Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected more than seven million people worldwide, contributing to 0.4 million deaths as of June 2020. The fact that the virus uses angiotensin-converting enzyme (ACE)-2 as the cell entry receptor and that hypertension as well as cardiovascular disorders frequently coexist with COVID-19 have generated considerable discussion on the management of patients with hypertension. In addition, the COVID-19 pandemic necessitates the development of and adaptation to a “New Normal” lifestyle, which will have a profound impact not only on communicable diseases but also on noncommunicable diseases, including hypertension. Summarizing what is known and what requires further investigation in this field may help to address the challenges we face. In the present review, we critically evaluate the existing evidence for the epidemiological association between COVID-19 and hypertension. We also summarize the current knowledge regarding the pathophysiology of SARS-CoV-2 infection with an emphasis on ACE2, the cardiovascular system, and the kidney. Finally, we review evidence on the use of antihypertensive medication, namely, ACE inhibitors and angiotensin receptor blockers, in patients with COVID-19.
COVID-19 and thromboembolic complications The risk of venous and arterial thromboembolic complications has been reported to be higher in patients with COVID-19. Klok et al. demonstrated the cumulative incidence of venous thromboembolism (VTE) in 27% and ischemic stroke in 3.7% of patients with COVID-19 pneumonia . Lodigiani et al. also reported that among 388 COVID-19 inpatients, the ratio of thromboembolic events, including VTE, ischemic stroke, and ischemic heart disease, was higher in intensive care unit (ICU) patients (27.6%) than in patients in the general ward (6.6%) . Regarding stroke, patients with severe infection exhibited neurologic manifestations such as acute cerebrovascular diseases (5.7% in severe vs 0.8% in nonsevere, respectively) . In SARS, a case of VTE in multiple organs was described , but there are very few reports on SARS-induced thrombotic complications. Large-artery ischemic strokes occurred in 0.7% of Taiwanese  and 2% of Singaporean  SARS patients. For cases in Singapore, the authors considered that stroke occurred as a side effect of intensive treatment, such as intravenous immunoglobulin; thus, the incidence of VTE and ischemic stroke in COVID-19 patients appears to be remarkably higher than that in SARS patients. According to several reports of “stroke cases” with COVID-19 [80,81,82,83,84], almost all showed elevated plasma D-dimer levels. Additionally, higher D-dimer levels on admission effectively predicted in-hospital mortality in patients with COVID-19 [4, 85, 86]. Among thromboembolic complications, VTE was a common complication in hospitalized patients (observed in 20%) with COVID-19 and was associated with death (adjusted hazard ratio [HR]: 2.4) . In particular, lower extremity deep-vein thrombosis (DVT) was detected in 85.4% of critically ill COVID-19 patients . These findings indicate that abnormalities in the coagulation cascade result in VTE and stroke after SARS-CoV-2 infection. Therefore, systemic anticoagulation therapy may improve outcomes in COVID-19 patients .
Possible mechanisms of SARS-CoV-2-induced endothelial injury SARS-CoV-2-induced ischemic organ damage appears to be associated with a hyperinflammatory state, cytokine storm, vascular endothelial damage or fibrinogen consumption coagulopathy (Fig. 1) . Yang et al. clearly reviewed the underlying mechanisms of the dysfunctional coagulatory response in the pathogenesis of influenza A virus . Toll-like receptors (TLRs) have a central role in innate immunity. Viral pathogen-associated molecular patterns such as viral proteins, double-stranded RNA, and single-stranded RNA initially activate the innate immune system . Using in silico studies on the interaction of the SARS-CoV-2 spike glycoprotein with human TLRs, Choudhury et al. demonstrated that TLR4 is most likely to be involved in recognizing molecular patterns from SARS-CoV-2 to induce inflammatory responses . Other TLRs, such as TLR5, TLR7, and TLR8, have been also reported to also be involved in SARS-CoV-2 infection [93, 94]. TLRs activate a common signaling pathway via MyD88, leading to the production of proinflammatory cytokines . Further activation of the innate immune response to eradicate the virus induces overproduction of pro-inflammatory cytokines, resulting in a “cytokine storm”  of overactivated neutrophils, monocytes, and lymphocytes. Coagulation is a highly organized process that involves endothelial cells (ECs), platelets and coagulation factors in the sequential action of primary and secondary hemostasis and fibrinolysis . Inflammatory cytokines and leukocyte activation lead to EC activation and endothelial dysfunction via multiple mechanisms, including direct damage, loss of tight junctions, and hyperpermeability induced by inflammatory factors . Activated or injured ECs initiate coagulation by activating platelets and expression of coagulation components (Fig. 1). Visseren et al. found that respiratory virus-infected ECs exhibit procoagulant activity associated with the induction of tissue factor (TF) expression . The coagulation cascade is initiated after exposure of TF to the blood. Recently, Varga et al. reported the pathology of EC dysfunction in COVID-19 based on postmortem analysis of three cases . As ECs express ACE2 , viral inclusion structures in ECs and diffuse endothelial inflammation, such as endotheliitis, has been observed. These results suggest that SARS-CoV-2 virus infection directly and indirectly injures ECs and may activate the coagulation pathway. Very recently, Ackermann et al. performed morphologic and molecular analyses in the peripheral lung of seven cases of COVID-19 at autopsy , and severe EC injury associated with the presence of intracellular virus, disrupted cell membranes, widespread thrombosis with microangiopathy, and new vessel growth were observed. Ma et al. reported that human umbilical vein endothelial cells (HUVECs) express both ACE2 and TMPRSS2 mRNAs . Human dermal microvascular endothelial cells are also known to express TMPRSS2 . However, whether SARS-CoV-2 induces EC injury directly or indirectly remains unclear. An increase in vascular permeability induced by EC injury plays a pathogenic role in the development of pulmonary fibrosis , and acute respiratory distress syndrome (ARDS) is characterized by acute respiratory failure, bilateral pulmonary infiltrates, and noncardiogenic pulmonary edema resulting from vascular hyperpermeability . Thus, EC injury can lead to respiratory dysfunction and may be a key factor that determines the clinical outcome of COVID-19 patients.
COVID-19 and Kawasaki disease Verdoni et al. surprisingly reported a 30-fold increase in the incidence of Kawasaki-like disease (KLD) during the SARS-CoV-2 epidemic . In that study, 10 patients were diagnosed with KLD between February 18, 2020 and April 20, 2020, compared with 19 patients in the five years before the beginning of the COVID-19 pandemic . Two of 10 patients were positive for SARS-CoV-2 by reverse-transcriptase quantitative PCR assay, and eight of 10 patients diagnosed with KLD were positive for SARS-CoV-2 IgG and/or IgM antibodies. Kawasaki disease (KD) is an acute systemic vasculitis with coronary artery abnormalities that predominantly affects young children . Necrotizing arteritis, subacute chronic vasculitis, and luminal myofibroblastic proliferation are three linked processes associated with KD . Although a correlation between viral infections and KD was reported [108, 109], it is not clear whether KD-associated infections are causal or incidental. KD might also be associated with a dysregulated innate immune response; however, a link between SARS-CoV-2 infection and KLD has not been demonstrated.
Myocardial injury associated with COVID-19 Clinical manifestations of cardiovascular disorders associated with COVID-19 are diverse, with heart failure, arrhythmia, cardiogenic shock, acute myocardial infarction (AMI), and myocarditis having been reported [4, 85, 111,112,113,114]. In an initial report from Wuhan, China, Huang et al. documented that acute cardiac injury, as defined by the elevation of cardiac biomarkers (e.g., troponin I) or new abnormalities in electrocardiography and echocardiography, was present in 12.2% of 41 inpatients with COVID-19 . In another study, acute cardiac injury (7.2%; using the same definition as above) and arrhythmia (16.7%) were common complications among 138 hospitalized patients with COVID-19 . Cardiac complications in COVID-19 are associated with a poor clinical outcome [116, 117]. In one study, 19.7% of 416 hospitalized patients with COVID-19 had abnormally high levels of troponin I, and those with elevated troponin I levels had higher mortality (51.2%) than did those with lower levels (4.5%) . Another study showed that elevation in troponin T levels is associated with the occurrence of malignant arrhythmias and fatal outcomes .\
As described above, SARS-CoV-2 infection promotes vascular endothelial injury and thromboembolism, which can result in ischemic heart disease and stroke [84, 112]. However, cases of myocardial injury with no evidence of obstructive coronary disease have also been reported [114, 118, 119], suggesting that COVID-19 interacts with the cardiovascular system through multiple mechanisms.
Possible mechanisms of cardiovascular injury in COVID-19 Although the molecular causes of myocardial injury in COVID-19 have remained elusive, several mechanisms can be considered. Severe viral infection triggers systemic inflammatory response syndrome, which increases the risk of plaque rupture and thrombus formation, resulting in the occurrence of atherosclerotic diseases. For example, there is a significant association between the incidence of AMI and influenza . In addition, several papers have reported the occurrence of AMI in COVID-19 patients [112, 121], though more studies are necessary to determine the actual prevalence. Cytokine storms can both cause plaque instability and promote cardiovascular inflammation and myocardial depression [122, 123], which may be involved in myocarditis and stress-induced cardiomyopathy in COVID-19 patients [114, 124]. Furthermore, recent data suggest that a substantial portion of patients with COVID-19 have risk factors for atherosclerotic disease, which include hypertension, obesity, smoking, and diabetes mellitus [6, 85, 111, 115]. Because severe respiratory viral infection induces hypoxemia and abnormal hemodynamic changes, enhanced BP variability may also trigger cardiovascular events in COVID-19 patients with atherosclerotic risk factors. These mechanisms likely act in parallel to cause cardiac damage, resulting in severe clinical manifestations such as AMI, ventricular arrhythmias, and congestive heart failure.
It is currently unknown whether SARS-CoV-2 infects cardiomyocytes. Autopsy studies have reported the detection of SARS-CoV-2 RNA in the heart . However, the cell types in which viral RNA was detected were not defined. Endomyocardial biopsy in a case of COVID-19 with cardiogenic shock revealed viral particles in interstitial macrophages but not in cardiomyocytes . Although ACE2 is expressed in human cardiomyocytes , there appears to be little expression of TMPRSS2 in these cells . Therefore, the direct pathogenic role of SARS-CoV-2 in cardiomyocytes needs further investigation.
Acute kidney injury (AKI) in COVID-19: incidence and clinical significance In addition to cardiac complications, accumulating data indicate that renal abnormalities frequently accompany COVID-19, though there does seem to be a geographic difference in the occurrence of AKI. Several single-center studies from Wuhan report that AKI developed in 3–7% of patients with COVID-19 [85, 115, 128], and the reported incidence of AKI in a multicenter study involving 1099 in-hospital patients in 30 provinces across mainland China was 0.5% . Studies in the US found AKI incidence to be higher than that in the aforementioned reports. For instance, the incidence of AKI was 19.1% among critically ill patients in a small single-center study in Seattle , and in a multicenter study conducted in the largest academic health system in New York [6, 130], AKI occurred in 36.6% of 5449 patients admitted with COVID-19, of whom 14.3% required renal replacement therapy (RRT). This geographic difference in the occurrence of AKI might be explained by several factors, including disease severity, ethnicity, and comorbid conditions (such as diabetes and coronary artery disease), all of which are reported to be independent risk factors for AKI in COVID-19 .
AKI in COVID-19 is highly associated with respiratory failure. In one study, as many as 89.7% of mechanically ventilated patients developed AKI, whereas AKI occurred in 21.7% of nonventilated patients . The demand for RRT may significantly increase during the COVID-19 pandemic, and clinicians should be aware of the possibility of facing challenges in delivering RRT to COVID-19 patients . Moreover, in line with findings for SARS , the mortality rate seems much higher among COVID-19 patients with AKI than among those without AKI. In a report by Zhou et al. , AKI was observed only in 0.7% of survivors, whereas 50.0% of nonsurvivors had AKI. Consistently, a dose-dependent relationship between mortality and the severity of AKI was observed in a different cohort, with stage 3 AKI being associated with a fourfold increase in mortality risk . A poor prognosis for COVID-19 patients with AKI was also confirmed in a US cohort . In addition, renal abnormalities associated with COVID-19 may not necessarily be limited to AKI. Pei et al. reported that proteinuria and hematuria were seen in 65.7% and 41.7% of 333 patients with COVID-19 pneumonia, respectively . Glomerulopathy associated with COVID-19 has also been reported [135, 136].
Mechanisms of kidney injury associated with COVID-19 Multiple mechanisms explaining the occurrence of kidney injury in COVID-19 have been proposed, which include but are not limited to the following: hemodynamic instability and renal ischemia, ARDS and the cytokine storm, rhabdomyolysis, hypercoagulability and thrombosis, cardiac failure and kidney congestion, and direct renal infection of SARS-CoV-2. In one study, AKI was more common in patients with cardiac injury than in those without cardiac injury, suggesting a cardio-renal interaction . In autopsy data for 26 cases, diffuse proximal tubule injury was prominent, along with erythrocyte aggregates in peritubular capillaries, ischemic changes with fibrin thrombi in glomeruli, and pigmented casts indicative of rhabdomyolysis . Of note, this study identified virus particles with crown-like morphology in electron microscopy within renal tubules and podocytes, which was accompanied by degenerative changes such as vacuolization and necrotic epithelia. Another study also identified abundant viral forms in the area of vacuolated tubules in a case of COVID-19 at autopsy . These reports were followed by the demonstration of SARS-CoV-2 RNA in the kidney [125, 139]. Such histopathological analyses of cases postmortem indicate that SARS-CoV-2 may have tropism for the kidney, especially in severe cases, though the pathogenic role of direct infection remains undetermined. ACE2 is abundant in renal proximal tubules [31, 140], and its levels are altered in disease states such as diabetes mellitus [140,141,142]. However, TMPRSS2 is highly expressed in the more distal portion of the renal tubules . At present, it is unclear how SARS-CoV-2 enters renal cells and whether comorbid conditions affect the cellular tropism of the virus in the kidney. It also remains to be determined whether renal infection with SARS-CoV-2 indeed contributes to kidney injury.
COVID-19 in advanced CKD Several lines of evidence suggest that CKD patients, especially those at advanced stages, are vulnerable to SARS-CoV-2 infection. In a multicenter study of 5700 patients hospitalized with COVID-19, end-stage kidney disease (ESKD) was present in 3.5% of all cases . Conversely, the prevalence of laboratory-confirmed COVID-19 was 2.1% in 7154 patients undergoing hemodialysis in Wuhan, which was apparently higher than the morbidity of the general population in that area (~0.5% as of March 2020) . In a cross-sectional study of 3802 cases with SARS-CoV-2 test results, CKD was associated with a positive SARS-CoV-2 result after adjustment for potential confounding variables . Moreover, a higher baseline serum creatinine level is an independent risk factor for in-hospital death in COVID-19 , suggesting that ESKD patients are at high risk of developing severe disease. In recent reports, the overall mortality rate for ESKD patients with COVID-19 was 29% (out of 94 cases) in Italy  and 31% (of 59 cases) in New York . The basis for such vulnerability is likely multifactorial, and both medical (older age, immune cell dysfunction, cardiovascular and pulmonary comorbidities) and environmental factors need to be considered [147, 148]. Currently, several guiding principles have been proposed to mitigate the risk of COVID-19 in ESKD patients [149,150,151].
Antihypertensive agents during the COVID-19 pandemic Use of ACE inhibitors and ARBs in patients with COVID-19 Because ACE inhibitors and ARBs may increase the amount of ACE2, whether these drugs should be discontinued during the COVID-19 pandemic has been a topic of discussion [152, 153]. The role of ACE2 in the pathophysiology of COVID-19 as well as experimental evidence for ACE2 and RAS inhibitors are reviewed in detail in the previous sections. In the following sections, we discuss the clinical evidence for COVID-19 and antihypertensive agents. Although several reports in an early phase of the COVID-19 pandemic have suggested the relationship between COVID-19 and ACE inhibitors or ARBs [154, 155], it is possible that the association between COVID-19 and hypertensive medication results from reverse causality because older patients, who are at the highest risk for COVID-19, tend to have multiple comorbidities, including hypertension and CVD. Moreover, adjustments for age and other possible confounding factors were not performed in most of the early studies [156,157,158]. Several recent reports analyze the effect of ACE inhibitors and ARBs on clinical outcomes in patients with COVID-19 and hypertension [159, 160]. A retrospective, single-site, cohort study from Wuhan compared clinical outcomes among 126 COVID-19 patients with pre-existing hypertension (43 of whom were taking either ACE inhibitors or ARBs; 83 of whom were not taking these agents) and 125 age- and sex-matched COVID-19 control patients without hypertension . In that study, it was found that ACE inhibitors or ARBs did not increase the risk of morbidity or mortality in patients with SARS-CoV-2 infection. Moreover, the study showed a nonsignificant trend toward marginally lower critical illness and death rates in patients taking ACE inhibitors or ARBs compared to those taking other antihypertensive agents. In a study from Spain, a case-population study (1139 cases and 11,390 population controls) showed that users of ACE inhibitors or ARBs had an adjusted odds ratio for COVID-19 requiring admission to hospital of 0.94 (95% CI 0.77–1.15) compared to users of other antihypertensive drugs, with no increased risk for ACE inhibitors or ARBs . This study concluded that ACE inhibitors or ARBs do not increase the risk of COVID-19 requiring admission to the hospital, including fatal cases and those admitted to ICU, and that these agents should not be discontinued to prevent the development of severe COVID-19 . Two other retrospective cohort studies from China comparing disease severity and mortality rates between hypertensive patients taking ACE inhibitors or ARBs and those not taking these agents are available [161, 162]. One, a single-center study, showed that the percentage of patients taking ACE inhibitors and ARBs did not differ between those with severe and nonsevere infections or between survivors and nonsurvivors . In the other, a multicenter cohort study, hypertensive patients with COVID-19 who were taking ACE inhibitors or ARBs were compared with those who were taking antihypertensive drugs other than ACE inhibitors and ARBs as well as patients with COVID-19 without hypertension . The risk for 28-day all-cause mortality was lower in the ACE inhibitor/ARB group than in the control group (adjusted HR 0.42, 95% CI 0.19–0.92; P = 0.03) and in matched subgroup analysis (adjusted HR 0.30, 95% CI 0.12–0.70; P = 0.01). In addition, two clinical studies from northern Italy and from New York provide further evidence on the association between antihypertensive medication and COVID-19 [163, 164]. In the case-control study in Italy, which included 6272 patients with COVID-19 and 30,759 controls matched for age, sex, and municipality of residence, after adjustment for drugs and coexisting conditions, the odds ratios for the use of ACE inhibitors and ARBs were 0.96 (95% CI 0.87–1.07) and 0.95 (95% CI 0.86–1.05), respectively, among all patients and 0.91 (95% CI 0.69–1.21) and 0.83 (95% CI 0.63–1.10), respectively, among patients who had a severe or fatal course of the disease . In the New York study, none of the major classes of antihypertensive drugs, including ACE inhibitors and ARBs, were associated with a positive SARS-CoV-2 test or disease severity . Taken together, the data from these six studies, although retrospective, from different countries [159,160,161,162,163,164] provide evidence for continuing treatment with ACE inhibitors or ARBs in patients with hypertension during the COVID-19 pandemic. Moreover, a recent meta-analysis showed the potential benefit of ACE inhibitors or ARBs in patients with hypertension . In nine studies comprising 3936 patients with hypertension and COVID-19, ACE inhibitors or ARB treatment was not associated with disease severity but was related to lower mortality from COVID-19 compared with other antihypertensive drugs. Although future well-designed randomized controlled trials are needed, these results suggest that treatment with ACE inhibitors or ARBs should be continued in COVID-19 patients with hypertension [165,166,167].
Use of other antihypertensive agents in patients with COVID-19 The aforementioned two studies on RAS inhibitors also address the association of COVID-19 with other classes of antihypertensive agents [163, 164]. In one study, the adjusted odds ratios for COVID-19 associated with the use of calcium-channel blockers, beta-blockers, thiazide diuretics, loop diuretics, and MRA were 1.03 (95% CI 0.95–1.12), 0.99 (95% CI 0.91–1.08), 1.03 (95% CI 0.86–1.23), 1.46 (95% CI 1.23–1.73), and 0.90 (95% CI 0.75–1.07), respectively . Thus, none of the antihypertensive agents except loop diuretics were associated with an increased risk of COVID-19 in multivariate analysis. In the study population, loop diuretics were used more frequently in patients with COVID-19 than controls (13.9% versus 7.8%; relative difference, 43.6%) , and their use may reflect the existence of severe comorbidities such as heart failure and renal dysfunction, the severities of which were not appropriately quantified . In another study, calcium-channel blockers, beta-blockers, and thiazide diuretics were not associated with an increased likelihood of a positive SARS-CoV-2 test .
Statements on the use of antihypertensive agents from hypertensive societies and associations worldwide The International Society of Hypertension , the European Society of Hypertension , the European Society of Cardiology , and the American Heart Association/Heart Failure Society of America/American College of Cardiology  have already made a statement on the use of RAS inhibitors during the COVID-19 pandemic. the Japanese Society of Hypertension  and the Japanese Circulation Society [173, 174] have also provided statements regarding the management of cardiovascular diseases during the COVID-19 pandemic. All these statements indicate that there is no good evidence to change or discontinue ACE inhibitors or ARBs to avoid or manage SARS-CoV-2 infection.
Current conclusion regarding the use of antihypertensive agents during the COVID-19 pandemic In the early phase of the COVID-19 pandemic, there was considerable confusion regarding whether ACE inhibitors or ARBs may have adverse effects on COVID-19 patient morbidity and mortality, which was based on the speculation that ACE2 can be upregulated by ACE inhibitors or ARBs. However, the evidence of ACE2 upregulation is limited to experimental studies. Furthermore, there have been no clinical studies supporting the hypothesis that ACE inhibitors and ARBs augment susceptibility to infection and worsen all-cause mortality and cardiovascular outcomes in COVID-19 patients. Thus, treatment with ACE inhibitors and ARBs should be continued in high-risk patients who have received guideline-directed medical therapy, and hypertension should be managed in accordance with the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH2019) . Areas of uncertainty and future perspectives
In this article, we review recent studies on COVID-19 in the context of hypertension and related diseases. As discussed in detail, there are no reliable reports on whether SARS-CoV-2 infection risk is increased in patients with hypertension. Hypertension is known to be associated with endothelial injury, especially in the elderly , and recent evidence suggests that thromboembolism triggered by endothelial injury is one of the important complications that influence disease outcome in COVID-19. At this time, it is unclear whether pre-existing endothelial injury increases the severity of COVID-19; however, hypertensive patients with atherosclerotic diseases may need to be carefully monitored for the occurrence of new-onset CVDs during SARS-CoV-2 infection.
Given that hypertension is the leading contributor to the development of cardiovascular and kidney diseases and given that myocardial injury and advanced CKD are associated with an increased risk of severe disease following SARS-CoV-2 infection, optimal management of hypertension can contribute to a better prognosis of COVID-19 by mitigating the progression of these disorders. Regardless, a major challenge is to achieve target BP control in the “New Normal” lifestyle, in which health care workers may have a reduced opportunity for in-person clinical examination of patients. In the Great East Japan Earthquake in 2011, medical care for patients with hypertension was compromised (“disaster hypertension”) . After the recognition of BP increases following the disaster, which may have contributed to the increased cardiovascular events [176, 177], the remote BP monitoring system using information and communication technology (ICT) was introduced and was indeed useful in achieving target BP control [178, 179]. Therefore, in the post-COVID-19 era, medical practice using ICT may need to be widely implemented for the management of hypertension. In addition, the COVID-19 pandemic may increase the risk of mental disorders—owing to, for example, anxiety, economic issues, and decreased physical activity—all of which can potentially compromise BP control. It is currently unknown whether the COVID-19 pandemic will affect BP control and the development of CVDs in the long term; nonetheless, it is necessary to carefully monitor each patient’s BP.
Last, in addition to the development of effective treatment, vaccination for SARS-CoV-2 will of course be helpful. In the case of influenza infection, several epidemiological studies and randomized control trials have clearly shown that there is a strong inverse relationship between influenza vaccination and the risk of cardiovascular events .
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