key: cord-1032008-5lbto0jk
authors: Touyz, Rhian M; Boyd, Marcus OE; Guzik, Tomasz; Padmanabhan, Sandosh; McCallum, Linsay; Delles, Christian; Mark, Patrick B; Petrie, John R; Rios, Francisco; Montezano, Augusto C; Sykes, Robert; Berry, Colin
title: Cardiovascular and renal risk factors and complications associated with COVID-19
date: 2021-06-16
journal: CJC Open
DOI: 10.1016/j.cjco.2021.05.020
sha: b7b0ef4675ebc314ef9497da262bcc59359b7137
doc_id: 1032008
cord_uid: 5lbto0jk

The current COVID-19 pandemic, caused by the SARS-CoV-2 virus (Severe Acute Respiratory Syndrome-Coronavirus-2), represents the largest medical challenge in decades. It has exposed unexpected cardiovascular vulnerabilities at all stages of the disease (pre-infection, acute phase and subsequent chronic phase). The major cardiometabolic drivers identified to have epidemiological and mechanistic associations with COVID-19 are abnormal adiposity, dysglycemia, dyslipidemia, and hypertension. Hypertension is of particular interest, because components of the renin-angiotensin system (RAS), which are critically involved in the pathophysiology of hypertension, are also implicated in COVID-19. Specifically ACE2, a multifunctional protein of the RAS, which is part of the protective axis of the RAS, is also the receptor through which SARS-CoV-2 enters host cells causing viral infection. Cardiovascular and cardiometabolic co-morbidities not only predispose to COVID-19, but are complications of SARS-CoV-2 infection. In addition, increasing evidence indicates that acute kidney injury is common in COVID-19, that it occurs early and in temporal association with respiratory failure and is associated with poor prognosis, especially in the presence of cardiovascular risk factors. Here we discuss cardiovascular and kidney disease in the context of COVID-19 and provide recent advances on putative pathophysiological mechanisms linking cardiovascular disease and COVID-19, focusing on the RAS and ACE2 as well as the immune system and inflammation. We provide up-to-date information on the relationship between hypertension, diabetes, and COVID-19 and emphasize the major cardiovascular diseases associated with COVID-19. We also briefly discuss emerging cardiovascular complications associated with long COVID-19, notably postural tachycardia syndrome (POTS).

The global ramifications of CoronaVIrus Disease-19 , caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus-2)), have been farreaching, impacting the health of millions, straining national healthcare systems worldwide and weakening global economic stability (1,2). Although presenting clinically as a respiratory infection COVID-19 is increasingly being regarded as a systemic disease not solely restricted to the respiratory system. Patients hospitalized for COVID-19 were also found to have increased rates of septic shock, acute kidney injury, rhabdomyolysis and disseminated intravascular coagulation (DIC) (3) .

Moreover, in addition to the lungs, COVID-19 has been found to cause dysfunction of multiple organs affecting the heart, kidneys and liver (4, 5) , and it has also been postulated that SARS-CoV-2 may invade the central nervous system similar to other coronaviruses, although conclusive data are lacking (6) . Emerging evidence clearly indicates complex interactions between COVID-19 and the cardiovascular system, with poorer outcomes for those with underlying comorbidities, and the possibility of direct and long-lasting cardiovascular damage (7, 8) .

Since the identification of SARS-CoV-2 in humans, a multitude of cardiovascular complications including myocardial injury, heart failure, arryhthmias, thromboembolic disease, as well as kidney disease, have been reported, with approximately 1 in 4 patients affected (9,10) (figure 1). Physiological stress due to hypoxia, hypotension and tachycardia; provocation of acute coronary syndromes or arrhythmia; direct viral infiltration; or the effects of systemic inflammation and coagulopathies are implicated.

Additionally, pre-existing coronary artery disease and cardiovascular risk factors such as diabetes, obesity, chronic kidney disease or hypertension are associated with increased risk of severe COVID-19 infection and mortality (11, 12) . These associations have been linked to the important role of angiotensin converting enzyme 2 (ACE2), a component of the renin angiotensin system (RAS), and the receptor through which SARS-CoV-2 mediates infection (13) (14) (15) (16) . The connection between SARS-CoV2 infection and cardiovascular disease is not new as other viruses in the Coronaviridae family including SARS-CoV and Middle East respiratory syndrome (MERS-CoV), have long been known to be associated with myocarditis and heart disease, possibly through ACE2 tropism (17) (18) (19) (20) (21) .

This review provides an overview of cardiovascular, cardiometabolic and kidney diseases as risks associated with COVID-19 and as complications and long-term sequelae of SARS-CoV-2 infection. We also highlight the importance of ACE2, a component of the RAS, and inflammation as key factors in COVID-19-related cardiovascular disease.

ACE2 is a carboxypeptidase that exists in both membrane-bound and soluble forms.

The majority of the protein that comprises the N-terminal domain, including the catalytic site, of membrane-bound ACE2 is oriented extracellularly, with a transmembrane domain anchoring it to the cell membrane. The soluble form of ACE2 is cleaved and shed as the N-terminal ectodomain and is typically found in the circulation at low concentrations, although it may increase under pathological conditions (22) (23) (24) . The primary physiological role of ACE2 in the RAS is its catalytic function to produce angiotensin-(1-9) (Ang-(1-9)) and angiotensin-(1-7) (Ang-(1-7)) from Ang I and Ang II respectively (25) . The major product of ACE2 activity is Ang-(1-7), which binds to the Mas receptor (MasR), inducing vasodilation and antiproliferative, anti-inflammatory, anti-fibrotic, anti-thrombotic, and anti-arrhythmogenic effects that are cardiovascular protective (26) (27) (28) . The sequence of events culminating in MasR activation is referred to as the ACE2-Ang-(1-7)-MasR axis and represents the protective side of the RAS (28) (29) (30) .

COVID-19 is attributed to SARS-CoV2, which uses ACE2 as its host cell entry receptor (31-33) (figure 2). ACE2 is widely expressed and is found in the heart, kidneys, testes, type 2 alveolar epithelial cells of the lung, enterocytes of the small intestine and endothelial and vascular smooth muscle cells of arteries, veins and lymphatics (34, 35) . The tissue distribution of host entry receptors is believed to broadly coincide with viral tropisms, and theoretically SARS-CoV-2 may be able to enter and infect any cell or tissue which expresses ACE2 (36, 37) . However, this notion has been challenged since ACE2-expressing human intestinal cell lines failed to be infected by SARS-CoV (38) . Similar findings have been reported for SARS-CoV-2 where there is a lack of evidence of ACE2 expression and replicative infection in human endothelial cells (39) . Expression of ACE2 alone may not be sufficient for viral infection and other factors, such as TMPRSS2, cathepsin and other proteases and binding proteins may be essential (40, 41) .

While the primary target of SARS-CoV-2 is the respiratory epithelium, there is some evidence that the virus via ACE2, directly invades cardiomyocytes of the heart causing viral myocarditis (42, 43) . Supporting evidence in experimental models showed that pulmonary infection with SARS-CoV resulted in an ACE2-dependent myocardial infection with subsequent decreased ACE2 expression (44) .

Beyond its role as the SARS-CoV-2 entry receptor, ACE2 may might play an indirect role in the pathophysiology of COVID-19 by influencing the inflammatory response. It may be possible that SARS-CoV-2 binding to ACE2 causes 'downregulation' of ACE2 and with reduced cleavage of Ang II to generate anti-inflammatory Ang-(1-7).

This would upregulate the detrimental ACE-Ang II-AT 1 R axis and downregulate the protective ACE2-Ang-(1-7) axis (30, 45) . While plausible, this has yet to be unambiguously demonstrated and proven. However considering the pathophysiological role of the ACE2-Ang-(1-7)-MasR axis in diabetes mellitus, hypertension, atherosclerosis, heart disease and kidney disease, patients with underlying cardiovascular pathologies may have their diseases acutely exacerbated, or potentially chronically worsened by SARS-CoV-2 (46, 47) . Fundamental to many of these processes is inflammation and activation of immune responses, which in severe COVID-19 may be associated with cytokine storm (48) .

Acute and chronic inflammatory responses are at the core of COVID-19 pathology (49) . This is clearly evidenced by the fact that dexamethasone is the only effective therapy in hospitalized patients as demonstrated by the RECOVERY trial (50, 51) .

Severe immune dysregulation is characteristic of COVID-19 and ranges from peripheral blood lymphopenia to splenic atrophy as reported in post-mortem examinations (49) . Circulating levels of pro-inflammatory cytokines are elevated in patients with COVID-19 and include classical cytokines such as IL-6 and TNF-a, as   well as IL-7, IL-2 , GM-CSF, C-X-C motif chemokine 10 (CXCL10), components of the cytokine release storm (51, 52) . Increased IL-6 is a clinical biomarker for cardiovascular morbidity and a predictor of mortality in COVID-19 (51, 53) .

Inflammation mediates cardiovascular pathology, acting directly on cardiac and vascular cells, and through further propagation of cardiovascular inflammation.

Mechanistically, COVID-19-related cytokines such as IL-6, IL-17 or TNF-a, induce oxidative stress and inflammation in endothelial and vascular smooth muscle cells, promoting micro-and macro-vascular disease (54, 55) . Oxidative stress is also key in IL-6-induced increases of adhesion molecule expression in endothelial cells. In addition to causing inflammation, a rapid surge in cytokine production is cardiotoxic inducing conduction abnormalities, atrial fibrillation, cardiac fibrosis and heart failure, phenomena observed in the acute phase of severe COVID-19 (56) . Whether the cytokine storm and IL-6 increase in COVID-19 are transient or sustained processes remains unclear, but monitoring these biomarkers may be important as they may be predictive of complications in long-term COVID-19.

While initial studies focused on cytokines involved in cytokine storm, subsequent analysis identified several distinct cellular immunophenotypes in patients with COVID-19. These studies identified inflammatory cells that may be responsible for rapid overproduction of cytokines in COVID-19. Using single cell RNA sequencing (scRNA-seq), a new immune phenotype in COVID-19 has been described, including a heterogeneous interferon-stimulated gene signature, downregulation of HLA class II and a developing neutrophil population (57) . These features are related to severe outcomes, and therefore also with cardiovascular pathologies (58, 59 

Cardiac injury and acute myocarditis are recognised complications of acute viral conditions in general (63) . Myocyte necrosis and mononuclear cell infiltrates are reported in cardiac biopsies from COVID-19 subjects. The most common pathological cause of myocyte necrosis appears to be microthrombi (64) . This is consistent with numerous early reports of fulminant myocarditis in COVID-19 (65) .

However the actual extent of myocarditis in COVID-19 is difficult to establish. 

Considering the importance of the immune system and inflammation in COVID-19

there has been enormous interest in targeting these processes therapeutically. Trials are currently under way to address the efficacy of immune targeted therapies in the prevention of severe COVID-19, which will have clear implications for its cardiovascular comorbidities.This includes therapeutic targeting of the IL-6 receptor (IL-6R) with tocilizumab which has been used in preventing and treating cytokine release storm in cancer, treatment of arthritis and giant cell or Takayasu arteritis and colchicine, a non-specific anti-inflammatory drug (75, 76) . Therefore it may provide an attractive possibility to target cytokine release storm in COVID-19, which would also have cardiovascular protective effects.

Initial studies at the onset of the pandemic reported high prevalence of hypertension and other comorbidities and mortality from COVID-19 (77, 78) . In a case-series study of 5,700 patients with COVID-19 in New York, hypertension (56.6%), obesity (41.7%), and diabetes (33.8%) were the most frequent comorbidities (77) . In a large study of over 72,000 patients with COVID-19 (confirmed, suspected or clinically diagnosed), the overall case fatality rate was 2.3%, but this increased significantly in the presence of comorbidities (10.5% for cardiovascular disease, 7.3% for diabetes, and 6% for hypertension) (79) . Findings from many studies in different countries

show that patients with COVID-19 and hypertension have a higher mortality risk when compared with non-hypertensives (77) (78) (79) .

The relationship between hypertension and COVID-19 is complex with some studies failing to report an association. In patients with laboratory-confirmed COVID-19

admitted to intensive care units at 65 USA hospitals there was no impact of hypertension on COVID-19 outcomes, although BMI>40 and coronary artery disease were independent predictors of 28-day mortality (80) . A multivariable analysis on adults with confirmed COVID-19 hospitalized at two hospitals in Wuhan reported that hypertension marginally increased the risk of severe infection and increased risk of mortality only in combination with diabetes or other comorbidities (81) . The OpenSAFELY analysis (82) incorporating primary care data from 17,278,392 patients in England showed that when adjusted only for age and sex, hypertension was associated with a significantly increased risk of death in patients with COVID-19. The authors also found strong evidence of interaction with age with hypertension associated with a higher risk up to the age of 70 years and a lower risk above 70 years (82) . High blood pressure is a predictor of heart failure during hospitalization increased variability of systolic blood pressure and diastolic blood pressure is associated with increased risk of mortality and intensive care admission (83, 84) . Increase in fatal and adverse respiratory outcomes have also been demonstrated across the spectrum of blood pressure categories -normotensive through grade I, grade II and III hypertension (85) .

Diagnosis, monitoring and management of hypertension are likely to have been adversely affected by the COVID-19 pandemic with a reduction in primary care visits (86) in particular face-to-face appointments, less clinic blood pressure measurements and lack of public health screening events. Patients with hypertension may also have been less inclined to seek healthcare visits due to unwillingness to burden services, shielding due to high clinical risk or fear of contracting the SARS-CoV-2 virus leading to late presentation of cardiovascular disease and poorer outcomes (87) .

The COVID-19 pandemic has highlighted socioeconomic and health inequalities in many countries worldwide. There is an established link between socioeconomic factors (such as education, low-income and occupation) and the risk of hypertension and rate of blood pressure control (88) . It is estimated that, compared to the least deprived areas, those from the most deprived areas are more likely to have hypertension and cardiovascular complications whilst some ethnic groups are disproportionately affected with greater rates in blacks and Asians compared to whites (89) . This increased risk may be, in part, explained by lifestyle factors including obesity, diet, physical inactivity, and alcohol intake (90) . COVID-19 has adversely affected those of lower socioeconomic status with mortality rates twice as high than in the least deprived areas (91, 92) .

Long COVID is a distinct condition post-COVID-19 of unknown cause, but it is likely to be due at least partly to an inflammatory reaction and vasculitis (70, 93) . Even consequence of the COVID-19 pandemic is unknown but given the scale of the infection especially among the young this will be a major concern for the future.

Considering the role of the RAS and specifically ACE2 in COVID-19 infection and pathophysiology, there has been enormous debate whether antihypertensive drugs that inhibit the RAS impact disease severity (97) (98) (99) (100) (101) . Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are considered first-line antihypertensive agents but also play a crucial role in the management of patients with renal disease, heart failure, myocardial infarction and other cardiovascular disorders. Both ACEI and ARBs reduce the AT1R-mediated effects of Ang II and decrease activity of the traditional ACE/Ang II/AT1R axis with possible unmasking of the ACE2/Ang (1-9) and Ang (1-7) pathway.

These effects on the protective arm of the RAS, together with reduced AT1R activity are thought to provide further tissue protection and to constitute an important part of the multifaceted mechanism of action of RAS blocking agents. It is therefore conceivable that patients at highest risk of more severe forms of COVID-19 benefit from the tissue protection offered by these drugs. Apart from immediate effects of ACEI and ARB on vascular tone and blood pressure there are numerous beneficial long-term effects related to their antifibrotic, antiproteinuric and anti-inflammatory actions. However, with ACE2 being the main receptor for the SARS-CoV-2 spike protein there has been some concern that upregulation of the ACE2 axis could increase the receptor availability for SARS-CoV-2 host cell entry and infection and more severe COVID-19.

These concerns are based primarily on experimental data in rodent models. For example, studies in hypertensive rats treated with the ACEI lisinopril or the ARB losartan caused upregulation of cardiac ACE2 mRNA expression (102) . It was concluded that increased Ang II metabolism by ACE2 contributes to the antihypertensive effects of these drugs (102) . This upregulation of ACE2 mRNA caused concerns in the initial stages of the COVID-19 pandemic. Driven more by theoretical considerations than conclusive data a number of hypothesis and opinion papers were published causing confusion in the field as to whether ACEi and ARBs should be withdrawn in COVID-19 patients (103).

On the other hand, some studies reported that inhibitors of the RAS have beneficial effects in patients with severe COVID-19 (104, 105) . There is now a large body of evidence that confirms that inhibitors of the RAS do not affect the risk of COVID-19.

A large study in the Lombardy region of Italy showed that, because of the higher prevalence of cardiovascular risk factors, patients with COVID-19 were more likely to take RAS blocking agents but that the use of these drugs was not independently associated with the risk of COVID-19 (106) . Another study in New York hospitals found no association between the likelihood of a positive COVID-19 test and use of any of the five major classes of antihypertensive agents (107) . Other studies in the UK and China reported that patients on ACEI or ARB were at reduced risk of severe COVID-19 and that these drugs were not associated with increased risks of receiving intensive care unit care (108, 109 

The first autopsy series from patients with COVID-19 in Wuhan described features of acute respiratory distress syndrome (ARDS) and evidence of small vessel occlusion, highlighting associated pulmonary microvascular thromboembolic disease (125) .

More recent post-mortem studies have provided further pathologic details including bilateral acute changes with diffuse alveolar damage with vascular congestion, intra-alveolar edema, hemorrhage, proteinaceous exudate, macrophages, denudation and reactive hyperplasia of pneumocytes and patchy inflammatory cellular infiltration comprising multinucleated giant cells, lymphocytes (CD4+ve), eosinophils and neutrophils. A consistently reported feature in post-mortem analysis from many case series is microvascular thrombi, neutrophil extracellular traps (networks of extracellular neutrophil-derived DNA), and neutrophil-platelet aggregates contributing to extensive microvascular damage and thrombotic occlusion (126, 127) . These vascular changes have been attributable, in part, to dysregulation of the endothelial ACE2 receptor with associated bradykinin-mediated lung edema and pro-thrombotic state (127) . Beyond the lungs, autopsy findings reveal widespread microthrombi in many organs including the heart, kidneys and lungs and to a lesser extent in the brain (128) . These phenomena may underlie multisystem organ failure in patients with severe forms of COVID-19, especially in African Americans (129) .

The In vitro studies demonstrated that SARS-CoV-2 infection promotes activation of platelets, neutrophils and endothelial cells, with associated activation of coagulation factors, thrombin generation, fibrin production, increased plasminogen activator inhibitor-1 (PAI-1):tissue plasminogen activator (t-PA) ratio and production of proinflammatory cytokines, processes that promote hypercoagulation (131) . In particular, direct viral infection of pneumocytes and endothelial cells promotes an immune and inflammatory response characterized by activation of T cells, neutrophils, macrophages, monocytes and platelets leading to cytokine production (IL-1, IL-6, IL-10, TNF), increased PAI-1 expression and consequent thrombus formation (114) . Microthrombi in COVID-19 typically contain fibrin, platelets, neutrophils and neutrophil extracellular traps (NETs), which are tangles of DNA from degenerated neutrophils (129) . NETs further contribute to hypercoagulation by stimulating the extrinsic pathway and activating platelets (132) .

While there is a clear association between hypercoagulable states and COVID-19, it still remains unclear to what extent SARS-CoV-2 increases the risk of thromboembolic disease. Some studies failed to show differences in hospitalassociated venous thromboembolism in patients with COVID-19 versus patients with non-COVID-19 illness, suggesting that the coagulopathy is not specific to the virus, but rather due to the overall illness severity and complications of the disease (133).

Nevertheless clinical guidelines suggest that thromboprophylaxis should be considered for all hospitalized patients with COVID-19 in the absence of contraindications (113, 128, 134) .

Early recognition and management of thromboembolism risk, based on CRP or Ddimer levels and impending cytokine storm, based on serum ferritin, was associated with improved COVID-19 survival and hospital outcomes in a traffic light-driven personalized care approach (135) . Current guidelines from the American College of Chest Physicians (ACCP) suggest prophylaxis with low-molecular weight heparin or fondaparinux rather than direct oral anticoagulants or fractionated heparin in hospitalized patients with COVID-19 who do not have contraindications, such as bleeding (136) . However optimal anticoagulation strategies are still unclear and prospective clinical trials to determine best therapeutic approaches are awaited.

Infection with viral pathogens has been suggested to associate with an increased risk of myocardial infarction (MI) and cardiovascular risk from the early 20 th century, with a study reporting the highest incidence of heart disease within the first seven days of infection (136) . Conversely, during the initial global spread of COVID-19 a reduction in the reported incidence of acute MI was observed compared with previous years (137, 138) . This was mainly due to behavioural changes by patients.

They were more likely to die at home by delaying medical contacts, or eventually presenting 'late' (139) . These behaviours can be explained by social anxiety towards hospitals, social distancing measures and reduction in usual outpatient activities may be implicated (138) . Presenting late, with more complex illness inevitably will be more likely increase persisting chronic sequelae.

Systemic pathogenic infection may pre-dispose to acute type 1 MI due to increased levels of circulating inflammatory cytokines in COVID-19 and resultant macrophage activity within atherosclerotic plaques, leading to coronary plaque rupture and thrombosis. Acute SARS-CoV-2 infection is also associated with a pro-thrombotic and pro-coagulable state; when combined with risk factors such as diabetes which is associated with impaired fibrinolysis and increased platelet activation, coronary thrombosis may occur (140) . 

Cardiovascular injury is associated with history of prior cardiovascular disease, and elevated cardiac enzymes in the context of COVID-19 are associated with poorer outcomes compared with other causes of non-acute coronary syndromes or myocardial injury (140) . Direct effect on the heart secondary to viral infiltration has been reported but appears to be uncommon (141) . Cardiac pericytes and cardiomyocytes express ACE2 transmembrane receptor proteins, and fusion with the S protein of SARS-CoV-2 coronavirus is proposed as a source of cell invasion (142) .

However, to-date reports of direct cardiac infiltration in deceased patients at autopsy describe evidence of virus particles within the interstitium or macrophages rather than within cardiomyocytes (143) .

Pathology studies have identified cardiac lymphocytic or eosinophilic infiltration either at autopsy or following endomyocardial biopsy in patients with COVID-19. The majority of reports are case studies or series with small sample size which limits assessment of incidence of myocarditis in hospitalized patients with COVID-19 (144) . Rather than direct effects of viral invasion, it has been reported that myocarditis in patients with COVID-19 is secondary to cytokine induced inflammatory myocarditis (144) . infection (149, 150) . Mechanisms implicated in COVID-19-related cardiomyopathy include catecholamine surge and cytokine storm.

Atrial fibrillation is the most frequently encountered arrhythmia newly diagnosed in patients with COVID-19 occurring in approximately 1 in 5 hospitalized patients and associated with increased likelihood of mortality (151) . Premature ventricular complexes, ventricular tachycardia and bradycardia have also been reported although it is noted that pre-existing rhythm abnormalities were present in a proportion of these patients (152) . Sudden cardiac death has been reported in case studies however, QTc prolonging medications were prescribed in these patients including quinolone antibiotics, or hydroxychloroquine which has been shown to have no benefit in hospitalized patients (153) . Heart failure patients on advanced therapies including those needing heart transplantation require special care and involvement of advanced heart failure team members because they are at very high risk due to immunosuppression and hemodynamic instability (156) . The International Society for Heart and Lung

Transplantation guidelines suggest holding immunosuppressive drugs in moderate to severe presentations of COVID-19 (157) . Successful heart transplantation has been described for COVID-19-associated post-infectious fulminant myocarditis (158)

In addition to hypertension and obesity, diabetes is strongly associated with COVID-19 (159, 160) . Large population studies reported that people with type 2 diabetes are more than twice as likely to have died from COVID-19 than those without diabetes in the background population (after adjustment for age, sex, ethnicity, social deprivation and geographical region) (161) . The risk is even higher in people with type 1 diabetes (159, 160) . Patients with diabetes who developed fatal or intensive care unit-requiring COVID-19 have more comorbidities and complications (e.g. retinopathy) but also poorer glycaemic control and higher rates of previous ketoacidosis or hypoglycaemia hospitalisation (162) .

The mechanisms by which diabetes status, and in particular high blood glucose, predispose to poorer outcomes are currently under intense investigation. It is highly relevant in this regard that the ACE2 receptor is expressed on pancreatic β-cells, potentially predisposing to cell damage and loss of endogenous insulin secretion (163) . Clinical experience indicates that people with diabetes who develop COVID-19 are more likely to develop acute metabolic decompensation, including ketoacidosis, itself associated with poorer outcomes. In keeping with the hypothesis of direct toxicity of SARS-CoV-2 to β-cells increased rates of diagnosis of type 1 diabetes have been reported (163, 164) .

However, additional mechanisms are clearly also in play. Hyperglycaemia is associated with elevated levels of proinflammatory cytokines, in particular IL-6: the resultant pro-inflammatory milieu is associated with susceptibility to infection with coronaviruses (163) . Moreover, associated oxidative stress facilitates entry of the virus into host cells and activation of hypoxia-inducible factor-1α, promoting rapid viral replication and the development of cytokine "storm" -a syndrome that often signals the sharp deterioration of people with COVID-19 after a few days of illness (163, 164) . 

Although renal involvement was not a major feature of the early reports of COVID-19

from Wuhan, it is now clear that together with the vascular system and heart, the kidneys are often affected in COVID-19 infection severe enough to require hospitalisation. The clinical manifestations of renal involvement in COVID-19 can vary in severity from haematuria and/or proteinuria, acute kidney injury (AKI) and the need for renal replacement therapy (RRT, i.e. dialysis or haemofiltration) (167) (168) (169) .

In patients with severe illness requiring management in intensive care units the proportion of patients requiring KRT is generally reported to be 20-30% (170, 171) .

Acute kidney injury in patients with COVID-19 may lead to volume overload that could exacerbate pre-existing chronic heart failure, leading to poor outcomes.

The major risk factors associated with developing biochemical AKI and need for RRT in COVID-19 are generally similar to those associated with more severe COVID-19 infection, include male gender, diabetes, non white race, obesity, pre-existing chronic kidney disease, hypertension and age (170) (171) (172) . COVID-19 disease severity is also associated with increasing risk of requiring RRT. Whilst any critical illness e.g., pneumonia, major surgery, trauma, sepsis is associated with a risk of AKI and subsequent need for RRT, emerging data suggest that for an equivalent disease severity, COVID-19 infection appears more likely to provoke AKI (173) . The presence of AKI is associated with increased risk of mortality in patients with COVID-19, although whether this simply represents a marker of severe infection or a specific implication of AKI is challenging to dissociate (182, 183) . Knowledge of the longer-term implications of cardiovascular and renal involvement in COVID-19 are still evolving. It seems likely that many patients with kidney disease will not return to their pre-COVID-19 renal function. Longer term follow up studies will inform this.

Existing data suggest that 25-35% patients have not returned to baseline kidney function at the time of hospital discharge and hence have de novo or more severe CKD than before COVID-19 infection (168, 169, 183) .

Early in the pandemic it became apparent that symptoms of COVID-19 could persist after the acute illness and that many patients who recover from COVID-19 infection experience symptoms for many months after recovery. This condition, called 'long COVID-19', 'long haulers' or 'post-acute sequelae of SARS-CoV-2 infection' is associated with multiple cardiopulmonary and neurological symptoms including severe chronic fatigue, palpitations, chest pain, breathlessness and dysautonomia, features that are characteristic of postural tachycardia syndrome (POTS) (184) (185) (186) .

POTS impacts heart rate, blood pressure and cardiac function and is caused by many factors including viral infections (187) . While it still remains unclear whether SARS-CoV2 triggers POTS, emerging evidence indicates a close association between COVID-19 and POTS-like symptoms. Current treatment strategies focuses primarily on lifestyle modifications, and salt and fluid repletion (185) (186) (187) . The potential health burden of long COVID-POTS is significant, which has prompted a Statement paper on the topic by the American Autonomic Society (188) .

It is beyond the scope of the present review to discuss specific protocols in the treatment of patients with cardiovascular disease who are at risk of COVID-19, but the reader is referred to current guidance and opinion papers (189) (190) (191) (192) (193) . In general management decisions in the treatment of COVID-19 patients with pre-existing cardiovascular disease should be considered on a case-to-case basis.

Cardiovascular patients should be protected as much as possible from exposure to SARS-CoV2-infected individuals. Unless otherwise contra-indicated, cardiovascular patients should be encouraged to be vaccinated against SARS-CoV2.

While there is a clear association between cardiovascular disease and COVID-19 it should be highlighted that many of the studies are retrospective and hence subject to bias and confounding. Dissociating the very strong effect of age on COVID-19 outcomes with other comorbidities whose prevalence increase with age, namely hypertension, diabetes and other cardiovascular diseases is challenging. However, resolving this relationship is critical as this will have implications on management of patients. In the same light, while heart injury seems to be common in patients with severe COVID-19, the long-term health implications and potential 'lingering' effects of cardiovascular damage remain unclear. Moreover, the relevance of cardiovascular disease in SARS-CoV-2 positive, asymptomatic COVID-19 patients is unknown and as stated by Anthony Fauci MD, director of the National Institute of Allergy and Infectious Diseases and reported by Abbasi, the cardiac effects 'may be clinically inconsequential, or could lead to chronic effects' (194) . In addition the long-term impact of the indirect effects of COVID-19, such as delayed treatment of cardiovascular disease, is still unclear.

There is still no curative therapy for COVID-19, but the successful repurposing of drugs such as remdesivir and dexamethasone, together with successful immunisation programmes will likely improve the situation. However, as variants of SARS-CoV-2 emerge for which current vaccines offer reduced protection, it is increasingly likely that the pandemic will continue in some form for several years, Immunophenotyping studies show that cellular responses in COVID-19 differ between patients and may take a form of several immunophenotypes. Mfmacrophage; EMRAeffector memory expressing CD45RA; Tfh-T follicular helper cells; ACE2-angiotensin converting enzyme 2; t-bett-box transcription factor.

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Pathophysiological characteristics and therapeutic approaches for pulmonary injury and cardiovascular complications of coronavirus disease Cardio Pathol

First case of COVID-19 complicated with fulminant myocarditis: a case report and insights

SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS

The pivotal link between ACE2 deficiency and SARS-CoV-2 infection

Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice

The Science Underlying COVID-19: Implications for the Cardiovascular System

The cytokine storm and COVID-19

The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokinereceptor system

Dexamethasone in Hospitalized Patients with Covid-19

Therapeutic potential, risks, and future projection during COVID-19 pandemic

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2infection: Review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts

Association of COVID-19 inflammation with activation of the C5a-C5aR1 axis

Oxidative Stress as Key Player in Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection

COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options

Mortality in COVID-19 disease patients: Correlating the association of major histocompatibility complex (MHC) with severe acute respiratory syndrome 2(SARS-CoV-2) variants

BTK/ITK dual inhibitors: Modulating immunopathology and lymphopenia for COVID-19 therapy

Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications

Immune system-mediated atherosclerosis caused by deficiency of long non-coding RNA MALAT1 in ApoE-/-mice

Long noncoding RNA NEAT1 modulates immune cell functions and is suppressed in early onset myocardial infarction patients

Evidence of SARS-CoV-2 mRNA in endomyocardial biopsies of patients with clinically suspected myocarditis tested negative for COVID-19 in nasopharyngeal swab

Microthrombi as a Major Cause of Cardiac Injury in COVID-19: A Pathologic Study

COVID-19 and Myocarditis: What Do We Know So Far? CJC Open

SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes

SARS-CoV-2 infection and overactivation of Nlrp3 inflammasome as a trigger of cytokine "storm" and risk factor for damage of hematopoietic stem cells

Myocarditis in Humans and in Experimental Animal Models

The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2

COVID-19 is, in the end, an endothelial disease

Coronavirus disease-19: The multi-level, multi-faceted vasculopathy

COVID-19-A vascular disease

Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science

Functional SARS-CoV-2-Specific Immune Memory Persists after Mild COVID-19

FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological diseasemodifying antirheumatic drugs: 2016 update

Arterial hypertension and risk of death in patients with COVID-19 infection: Systematic review and meta-analysis

Association Between Blood Pressure Control and Coronavirus Disease 2019 Outcomes in 45 418 Symptomatic Patients With Hypertension: An Observational Cohort Study

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

Factors Associated With Death in Critically Ill Patients With Coronavirus Disease 2019 in the US

Independent and combined effects of hypertension and diabetes on clinical outcomes in patients with COVID-19: A retrospective cohort study of Huoshen Mountain Hospital and Guanggu Fangcang Shelter Hospital

Factors associated with COVID-19-related death using OpenSAFELY

Blood pressure control and adverse outcomes of COVID-19 infection in patients with concomitant hypertension in Wuhan, China

Hypertension, renin-angiotensin-aldosterone system inhibition, and COVID-19

Influence of blood pressure control and application of renin-angiotensin-aldosterone system inhibitors on the outcomes in COVID-19 patients with hypertension

Reduction in face-to-face GP consultations

COVID-19 pandemic and admission rates for and management of acute coronary syndromes in England

Trends and Inequalities in the Health Care and Hypertension Outcomes in China

Prevalence, treatment, and control of hypertension by sociodemographic factors among the Dutch elderly

Socioeconomic Status and Cardiovascular Outcomes: Challenges and Interventions

Socio-economic status and COVID-19-related cases and fatalities

Association of Social and Demographic Factors With COVID-19 Incidence and Death Rates in the US

COVID-19 and Cardiovascular Disease

Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)

Association of hypertension and antihypertensive treatment with COVID-19 mortality: a retrospective observational study

Association of Cardiac Infection With SARS-CoV-2 in Confirmed COVID-19 Autopsy Cases

SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19?

Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic?

Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics

Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China

Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy

Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2

Sound Science before Quick Judgement Regarding RAS Blockade in COVID-19

Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19

Effects of Angiotensin II Receptor Blockers and ACE (Angiotensin-ConvertingEnzyme) Inhibitors on Virus Infection, Inflammatory Status, and Clinical Outcomes in Patients With COVID-19 and Hypertension: A Single-Center Retrospective Study

Renin-angiotensinaldosterone system blockers and the risk of Covid-19

Renin-angiotensinaldosterone system inhibitors and risk of Covid-19

Risk of severe COVID-19 disease with ACE inhibitors and angiotensin receptor blockers: cohort study including 8.3 million people

Renin-angiotensin system blocker and outcomes of COVID-19: a systematic review and meta-analysis

Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers

Statement of the European Society of Hypertension (ESH) on hypertension, renin-angiotensin system (RAS) blockers and COVID-19

NephJC statement on SARS-CoV-2 virus, COVID-19, and ACEi/ARB treatment

Diagnosis, Management, and Pathophysiology of Arterial and Venous Thrombosis in COVID-19 JAMA

COVID-19-associated coagulopathy: An exploration of mechanisms

COVID-19 coagulopathy: an evolving story

D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19

Dynamic relationship between D-dimer and COVID-19 severity

Profile of natural anticoagulant, coagulant factor and anti-phospholipid antibody in critically ill COVID-19 patients

Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Thromboembolic events in patients with severe pandemic influenza A/H1N1

Cardiovascular implications of COVID-19 versus influenza infection: a review

Thrombosis in hospitalized patients with viral respiratory infections versus COVID-19

Hypercoagulability of COVID-19 patients in intensive care unit. A report of thromboelastography findings and other parameters of hemostasis

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Immunothrombotic dysregulation in COVID-19 pneumonia is associated with respiratory failure and coagulopathy

A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression

Registry of arterial and venous thromboembolic complications in patients with COVID-19

Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans

Endothelial Dysfunction and Thrombosis in Patients With COVID-19-Brief Report

Elevated plasmin(ogen) as a common risk factor for COVID-19 susceptibility

Neutrophil extracellular traps in COVID-19

Postdischarge venous thromboembolism following hospital admission with COVID-19

Factors associated with hospitalization and critical illness among 4,103 patients with COVID-19 disease in New York City

Increase in COVID-19 inpatient survival following detection of Thromboembolic and Cytokine storm risk from the point of admission to hospital by a near real time Traffic-light System (TraCe-Tic)

Acute Myocardial Infarction after Laboratory-Confirmed Influenza Infection

The Covid-19 Pandemic and the Incidence of Acute Myocardial Infarction

Fewer presentations to metropolitan emergency departments during the COVID-19 pandemic

Community and healthcare systemrelated factors feeding the phenomenon of evading medical attention for timedependent emergencies during COVID-19crisis

Clinical significance of Coronavirus disease 2019 (COVID-19) in hospitalized patients with myocardial injury

SARS-CoV-2 in cardiac tissue of a child with COVID-19-related multisystem inflammatory syndrome

COVID-19 and the Heart

Myocarditis in COVID-19 patients: current problems

Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection

Microvascular dysfunction in COVID-19: the MYSTIC study

Endothelial cell infection and endotheliitis in COVID-19

The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications

The Chief Scientist Office Cardiovascular and Pulmonary Imaging in SARS Coronavirus disease-19 (CISCO-19) study

Characteristics and outcome of patients with COVID-19 complicated by Takotsubo cardiomyopathy: case series with literature review

SARS-CoV-2 triggered Takotsubo in 38 patients

Atrial Fibrillation is an Independent Predictor for In-hospital Mortality in Patients Admitted with SARS-CoV-2 Infection. Heart Rhythm. Epub ahead of print 22

Predictors and Prognostic Implications of Cardiac Arrhythmias in Patients Hospitalized for COVID-19

Sudden cardiac death in COVID-19 patients, a report of three cases

Mechanisms of COVID-19-induced heart failure: a short review

Heart Failure with preserved ejection fraction according to the HFA-PEFF score in COVID-19 patients: clinical correlates and echocardiographic findings

Heart failure and COVID-19

Guidance for cardiothoracic transplant and ventricular assist device centers regarding the SARS CoV-2 pandemic

Successful heart transplantation for COVID-19-associated post-infectious fulminant myocarditis. ESC Heart Fail

Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study

Colhoun HM; Public Health Scotland COVID-19 Health Protection Study Group; Scottish Diabetes Research Network Epidemiology Group. Risks of and risk factors for COVID-19 disease in people with diabetes: a cohort study of the total population of Scotland

Diabetes is associated with increased risk for in-hospital mortality in patients with COVID-19: a systematic review and metaanalysis comprising 18,506 patients

Hyperglycemia is Associated With Increased Mortality in Critically Ill Patients With COVID-19

COVID-19 and diabetes: a co-conspiracy (editorial)?

The Impact of Diabetes Mellitus in COVID-19: A Mechanistic Review of Molecular Interactions

Elevated Glucose Levels Favor SARS-CoV-2 Infection and Monocyte Response through a HIF-1α/Glycolysis-Dependent Axis

Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19

AKI in Hospitalized Patients with COVID-19

AKI Treated with Renal Replacement Therapy in Critically Ill Patients with COVID-19

Acute Kidney Injury in a National Cohort of Hospitalized US Veterans with COVID-19

Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study

Acute kidney injury associated with COVID-19: A retrospective cohort study

AKI in Hospitalized Patients with and without COVID-19: A Comparison Study

Comparative evaluation of clinical manifestations and risk of death in patients admitted to hospital with covid-19 and seasonal influenza: cohort study

SARS-CoV-2 renal tropism associates with acute kidney injury

Immunity, endothelial injury and complement-induced coagulopathy in COVID-19

Kidney Infarction in Patients With COVID-19

Acute Kidney Injury in COVID-19: Emerging Evidence of a Distinct Pathophysiology

Multiorgan and Renal Tropism of SARS-CoV-2

Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China

Histopathologic and Ultrastructural Findings in Postmortem Kidney Biopsy Material in 12 Patients with AKI and COVID-19

COVID-19-Associated Kidney Injury: A Case Series of Kidney Biopsy Findings

Kidney Biopsy Findings in Patients with COVID-19

COVID-19, fatigue, and dysautonomia

The possible association between COVID-19 and postural tachycardia syndrome

Postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders after COVID-19 infection: a case series of 20 patients

COVID-19 Dysautonomia.Front Neurol

Long-COVID postural tachycardia syndrome: an American Autonomic Society statement

CAPACITY-COVID: a European Registry to determine the role of cardiovascular disease in the COVID-19 pandemic

Scientific Reviewer Committee. Guidance for the Management of Patients with Vascular Disease or Cardiovascular Risk Factors and COVID-19: Position Paper from VAS-European Independent Foundation in Angiology/Vascular Medicine

Prevention Treatment of VTE Associated with COVID-19 Infection Consensus Statement Group. Prevention and Treatment of Venous Thromboembolism Associated with Coronavirus Disease 2019 Infection: A Consensus Statement before Guidelines

Guidelines for Balancing Priorities in Structural Heart Disease During the COVID-19 Pandemic