacles of this process and aims to provide pragmatic guidance to aid clinicians and administrators during this challenging time.

A cost-effectiveness analysis of a proactive management strategy for the Sprint Fidelis recall: a probabilistic decision analysis model.

BACKGROUND: The management of the recall is complicated by the competing risks of lead failure and complications that can occur with lead revision. Many of these patients are currently undergoing an elective generator change--an ideal time to consider lead revision. OBJECTIVE: To determine the cost-effectiveness of a proactive management strategy for the Sprint Fidelis recall. METHODS: We obtained detailed clinical outcomes and costing data from a retrospective analysis of 341 patients who received the Sprint Fidelis lead in British Columbia, where patients younger than 60 years were offered lead extraction when undergoing generator replacement. These population-based data were used to construct and populate a probabilistic Markov model in which a proactive management strategy was compared to a conservative strategy to determine the incremental cost per lead failure avoided. RESULTS: In our population, elective lead revisions were half the cost of emergent revisions and had a lower complication rate. In the model, the incremental cost-effectiveness ratio of proactive lead revision versus a recommended monitoring strategy was $12,779 per lead failure avoided. The proactive strategy resulted in 21 fewer failures per 100 patients treated and reduced the chance of an additional complication from an unexpected surgery. CONCLUSIONS: Cost-effectiveness analysis suggests that prospective lead revision should be considered when patients with a Sprint Fidelis lead present for pulse generator change. Elective revision of the lead is justified even when 25% of the population is operated on per year, and in some scenarios, it is both less costly and provides a better outcome.

Restriction of human immunodeficiency virus type 1 by TRIM-CypA occurs with rapid kinetics and independently of cytoplasmic bodies, ubiquitin, and proteasome activity.

TRIM-CypA is an owl monkey-specific variant of the retrovirus restriction factor TRIM5alpha. Here, we exploit its modular domain organization and cyclosporine sensitivity to probe the kinetics and mechanism of TRIM5-mediated restriction. Time of addition/withdrawal experiments reveal that inhibition of incoming human immunodeficiency virus type 1 capsids by TRIM-CypA occurs within minutes of their delivery to the target cell cytoplasm. However, while TRIM-CypA restriction is partly dependent on a RING domain, restriction occurs independently of the ubiquitin/proteasome system. Moreover, tagged TRIM-CypA proteins can be fully active as restriction factors without forming cytoplasmic bodies.

Human tripartite motif 5alpha domains responsible for retrovirus restriction activity and specificity.

The tripartite motif 5alpha protein (TRIM5alpha) is one of several factors expressed by mammalian cells that inhibit retrovirus replication. Human TRIM5alpha (huTRIM5alpha) inhibits infection by N-tropic murine leukemia virus (N-MLV) but is inactive against human immunodeficiency virus type 1 (HIV-1). However, we show that replacement of a small segment in the carboxy-terminal B30.2/SPRY domain of huTRIM5alpha with its rhesus macaque counterpart (rhTRIM5alpha) endows it with the ability to potently inhibit HIV-1 infection. The B30.2/SPRY domain and an additional domain in huTRIM5alpha, comprising the amino-terminal RING and B-box components of the TRIM motif, are required for N-MLV restriction activity, while the intervening coiled-coil domain is necessary and sufficient for huTRIM5alpha multimerization. Truncated huTRIM5alpha proteins that lack either or both the N-terminal RING/B-Box or the C-terminal B30.2/SPRY domain form heteromultimers with full-length huTRIM5alpha and are dominant inhibitors of its N-MLV restricting activity, suggesting that homomultimerization of intact huTRIM5alpha monomers is necessary for N-MLV restriction. However, localization in large cytoplasmic bodies is not required for inhibition of N-MLV by huTRIM5alpha or for inhibition of HIV-1 by chimeric or rhTRIM5alpha.

Cyclophilin interactions with incoming human immunodeficiency virus type 1 capsids with opposing effects on infectivity in human cells.

Cyclophilin A (CypA) is a peptidyl-prolyl isomerase that binds to the capsid protein (CA) of human immunodeficiency virus type 1 (HIV-1) and by doing so facilitates HIV-1 replication. Although CypA is incorporated into HIV-1 virions by virtue of CypA-Gag interactions that occur during virion assembly, in this study we show that the CypA-CA interaction that occurs following the entry of the viral capsid into target cells is the major determinant of CypA's effects on HIV-1 replication. Specifically, by using normal and CypA-deficient Jurkat cells, we demonstrate that the presence of CypA in the target and not the virus-producing cell enhances HIV-1 infectivity. Moreover, disruption of the CypA-CA interaction with cyclosporine A (CsA) inhibits HIV-1 infectivity only if the target cell expresses CypA. The effect of CsA on HIV-1 infection of human cells varies according to which particular cell line is used as a target, and CA mutations that confer CsA resistance and dependence exert their effects only if target cells, and not if virus-producing cells, are treated with CsA. The differential effects of CsA on HIV-1 infection in different human cells appear not to be caused by polymorphisms in the recently described retrovirus restriction factor TRIM5alpha. We speculate that CypA and/or CypA-related proteins affect the fate of incoming HIV-1 capsid either directly or by modulating interactions with unidentified host cell factors.

Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5alpha.

Mammalian cells express several factors that act in a cell-autonomous manner to inhibit retrovirus replication. Among these are the Friend virus susceptibility factor 1/lentivirus susceptibility factor 1/restriction factor 1 (Ref1) class of restriction factors, which block infection by targeting the capsids of diverse retroviruses. Here we show that lentivirus susceptibility factor 1 and Ref1 are species-specific variants of tripartite interaction motif 5alpha (TRIM5alpha), a cytoplasmic body component recently shown to block HIV-1 infection in rhesus macaque cells, and can indeed block infection by widely divergent retroviruses. Depletion of TRIM5alpha from human cells relieved restriction of N-tropic murine leukemia virus (N-MLV), and expression of human TRIM5alpha in otherwise nonrestricting cells conferred specific resistance to N-MLV infection, indicating that TRIM5alpha is Ref1 or an essential component of Ref1. TRIM5alpha variants from humans, rhesus monkeys, and African green monkeys displayed different but overlapping restriction specificities that were quite accurately predicted by the restriction properties of the cells from which they were derived. All TRIM5alpha variants could inhibit infection by at least two different retroviruses, and African green monkey TRIM5alpha was able to inhibit infection by no less than four divergent retroviruses of human, non-human primate, equine, and murine origin. However, each TRIM5alpha variant was unable to restrict retroviruses isolated from the same species. These data indicate that TRIM5alpha can confer broad innate immunity to retrovirus infection in primate cells and is likely to be an important natural barrier to cross-species retrovirus transmission.

Species-specific tropism determinants in the human immunodeficiency virus type 1 capsid.

Retroviral tropism is determined in part by cellular restriction factors that block infection by targeting the incoming viral capsid. Indeed, human immunodeficiency virus type 1 (HIV-1) infection of many nonhuman primate cells is inhibited by one such factor, termed Lv1. In contrast, a restriction factor in humans, termed Ref1, does not inhibit HIV-1 infection unless nonnatural mutations are introduced into the HIV-1 capsid protein (CA). Here, we examined the infectivity of a panel of mutant HIV-1 strains carrying substitutions in the N-terminal CA domain in cells that exhibit restriction attributable to Lv1 or Ref1. Manipulation of HIV-1 CA could alter HIV-1 tropism, and several mutations were identified that increased or decreased HIV-1 infectivity in a target-cell-specific manner. Many residues that affected HIV-1 tropism were located in the three variable loops that lie on the outer surface of the modeled HIV-1 conical capsid. Some tropism determinants, including the CypA binding site, coincided with residues whose mutation conferred on HIV-1 CA the ability to saturate Ref1 in human cells. Notably, a mutation that reverses the infectivity defect in human cells induced by CypA binding site mutation inhibits recognition by Ref1. Overall, these findings demonstrate that exposed variable loops in CA and a partial CypA "coat" can modulate restriction and HIV-1 tropism and suggest a model in which the exposed surface of the incoming retroviral capsid is the target for inhibition by host cell-specific restriction factors.

A population-based evaluation of a regional asthma education centre.

BACKGROUND: A population-based, ecological evaluation was conducted to determine the impact of a regional asthma education centre on reducing asthma-related morbidity and improving the quality of prescribing. METHODS: The number of emergency department (ED) visits for respiratory-related illness and the prescribing of antiasthmatic medications were monitored during consecutive 18-month pre- and postintervention periods in two communities with similar health care resources. Using defined daily doses, the quality of prescribing was assessed by calculating the ratio of inhaled corticosteroids to inhaled, short-acting beta 2-agonists. RESULTS: The reduction in the rate of respiratory-related ED visits in subjects five to 45 years of age was 410 per 10,000 people and 450 per 10,000 people for the intervention and nonintervention communities, respectively. A significant reduction in the rate of ED visits of 698 per 10,000 people was found for patients aged 35 to 45 years in the intervention community (P<0.05). The reduction achieved statistical significance in the nonintervention community in younger patients: 557 per 10,000 people and 567 per 10,000 people for patients aged five to 14 years and 15 to 24 years, respectively (P<0.05). The ratio of inhaled corticosteroids to inhaled beta 2-agonists increased from 0.47 to 0.78 in the intervention community--a 66% change. However, over the course of the preintervention period, the prescribing ratio was already increasing in this community. The corresponding ratios were 0.47 and 0.53 in the nonintervention community--an increase of 13%. CONCLUSIONS: A conclusive association between the establishment of an asthma education centre and changes in health care use or the quality of prescribing could not be demonstrated.

Capsid-dependent and -independent postentry restriction of primate lentivirus tropism in rodent cells.

Retrovirus tropism can be restricted by cellular factors such as Fv1, Ref1, and Lv1 that inhibit infection by targeting the incoming viral capsid. Here, we show that rodent cells exhibit differential sensitivity to infection by vesicular stomatitis virus G-pseudotyped lentiviruses and that differences between human immunodeficiency virus type 1 and simian immunodeficiency virus (SIVmac) infectivity are sometimes, but not always, governed by determinants in capsid-p2. In at least one case, resistance to SIVmac infection could be eliminated by saturation of target cells with noninfectious SIVmac particles. However, cross-saturation experiments and analysis of Fv1-null cells engineered to express natural or artificial Fv1 proteins revealed that lentivirus restriction in mouse cells is independent of Fv1. Overall, these findings indicate that novel restriction factors in rodents can modulate sensitivity to specific primate lentiviruses.

Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors.

Many mammalian species express restriction factors that confer host resistance to retroviral infection. Here we show that HIV-1 sensitivity to restriction factors is modulated by cyclophilin A (CypA), a host cell protein that binds the HIV-1 capsid protein (CA). In certain nonhuman primate cells, the CA-CypA interaction is essential for restriction: HIV-1 infectivity is increased >100-fold by cyclosporin A (CsA), a competitive inhibitor of the interaction, or by an HIV-1 CA mutation that disrupts CypA binding. Conversely, disruption of CA-CypA interaction in human cells reveals that CypA protects HIV-1 from the Ref-1 restriction factor. These findings suggest that HIV-1 has co-opted a host cell protein to counteract restriction factors expressed by human cells and that this adaptation can confer sensitivity to restriction in unnatural hosts. Manipulation of HIV-1 CA recognition by restriction factors promises to advance animal models and new therapeutic strategies for HIV-1 and AIDS.

Restriction of multiple divergent retroviruses by Lv1 and Ref1.

The mouse gene Fv1 encodes a saturable restriction factor that selectively blocks infection by N-tropic or B-tropic murine leukemia virus (MLV) strains. Despite the absence of an Fv1 gene, a similar activity is present in humans that blocks N-MLV infection (Ref1). Moreover, some non-human primate cell lines express a potentially related inhibitor of HIV-1 and/or SIVmac infection (Lv1). Here, we examine the spectrum of retrovirus-restricting activities expressed by human and African green monkey cell lines. Human cells restrict N-MLV and equine infectious anemia virus (EIAV), but not HIV-1, HIV-2, SIVmac or SIVagm, whilst AGM cells restrict N-MLV, EIAV, HIV-1, HIV-2 and SIVmac. Remarkably, in each example examined, restriction of infection by a given retrovirus can be abrogated at least partially by saturation with another retrovirus, provided that it is also restricted but regardless of whether it is closely related. These data suggest that restriction factors in human and non-human primate cells are able to recognize and block infection by multiple, widely divergent retroviruses and that the factors themselves may be related.

Cellular inhibitors with Fv1-like activity restrict human and simian immunodeficiency virus tropism.

Many nonhuman primate cells are unable to support the replication of HIV-1, whereas others are nonpermissive for infection by simian immunodeficiency virus from macaques (SIVmac). Here, we show that restricted HIV-1 and SIVmac infection of primate cell lines shares some salient features with Fv1 and Ref1-mediated restriction of murine retrovirus infection. In particular, the nonpermissive phenotype is most evident at low multiplicities of infection, results in reduced accumulation of reverse transcription products, and is dominant in heterokaryons generated by fusion of permissive and nonpermissive target cells. Moreover, in nonpermissive primate cells, HIV-1 and SIVmac infection is cooperative, and enveloped HIV-1 virus-like particles, minimally containing Gag and protease, abrogate restriction. In African green monkey cells, HIV-1 virus-like particles ablate restrictions to HIV-1 and SIVmac, suggesting that both are restricted by the same factor. Finally, a virus that contains an HIV-1 capsid-p2 domain in an SIVmac background exhibits a tropism for primate cells that is HIV-1-like rather than SIVmac-like. These data indicate the existence of one or more saturable inhibitors that are polymorphic in primates and prevent HIV and SIV infection by targeting the capsid of the incoming lentivirus particle.

Pim serine/threonine kinases regulate the stability of Socs-1 protein.

Studies of SOCS-1-deficient mice have implicated Socs-1 in the suppression of JAK-STAT (Janus tyrosine kinase-signal transducers and activators of transcription) signaling and T cell development. It has been suggested that the levels of Socs-1 protein may be regulated through the proteasome pathway. Here we show that Socs-1 interacts with members of the Pim family of serine/threonine kinases in thymocytes. Coexpression of the Pim kinases with Socs-1 results in phosphorylation and stabilization of the Socs-1 protein. The protein levels of Socs-1 are significantly reduced in the Pim-1(-/-), Pim-2(-/-) mice as compared with wild-type mice. Similar to Socs-1(-/-) mice, thymocytes from Pim-1(-/-), Pim-2(-/-) mice showed prolonged Stat6 phosphorylation upon IL-4 stimulation. These data suggest that the Pim kinases may regulate cytokine-induced JAK-STAT signaling through modulation of Socs-1 protein levels.