MINI REVIEW published: 30 October 2020 doi: 10.3389/fcvm.2020.588692 Small Resistance Artery Disease and ACE2 in Hypertension: A New Paradigm in the Context of COVID-19 María Galán 1,2* and Francesc Jiménez-Altayó 3* 1 Institut de Recerca del Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain, 2 Centro de Investigación en Red de Enfermedades Cardiovasculares, Madrid, Spain, 3 Departament de Farmacologia, de Terapèutica i de Toxicologia, Facultat de Medicina, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain Cardiovascular disease causes almost one third of deaths worldwide, and more than half are related to primary arterial hypertension (PAH). The occurrence of several deleterious events, such as hyperactivation of the renin–angiotensin system (RAS), and oxidative and inflammatory stress, contributes to the development of small vessel disease in PAH. Small resistance arteries are found at various points through the arterial tree, act as the major site of vascular resistance, and actively regulate local tissue perfusion. Experimental and clinical studies demonstrate that alterations in small resistance artery properties are important features of PAH pathophysiology. Diseased small vessels in PAH show decreased lumens, thicker walls, endothelial dysfunction, and oxidative stress Edited by: Guido Iaccarino, and inflammation. These events may lead to altered blood flow supply to tissues and University of Naples Federico II, Italy organs, and can increase the risk of thrombosis. Notably, PAH is prevalent among Reviewed by: patients diagnosed with COVID-19, in whom evidence of small vessel disease leading to Damiano Rizzoni, University of Brescia, Italy cardiovascular pathology is reported. The SARS-Cov2 virus, responsible for COVID-19, Gaetano Santulli, achieves cell entry through an S (spike) high-affinity protein binding to the catalytic domain Columbia University, United States of the angiotensin-converting enzyme 2 (ACE2), a negative regulator of the RAS pathway. *Correspondence: Therefore, it is crucial to examine the relationship between small resistance artery disease, María Galán mgalana@santpau.cat ACE2, and PAH, to understand COVID-19 morbidity and mortality. The scope of the Francesc Jiménez-Altayó present review is to briefly summarize available knowledge on the role of small resistance francesc.jimenez@uab.cat artery disease and ACE2 in PAH, and critically discuss their clinical relevance in the Specialty section: context of cardiovascular pathology associated to COVID-19. This article was submitted to Keywords: primary arterial hypertension, angiotensin-converting enzyme 2, COVID-19, SARS-CoV2, endothelial Hypertension, dysfunction, renin–angiotensin–aldosterone system, oxidative and inflammatory stress, small resistance arteries a section of the journal Frontiers in Cardiovascular Medicine Received: 25 August 2020 Accepted: 02 October 2020 INTRODUCTION Published: 30 October 2020 Hypertension remains the leading cause of death globally, accounting for 10.4 million deaths Citation: worldwide every year (1). Regrettably, the prevalence, morbidity, and mortality of hypertension are Galán M and Jiménez-Altayó F (2020) increasing (2). Current evidence demonstrates that alterations in small resistance artery properties Small Resistance Artery Disease and ACE2 in Hypertension: A New are important pathophysiological features of primary arterial hypertension (PAH). Diseased small Paradigm in the Context of COVID-19. vessels in PAH show decreased lumens, thicker walls, endothelial dysfunction, and increased Front. Cardiovasc. Med. 7:588692. oxidative stress and inflammation, events that may lead to altered blood flow supply to tissues and doi: 10.3389/fcvm.2020.588692 organs, and increase the risk of thrombosis. Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 October 2020 | Volume 7 | Article 588692 Galán and Jiménez-Altayó Microvessels, Hypertension, ACE2, and COVID-19 PAH is prevalent among patients diagnosed with coronavirus it acts upon circulating angiotensinogen of hepatic origin to disease 2019 (COVID-19), in whom rapid disease progression form the decapeptide angiotensin (Ang) I. Ang I is cleaved by has been reported. However, it is still not clear if raised blood angiotensin converting enzyme (ACE), found predominantly in pressure is a risk factor for increase COVID-19 lethality (3, 4). the lung capillaries, which removes two amino acids from the The severe acute respiratory syndrome coronavirus 2 (SARS- C-terminal of Ang I to form Ang II. In 2000, two independent CoV-2), responsible for COVID-19, achieves cell entry through research groups discovered an ACE homolog, ACE2 (17, 18), an S (spike) high-affinity protein binding to the catalytic domain which has distinct enzymatic actions and tissue distribution, of the angiotensin-converting enzyme 2 (ACE2), a negative and is predominantly expressed on the cell surface (19), though regulator of the renin–angiotensin system (RAS) pathway that a soluble form exists. Importantly, classical ACE inhibitors do has been shown to have protective effects in animal models of not affect ACE2 activity (18). ACE2 acts as a carboxypeptidase hypertension. Given the importance of small resistance artery removing a single C-terminal amino acid from Ang II generating disease and ACE2 in PAH, it is crucial to examine their Ang-(1–7) or, less efficiently, from Ang I leading to the formation relationship with SARS-CoV-2-induced endothelial cell injury of Ang-(1–9), whereas ACE removes the C-terminal dipeptide (5) to understand COVID-19 morbidity and mortality. from Ang I to form Ang II. Additionally, ACE2 cleaves a The objective of this review is to briefly summarize available terminal residue from several other bioactive peptides including knowledge on the role of small resistance artery disease in PAH neurotensin, dynorphin A (1–13), apelin-13, and des-Arg9 and the contribution of the ACE2 pathway, and critically discuss bradykinin (17, 20). their clinical relevance in the context of cardiovascular pathology Ang II is the principal effector of the RAS pathway, and causes associated to COVID-19. relevant biological actions through interaction with two cell- surface G-coupled receptors: AT1R and AT2R (21, 22). Activation of AT1R is responsible for the majority of physiological and SMALL RESISTANCE ARTERY DISEASE IN detrimental effects of Ang II, whereas AT2R activation promotes HYPERTENSION: THE CONTRIBUTION OF cardiovascular protection by partly opposing AT1R-induced THE RAS PATHWAY effects (23). Ang-(1–7) is a vasodilator and mediates protective effects in the cardiovascular system through the Mas receptor, The cause of PAH is still not known in spite of it represents which is involved in the regulation of blood pressure and possess 90–95% of cases. A transient increase in sympathetic activity anti-atherosclerotic and antifibrotics effects (24, 25). Ang-(1–9) is and cardiac output occurs during the early stages of the disease formed from Ang I by ACE2, carboxypeptidase A, and cathepsin (6). However, the event that consistently promotes the rise in A, and exerts vasculoprotective actions through AT2R receptors blood pressure is the increase in total peripheral resistance (7). (26, 27), though its biological actions are relatively unexplored. Peripheral resistance is determined by the lumen of vessels, Pharmacological agents targeting the RAS pathway and, especially resistance vessels (i.e., microcirculation), because their specifically, the synthesis of Ang II (ACE inhibitors) or Ang small lumens (<300 µm when relaxed) extremely slow the blood II receptor signaling (Ang II receptor blockers or ARBs) are flow through the arteries. effective in reversing hypertension-induced vascular remodeling An increase in peripheral resistance occurs when lumen in conductive and resistance arteries (28–31). In fact, several diameter narrows as, according to Poiseuille’s law, small decreases clinical studies reported that ACE inhibitors and ARBs improve in lumen diameter result in large increases in resistance to resistance vessels structure, whereas β-blockers do not (32, 33). flow. Lumen narrowing can develop because of structural, mechanical, and functional alterations. Structural remodeling of the small arteries is a hallmark of PAH pathophysiology (8). HYPERTENSION, ACE2, AND SARS-COV2 In PAH, resistance arteries suffer from eutrophic remodeling, INFECTION which increases the media/lumen ratio without a change in the media cross-sectional area, and enhanced wall stiffness PAH is a major risk factor of mortality worldwide being its (9–12). Mechanical forces on the vessel wall also contribute to prevalence in adults high and particularly high in the elderly (34). hypertensive remodeling in response to altered fluid shear stress Lately, the impact of hypertension is emphasized in the context and circumferential strain (11). Additionally, functional changes of the novel SARS-CoV-2 infection. The severity of COVID-19 can also contribute to increase peripheral resistance (12). Either and the poor outcome of SARS-CoV-2 infected patients is an increase or a decrease in the vasoconstrictor and vasodilator commonly associated with aging, hypertension, diabetes and influence, respectively, can promote lumen narrowing. For other cardiovascular disorders (35). Furthermore, the severity of instance, increases in myogenic tone (13), enhanced responses the primary respiratory syndrome is increased in patients with to norepinephrine (14), and endothelial dysfunction (15) can pre-existing cardiovascular disease (36). contribute to increase peripheral resistance. In hypertension, The use of RAS inhibitors is widely proven to reduce the increased pulse-wave velocity resulting from large vessel mortality in cardiovascular disease. RAS blockers are first- stiffening induces small vessel remodeling and endothelial injury, line drugs to treat hypertension and associated cardiovascular ultimately causing microvascular damage (16). The RAS pathway and renal comorbidities (37). Thus, ACE inhibitors, ARBs, controls systemic vascular resistance, by regulating blood volume and mineralocorticoid receptor antagonists are the standard and arterial pressure. When renin is released into the blood, therapy in hypertension and myocardial infarction (38, 39). The Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 October 2020 | Volume 7 | Article 588692 Galán and Jiménez-Altayó Microvessels, Hypertension, ACE2, and COVID-19 use of AT1R blockers and ACE inhibitors is encouraged in capacity for human cell infection (63, 64). In principle, the hypertensive patients because these drugs are vasoprotective, and virus has limited potential to escape soluble ACE2 mediated their associated increase in ACE2 expression (see the paragraph neutralization without simultaneously decreasing affinity for below) protects against hypertension (3, 4, 40). Discontinuation native ACE2 receptors, thereby attenuating virulence. Soluble of this therapy leads to deterioration of cardiac function and heart ACE2 has proven safe in healthy human subjects and 45 patients failure with a possible increase in mortality within a short period with lung disease (65, 66), and recombinant soluble ACE2 is of time (41). being tested in a clinical trial for COVID-19 in Guangdong Solid evidence from human and rodent studies suggests that province, China (Clinicaltrials.gov #NCT04287686). inhibition of RAS by AT1R blockers leads to upregulation of ACE2 (42, 43). Nevertheless, evidence of ACE inhibitors affecting SMALL RESISTANCE ARTERY DISEASE the expression of ACE2 is more limited (3, 44). Recently, the hypothesis that ACE inhibitors could act as a potential AND ACE2 IN COVID-19-RELATED risk factor for fatal COVID-19 by up-regulating ACE2 was VASCULAR PATHOLOGY proposed (45, 46). However, there is enough evidence that allows stating also the opposite hypothesis. Indeed, there is Advanced age, hypertension, diabetes mellitus and obesity, are currently no clinical data evidencing a direct link between all among the risk factors associated with a poor outcome ACE2 activity and SARS-CoV-2 associated mortality or between in COVID-19. These cardiovascular disease risk factors show RAS inhibitors intake and impaired outcome in COVID-19 a common link: they are associated with pre-established (4, 47). Recently, Sama et al. (2020) reported that neither ACE vascular dysfunction. This evidence rises the hypothesis an inhibitors, ARBs, nor mineralocorticoid receptor antagonists environment of deteriorated vascular cell function is more were associated with ACE2 concentrations in plasma in a wide prone to SARS-CoV-2 pathogenesis. Thus, SARS-CoV-2-infected cohort of patients with heart failure, albeit a group at high microvascular endothelial cells (ECs) may exacerbate endothelial risk for COVID-19 (48). Furthermore, ACE2 is a target for dysfunction (5). several coronaviruses and influenza viruses, and its expression and signaling pathway is severely affected by pneumonia virus Evidence of Hypertension-Like Small infection (49–51). The decrease of surface ACE2 levels leads to Resistance Artery Disease in COVID-19 increased Ang II local levels, an effect that probably contributes The endothelium is a crucial regulator of vascular tone by to the significant mortality rates resulting from SARS-induced releasing vasoconstrictors and vasodilators that contribute to acute lung injury and fibrosis (49, 52). Therefore, cardiovascular vessel homeostasis. Its function is impaired in hypertensive protection induced by ACE2-induced degradation of Ang II and patients, with the presence of reduced vasodilation (i.e., increase of Ang-(1–7) might be compromised (53–56), leading to endothelial dysfunction), increased vascular tone, inflammation RAS overstimulation (57). and thrombosis. In addition, ECs are linked to adjacent cells ACE2 is involved in infection and pathology induced to form cellular barriers between the blood and tissues that by SARS-CoV and the new SARS-CoV-2 which is causing restricts the movement of water, proteins, certain chemicals, and COVID-19 pandemic, through its unexpected function as the blood cells (67). Evidence indicates that SARS-CoV-2 is able to cell-surface receptor for the virus facilitating viral RNA entry in infect ECs from lung capillaries leading to the development of the lungs (58). Since the SARS-CoV outbreak in 2002, extensive acute respiratory distress syndrome (68). Pre-existing endothelial structural analyses has revealed key atomic-level interactions dysfunction due to aging is aggravated with the infection between the SARS-CoV spike protein receptor-binding domain of vascular cells by SARS-CoV-2 (5). Thus, patients with and its host receptor ACE2, which regulate both the cross- severe COVID-19 show vascular leakage and pulmonary edema, species and human-to-human transmissions of SARS-CoV. The because of EC dysfunction, lysis, and death (69). Notably, in spike glycoprotein (S protein) of SARS-CoV on the virion patients with COVID-19, EC infection occurs in tissues distal surface mediates receptor recognition and membrane fusion. from the primary infection site, leading to multi-organ failure During viral infection, the trimeric S protein is cleaved into (68). These outcomes could be the result of the disruption of the S1 and S2 subunits, and S1 subunits are released (59, 60). pulmonary EC barrier under the hypothesis that endothelium S1 directly binds to the extracellular peptidase domain of is a crucial target of SARS-CoV-2, which permits the virus to ACE2 through the receptor-binding domain, which in turn spread to distant target organs and may explain its systemic is recognized by the peptidase domain of ACE2 (61, 62), manifestations (70). A further consequence of endothelial whereas S2 is responsible for membrane fusion. An N-terminal damage in COVID-19 is the excessive activation of coagulation peptidase domain and a C-terminal collectrin-like domain, which pathways (69), a common feature in hypertensive patients. ends with a single transmembrane helix and a ∼40-residue Endothelial dysfunction in hypertension is partly due to intracellular segment, form full-length ACE2. The sequence of the presence of inflammatory and oxidative stress. Increased the 2019-nCoV spike protein (S protein), including its receptor- oxidative and inflammatory stress induced by activated immune binding motif that directly contacts ACE2, is similar to that of cells, inflammatory cell infiltration, and vasoactive molecules SARS-CoV. Moreover, several critical residues in 2019-nCoV promoting vasodilation, all contribute to EC de-structuring receptor-binding motif (particularly Gln493) provide favorable and dysfunction, which facilitate the amplification of the interactions with human ACE2, consistent with 2019-nCoV’s inflammatory response. The pulmonary microvascular ECs Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 October 2020 | Volume 7 | Article 588692 Galán and Jiménez-Altayó Microvessels, Hypertension, ACE2, and COVID-19 with inflammatory phenotype are more prone to vascular to interleukin-1β and interleukin-6 reduce acetylcholine- permeability, which facilitates neutrophil extravasation, and mediated relaxation, which is a hallmark of endothelial initiate arteriolar vasoconstriction (71). In addition, viral dysfunction commonly related to cardiovascular disease (15). pneumonia activates innate immune response by increasing the The cytokine-induced endothelial dysfunction is associated release of inflammatory mediators, which can induce systemic with an increase in superoxide anion production that reduces inflammatory response syndrome. Although respiratory failure nitric oxide bioavailability (85). Importantly, superoxide because of respiratory distress syndrome is the primary anion causes higher vasoconstriction in rat pulmonary vs. cause of mortality (72), many patients with COVID-19 systemic arteries, suggesting that the pulmonary artery bed exhibit a secondary exaggerated inflammatory response may be more prone to cytokine-induced vascular dysfunction called “cytokine storm,” a hyperinflammatory syndrome (86). Overall, the effects of cytokines on vascular reactivity characterized by a fulminant and fatal hypercytokinaemia are complex, and they are vascular bed and exposure with multiorgan failure (73). The cytokine storm leads time dependent, with short times inducing a direct effect to pulmonary parenchymal inflammation and edema that and longer times involving the contribution of crucial interfere with alveolar gas exchange and results in hypoxemia. secondary mediators such as nitric oxide, prostanoids, and Hypoxia and carbon dioxide retention cause the reflex endothelin (83). spasm of pulmonary blood vessels ending in pulmonary Because of available data show elevated plasma levels hypertension. The high levels of cytokines in these patients of certain inflammatory cytokines in some COVID-19 under an environment of EC dysfunction may amplify subpopulations, a cytokine storm-targeted rescue therapy the cascade of events leading to multi-organ failure and for patients with COVID-19 infection who exhibit rapid death. In fact, immune dysregulation observed in severe disease progression has been proposed (87). Nevertheless, course of COVID-19 is similar to immune dysregulation in an anti-cytokine approach has not yet been proven hypertension (74). CD4+ T-cells, and in particular CD8+ safe and effective. Several ongoing clinical trials are T-cells, are abnormally regulated in hypertension, showing investigating the use of tocilizumab, an interleukin-6 greater production of pro-inflammatory cytokines (75). receptor inhibitor, as a potential treatment for COVID- Moreover, hypertension is associated with a characteristic 19 (88), and a small (21 patients with severe or critical immunosenescent profile in CD8+ cells, which is prone to COVID-19) clinical trial in China (ID: ChiCTR2000029765) overproduction of cytokines, while are less efficient in antiviral has shown encouraging results. Other studies have defense (75, 76). observed that those patients with COVID-19 and hyperinflammation, could benefit from corticosteroids treatment, which induces immunosuppression that could Potential Impact of SARS-CoV-2–Induced improve mortality (73), whereas in those patients not showing “Cytokine Storm” on Small Resistance hyperinflammation corticosteroids might cause further lung Artery Properties injury (89). Recently, the pro-inflammatory cytokine and chemokine profile associated with COVID-19 disease severity, driving a more severe and fatal clinical course, has been unveiled in two Wuhan (China) Small Resistance Artery Disease and ACE2 populations. Several clinical studies have shown a notably in Vascular Pathology increase in circulating levels of different interleukins, C-reactive ACE2, which is highly expressed in SMCs and ECs, regulates protein, granulocyte-colony stimulating factor, interferon-γ cellular responses to inflammation (90). SARS-CoV-2 binds inducible protein 10, monocyte chemoattractant protein 1, to ACE2 reducing its activity (49–51, 91), which leads to RAS macrophage inflammatory protein 1-α, and tumor necrosis overstimulation (54). ACE2 deficiency exacerbates vascular factor-α (77, 78). Consistently, interleukin-1β, interleukin-2, injury (92), whereas reduced ACE2 activity can increase and interleukin-6 were identified decades ago as predictors of neutrophil infiltration and induce lung inflammation (93). outcome in severe adult respiratory distress syndrome (79). In addition, ACE2 protects from experimental acute lung Furthermore, tumor necrosis factor-α and interleukin-1β activate injury (94). Stimulation of the ACE2/Ang-(1–7)/Mas axis ECs to initiate coagulation pathways by expressing P-selectin, reduces SMC proliferation (95), migration (96), endothelial von Willebrand factor and fibrinogen (80), an effect that dysfunction (97), and thrombosis (98). Furthermore, previous might partly explain the hypercoagulability observed in COVID- studies have demonstrated that selective ATR2 activation 19 patients. suppresses the action of inflammatory cytokines both “in It is noticeable that several of these cytokines have been vitro” and “in vivo” (99–102). However, only few works previously associated with small vessel disease. Receptors for have reported the association between ACE2 and ATR2 tumor necrosis factor-α and interleukin-1β are expressed in (103, 104). Activation of ATR2 enhances ACE2 expression and both ECs and smooth muscle cells (SMCs) (81, 82). Long-term activity in human ECs contributing to the anti-inflammatory exposure to both cytokines can either reduce or increase effects of ATR2-mediated signaling (105). Furthermore, vasoconstrictor responses, an effect similar to that induced ACE2-induced activation of ATR2 by Ang-(1–7) after by exposure to interleukin-6 (83). In rat resistance arteries, ATR1 blockade is associated with improvement of vascular either subchronic “in vivo” (84) or “in vitro” (85) exposure remodeling (53). Frontiers in Cardiovascular Medicine | www.frontiersin.org 4 October 2020 | Volume 7 | Article 588692 Galán and Jiménez-Altayó Microvessels, Hypertension, ACE2, and COVID-19 FIGURE 1 | Potential role of SARS-CoV-2, responsible for COVID-19, in small resistance artery dysfunction and organ/tissue injury. The SARS-Cov2 virus infects endothelial cells from lung capillaries because it achieves cell entry through an S (spike) high-affinity protein binding to the catalytic domain of angiotensin-converting enzyme 2 (ACE2). The virus causes endothelial damage by increasing pro-inflammatory cytokines and chemokines expression and excessive activation of coagulation pathways. Furthermore, the interaction of SARS-CoV-2 with ACE2 compromises ACE2-induced degradation of angiotensin (Ang) II and reduces Ang-(1–7) levels, leading to renin–angiotensin system overstimulation. Altogether, these events may contribute to endothelial cell dysfunction and death, which can induce vascular leakage, pulmonary edema and parenchymal inflammation, hipoxemia and, ultimately, acute respiratory distress syndrome. Notably, in patients with COVID-19, peripheral manifestations of endothelial dysfunction occur in tissues distal from the primary infection site, probably because of the disruption of the pulmonary endothelial cell barrier that permits the virus to spread to distant target organs, and/or due to the secondary exaggerated inflammatory response (cytokine storm). This endothelial damage would cause small resistance artery dysfunction and alter blood flow supply to tissues and organs, increasing the risk of thrombosis and multi-organ failure. The presence of cardiovascular disease risk factors such as advanced age, hypertension, diabetes mellitus and obesity, which are associated with pre-existing endothelial dysfunction, may worsen the above-mentioned pathological mechanisms leading to poor outcome in COVID-19. IL, interleukins; CRP, C-reactive protein; G-CSF, granulocyte-colony stimulating factor; IP-10, interferon-γ inducible protein 10; MCP-1/CCL2, monocyte chemoattractant protein 1; MIP-1α/CCL3, macrophage inflammatory protein 1-α; TNF- α, tumor necrosis factor-α. CONCLUSIONS AND UPCOMING role of ACE2 in the anti-inflammatory actions of ATR2 PERSPECTIVES has not been studied “in vivo,” which warrants further investigation. Available evidence suggests that the use of Few works have been focused on describing the pharmacological interventions to increase NO bioavailability, anomalies and potential underlying mechanisms of enhance Ang-(1–7) and ATR2 signaling, and improve small resistance artery disease in COVID-19 (Figure 1). ACE2 activity might have a positive impact on small The dysfunction of these vessels, which resembles resistance artery disease in either hypertension or COVID-19 those from hypertensive patients, seems crucial for the (5, 106, 107). development of severe COVID-19, and for the long-term target organ damage observed during the follow-up of these patients. The present review highlights the beneficial roles of AUTHOR CONTRIBUTIONS ACE2 signaling in small arteries through the control of the RAS pathway. The reduction of circulating levels of FJ-A and MG conceived and drafted the manuscript. Ang II and the anti-inflammatory actions of Ang-(1–7) Both authors revised the manuscript for important and ATR2 signaling are the main mechanisms involved intellectual content and gave their final approval of the in ACE2-induced vasculoprotection. Nevertheless, the submitted version. Frontiers in Cardiovascular Medicine | www.frontiersin.org 5 October 2020 | Volume 7 | Article 588692 Galán and Jiménez-Altayó Microvessels, Hypertension, ACE2, and COVID-19 FUNDING the European Regional Development Fund (ERDF). MG was supported by funds provided by ISCIII (CP15/00126, Miguel This work was supported by grants from the Spanish Servet I program). Ministerio de Economía y Competitividad (MINECO)- Instituto de Salud Carlos III (ISCIII) (PI17/01837 to MG and SAF2014-56111-R to FJ-A); Generalitat de Catalunya ACKNOWLEDGMENTS (SGR-645 to FJ-A); and by CIBER on Cardiovascular Diseases (CIBERCV) (CB16/11/00257 to MG), an initiative from Carlos We thank Lídia Puertas-Umbert for her assistance in creating III National Institute of Health, Spain with co-funding from Figure 1. REFERENCES 17. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, et al. A novel angiotensin-converting enzyme-related carboxypeptidase 1. Global Burden of Disease Risk Factor Collaborators. Global, regional, and (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. (2000) 87:1–9. national comparative risk assessment of 84 behavioural, environmental doi: 10.1161/01.RES.87.5.e1 and occupational, and metabolic risks or clusters of risks for 195 18. Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. 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