Role of aldosterone in various target organ damage in patients with hypertensive emergency: A cross-sectional study

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Although the renin-angiotensin-aldosterone system (RAS) is enormously activated in this disorder, whether the RAS contributes to the development of the organ damage has not been fully elucidated. This cross-sectional study was conducted to characterize the association between RAS and the organ damage in patients with hypertensive emergencies. We enrolled 54 patients who visited our medical center with acute severe hypertension and multiple organ damage between 2012 and 2020. Upon admission, the hypertensive damage was evaluated, including severe kidney impairment (eGFR less than 30 mL/min/1.73 m 2 , SKI), severe retinopathy, concentric left ventricular hypertrophy (c-LVH), thrombotic microangiopathy (TMA) and heart failure with reduced ejection fraction (HFrEF). Among 54 patients, 30, 34 and 37 cases manifested SKI, severe retinopathy and c-LVH, respectively. Each population with these organ injuries had higher plasma aldosterone concentrations than the remaining subset but exhibited variable difference in systolic or diastolic blood pressure. Twenty-two patients had a triad of SKI, severe retinopathy and c-LVH, among whom 5 patients manifested TMA. Furthermore, the number of the damaged organs was correlated with plasma aldosterone levels (Spearman’s coefficient=0.47), with a strong association between plasma aldosterone (≥250 pg/mL) and 3 or more complications (odds ratio=8.49 [95%CI: 2.37-30.46]). In conclusion, in patients with hypertensive emergencies, a higher aldosterone level not only contributed to the development of the organ damage but also was associated with the number of damaged organs in each patient. Health sciences/Medical research Health sciences/Diseases/Cardiovascular diseases/Hypertension Figures Figure 1 Figure 2 Figure 3 Figure 4 What is known about the topic In hypertensive emergencies, markedly elevated blood pressure causes multiple target organ damage. Renin-angiotensin-aldosterone system is markedly activated in most cases of this disorder. What this study adds Aldosterone is closely associated with target organ damage. Higher aldosterone concentrations may be associated with the number of damaged target organs. Introduction Despite the progress in diagnostic medicine and therapeutic pharmacology, uncontrolled severe hypertension remains a matter of great concern in emergency medicine. A variety of organ damage ensues following the development of acute severe hypertension, including cerebral hemorrhage, heart failure, retinopathy and acute kidney impairment. Although the pathophysiology of organ injuries in hypertensive emergencies is attributed in large part to absolute levels and the pace of the changes in blood pressure (BP) [ 1 ], other factors may also contribute to the development of organ damage [ 2 ]. Because the renin-angiotensin-aldosterone system (RAS) is activated in these patients [ 3 , 4 ], it is reasonably surmised that RAS shares the responsibility for the organ damage with acute severe hypertension [ 5 – 7 ]. Nevertheless, there have been few studies that attempt to scrutinize comprehensively the role of RAS and BP in the pathophysiology of acute organ damage in hypertensive emergencies [ 3 ]. There are reported various incidence rates of acute target organ injuries among patients with hypertensive emergencies [ 8 ]. In patients with malignant hypertension, a subset of hypertensive emergencies, high-grade hypertensive retinopathy is observed, and renal functional impairment is reported to be common, with 63% of the patients manifesting this feature at the time of the presentation [ 9 ]. Furthermore, acute vascular endothelial damage could elicit thrombotic microangiopathy (TMA), which is characterized by fragmented erythrocytes and hemolytic anemia and is reported to be present in 25–44% of patients with malignant hypertension [ 7 , 10 ]. Left ventricular hypertrophy (LVH) is also observed frequently, which occurs most often in combination with other complications [ 2 , 4 , 8 ]. Although these observations imply that the patients with hypertensive emergencies possess multiple target organ injuries, it remains unknown which factors (e.g., BP or aldosterone) are associated more closely with the occurrence of multiple organ injuries. In the present study, we attempted to characterize the severe hypertension-induced injuries of various organs, including the kidney, heart, retina, and micro-vessels, in patients with hypertensive emergencies. Because RAS is recognized to be markedly activated in this disorder, we evaluated whether the augmented aldosterone was associated with or additively contributed to the development of these complications in patients with acute severe hypertension. Methods The aim of this cross-sectional study is to characterize various target organ damage induced by acute severe hypertension in patients with hypertensive emergencies, with special reference to plasma aldosterone levels. The study is a subanalysis of our original investigation that evaluated the effects of RAS inhibitors and other antihypertensive drugs on the temporal changes in renal function and prognosis in patients with hypertensive emergencies [ 11 ]. The Review Board and Ethics Committee of Tokyo Bay Urayasu-Ichikawa Medical Center approved the protocol of this study and waived the requirement for obtaining informed consent because of the retrospective nature of this study (approval No. 726). The opt-out information was shown in the following URL ( https://tokyobay-mc.jp/opt_out/ ). The study was conducted to conform to the principles of the Declaration of Helsinki and was registered at UMIN (ID#; UMIN000047340). Information from medical records was anonymized prior to final analysis. Study population and design During the period between April 2012 and August 2020, seventy-seven patients visited the emergency department of Tokyo Bay Urayasu-Ichikawa Medical Center, presenting with severe hypertension (systolicBP ≥ 180 mmHg and/or diastolic BP ≥ 120 mmHg) and the associated complications (Fig. 1 ). Among them, eighteen patients were transferred to other hospitals for further assessment and the treatment of severe hypertension, and five patients died upon admission; the causes of the death were brainstem hemorrhage (age = 64.5 [IQR: 60.8–73.8] y/o, n = 4) and aortic dissection (n = 1). Ultimately, 54 patients were eligible for further evaluation. At the time of admission, BP and laboratory data, including serum creatinine, hemoglobin A1c, hematocrit, urine protein/creatinine ratio, plasma renin activity, and aldosterone, were evaluated. Plasma aldosterone was measured with a traditional radioimmunoassay method. Hypertensive emergency-associated organ damage The hypertensive emergency-associated organ damage was evaluated upon admission. They included cardiac complications (heart failure with ejection fraction (EF) less than 40% [HFrEF], LVH, myocardial infarction), impaired renal function (estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m 2 or requirement for dialysis therapy), high-grade hypertensive retinopathy, cerebral complications (infarction, encephalopathy) and TMA. EF was assessed with cardiac ultrasound and hypertensive retinopathy was evaluated with Scheie’s classification, with grade 3 or 4 as high-grade retinopathy. Concentric LVH was defined according to the standard criteria [ 12 ]. TMA was determined based on the standard criteria (i.e., microangiopathic hemolytic anemia and thrombocytopenia [less than 15x10 4 /mm 3 ]). eGFR was assessed using the formula adapted to the Japanese population [ 13 ]. eGFR = 194×age − 0.287 ×serum creatinine − 1.094 (×0.739, if female) Statistical analysis The results are expressed as the median [lower quartile-upper quartile: IQR]. The comparison between two groups was made with the Mann-Whitney U test, and the data among 3 or more groups were compared with the Kruskal-Wallis test, followed by the Steel-Dwass post-hoc test. The chi-square or Fisher’s exact test was used to compare categorical variables, including the number of patients. Odds ratios (ORs) for each target organ damage were calculated in association with systolic BP, diastolic BP or plasma aldosterone. The relationship between the number of organ damage and various parameters, including plasma aldosterone concentration, systolic BP and diastolic BP, was analyzed using the Spearman's rank correlation test. Furthermore, the cut-off values of these parameters for 3 or more versus 2 or less organ injuries were determined, using the receiver operating characteristic (ROC) analysis. Then, logistic regression analysis was applied with inclusion of these parameters as independent variables and the adjusted OR for 3 or more complications was calculated. Statistical analyses were performed using the John Macintosh Project (JMP) statistical software (version 16, SAS Institute Inc., Cary, NC, USA). Statistical significance was set at p < 0.05. Results A. Patient characteristics Among the 54 patients enrolled in this study, approximately three-quarters of the patients were male and a half of the population had a smoking habit (Table 1). Although 77.8% of the patients were aware of having hypertension, only 21.4% of these subjects had been receiving antihypertensive treatment. Most of the patients were deemed to have essential hypertension but had no evidence of primary aldosteronism, renal vascular stenosis, or CKD, based on previous medical information and clinical examination [ 11 ]. Mild anemia and slightly elevated LDH were observed. Although the median value of the platelet count remained within the normal range, a quarter of the patients manifested the values less than 15x10 4 /mm 3 . eGFR was moderately to severely reduced; five patients commenced hemodialysis therapy upon admission (Fig. 1 ). Both plasma renin activity and aldosterone concentrations were elevated. B. Target organ damage on admission Among 54 survivors on admission, 3 patients suffered cerebral infarction (BP = 204 [IQR: 201–225]/128 [IQR: 124–129] mmHg, age = 48.0 [IQR: 46.5–54.5] y/o) and hypertensive encephalopathy developed in 1 patient (BP = 260/170 mmHg, age = 54 y/o, Fig. 1 ). Thirty patients (i.e., 55.6%) had moderately to severely impaired renal function (i.e., eGFR < 30 mL/min/1.73 m 2 or need for dialysis therapy, Fig. 2 A). In these patients, neither systolic nor diastolic BP differed from that in patients with eGFR ≥ 30 mL/min/1.73 m 2 . Plasma aldosterone was higher in patients with eGFR < 30 mL/min/1.73 m 2 though it did not reach a statistical significance (279 [IQR: 144–484] vs. 165 [IQR: 108–289] pg/mL, p = 0.085). Severe hypertensive retinopathy (H3/H4) was observed in 34 patients (i.e., 79.1%, Fig. 2 B). These patients manifested higher diastolic BP (p = 0.042) and elevated plasma aldosterone concentrations (313 [IQR: 173–504] vs. 131 [IQR: 99–164] pg/mL) and their systolic BP tended to be higher than that in patients with retinopathy H1/H2 (p = 0.081). Similarly, the patients with concentric LVH (n = 37) had higher aldosterone (285 [IQR: 150–466] vs. 163 [IQR: 120–197] pg/mL) and showed a higher tendency of systolic BP than those with no concentric LVH (p = 0.069, Fig. 2 C). Five patients (i.e., 9.3%) were diagnosed with TMA and had higher plasma aldosterone (321 [IQR: 298–591] vs 201 [IQR: 116–331] pg/mL) whereas the BP was nearly the same as in patients without TMA (Fig. 2 D). Ten patients (i.e., 19.2%) manifested a feature of HFrEF (EF < 40%), but neither systolic BP, diastolic BP nor plasma aldosterone differed between the patients with HFrEF and those with EF ≥ 40% (Fig. 2 E). Finally, there were observed diverse incidence rates among these five target organ complications (p < 0.001). The association between the target-organ damage and various parameters (systolic BP, diastolic BP, and aldosterone) was assessed, using the value approximate to the median for each parameter as a cut-off value. Thus, retinopathy and concentric LVH were associated with higher diastolic BP (≥ 140 mmHg) and systolic BP (≥ 220 mmHg), respectively, and both complications had higher associations with aldosterone (≥ 250 pg/mL, Supplementary Fig. 1). Reduced eGFR (< 30 mL/min/1.73 m 2 ) was marginally associated with aldosterone, but not with BP. Similarly, aldosterone ≥ 250 pg/mL was the only parameter that significantly affected the incidence of TMA. HFrEF had no association with BP or aldosterone. C. Association between BP/aldosterone and the number of complications The patients with hypertensive emergencies suffered multiple organ injuries (number of complications = 2.0 [IQR: 1.0–3.0]) when admitted to our hospital. Twenty-three patients (i.e., 42.6%) had 3 or more complications (Fig. 3 A), among whom 22 cases had a triad of severe kidney impairment, severe retinopathy and concentric LVH (a∩b∩c, Fig. 3 B). Of note, this population included all cases with TMA (n = 5), who had a longer history of smoking habits but similar levels of BP and aldosterone, compared with the remaining population (Supplementary table 1 ). The relationship between systolic/diastolic BP and the number of complications in each patient was depicted in Fig. 4 A. There was no difference in systolic or diastolic BP among the 4 groups with a single or multiple complications (p = 0.441 and p = 0.225, for systolic and diastolic BP, respectively). In contrast, plasma aldosterone was higher in patients who had 3 or 4 complications than in those with a single complication (Fig. 4 B); a positive correlation was found between these two parameters (Rs = 0.47). ROC analysis showed that the cut-off values for aldosterone, systolic BP and diastolic BP in association with 3 or more versus 1 or 2 complications were 257 pg/mL, 219 mmHg and 143 mmHg, respectively (Supplementary Fig. 2). The presence of 3 or more complications was strongly associated with higher plasma aldosterone concentrations (≥ 250 pg/mL), but not with systolic (≥ 220 mmHg) or diastolic BP (≥ 140 mmHg, Fig. 4 C). Discussion Hypertensive emergencies represent a form of acute severe hypertension with multiple organ damage and should bring about poor prognosis unless appropriately treated. Cardiac, renal and retinal disease are the commonly observed complications and traditionally, an acute and marked elevation in BP is recognized to be responsible for the development of these organ injuries. There is proposed, however, an additional thesis that enhanced aldosterone activity may play a substantial role in the pathogenesis of the acute organ injuries in hypertensive emergencies [ 3 , 4 , 14 ]. We therefore attempted to characterize the clinical features underlying the acute hypertensive organ damage, based on the levels of BP and aldosterone. Hypertensive emergencies and organ damage The present study demonstrated that the incidence of each complication varied depending on the target organs among our patients with hypertensive emergencies (i.e., 55.6%, 79.1%, 71.2%, 9.3%, and 19.2% for kidney impairment, severe retinopathy, concentric LVH, TMA, and HFrEF, respectively, p < 0.001, Fig. 2 ). Whereas we arbitrarily defined some of these complications, the differences in the incidence of the complications should be attributed to the diverse vulnerability of the organs to BP and aldosterone. Of note, although the patients with brainstem hemorrhage were not included for detailed evaluation because they died very early upon admission, their higher age (64.5 [IQR: 60.8–73.8] vs. 46.0 [IQR: 41.0–51.0] y/o) but similar systolic (219 [IQR: 209–226] vs. 221 [IQR: 200–236] mmHg) and diastolic BP (130 [IQR: 111–142] vs. 140 [IQR: 127–156] mmHg) were worthy of further investigation. Severe retinopathy constitutes a pivotal aspect in the pathological process of malignant hypertension, a major subset of hypertensive emergencies. Evidence has been accumulated that aldosterone, acting as a humoral mediator, contributes to the development of retinopathy through vascular endothelial dysfunction and retinal inflammation [ 5 , 15 – 18 ]. In the present study, we found that the patients with severe retinopathy had higher aldosterone levels along with diastolic BP (Fig. 2 ). Furthermore, higher aldosterone concentrations (≥ 250 pg/mL) were strongly associated with severe retinopathy (OR = 34.2 [95%CI: 1.83-638.38], Supplementary Fig. 1). Although acute severe hypertension-induced organ damage is recognized as the consequence of the organ ischemia and/or the hyperperfusion-induced capillary leakage attributed to disrupted blood flow autoregulation [ 19 ], elevated aldosterone levels may also act in concert with the hemodynamic factor to cause severe retinopathy. In addition to the classic action on renal electrolyte and body fluid balance, excess aldosterone may exert deleterious effects on various organs [ 5 – 7 ]. The present study revealed that higher plasma aldosterone was associated with severe kidney impairment (eGFR < 30 mL/min/1.73 m 2 ) and the development of TMA (Fig. 2 and Supplementary Fig. 1). Moreover, aldosterone, along with systolic BP, contributed to the development of concentric LVH. Because aldosterone causes endothelial dysfunction [ 15 , 16 ], acute complications of TMA, kidney impairment and severe retinopathy may be relevant to the previous reports showing aldosterone-mediated endothelial injury independent of renin or angiotensin [ 17 , 18 ]. Furthermore, aldosterone could play an important role as a factor promoting hypertrophic changes in cardiomyocytes [ 20 ] and may be responsible partly for the development of concentric LVH [ 6 ]. Elevated aldosterone may therefore facilitate multiple organ injuries under the milieu of acute severe hypertension. Of note, the present study showed that both kidney impairment and TMA were associated with elevated aldosterone, but neither systolic nor diastolic BP differed between the presence and the absence of these complications (Figs. 2 A, 2 D and Supplementary Fig. 1). In this regard, Akimoto et al. [ 7 ] found higher aldosterone levels in patients with TMA than in those without TMA. An experimental study also revealed that aldosterone played a crucial role in the pathogenesis of TMA, independently of hypertension, in stroke-prone spontaneously hypertensive rats [ 21 ]. Interestingly, van den Born et al. [ 10 ] demonstrated a close relationship between TMA and renal dysfunction in patients with malignant hypertension. They also showed that RAS activation was associated with enhanced microangiopathic damage and renal dysfunction [ 3 ]. In concert, it is reasonably inferred that aldosterone could participate in the development of microangiopathy and accelerate the progression of kidney impairment. We observed 10 cases with heart failure with reduced EF (< 40%). Although chronic exposure to excess aldosterone was associated with collagen accumulation in the myocardium [ 22 ], no difference in plasma aldosterone concentration was found between the subgroup with EF < 40% and that with EF ≥ 40% (Fig. 2 E). Other factors such as hypertension history, the presence of diabetes and reduced eGFR did not differ between these populations. Number of complications and BP/aldosterone The present study showed that 37 patients (i.e., 68.5%) had multiple organ injuries at the time of admission, and as many as 23 cases (i.e., 42.6%) possessed 3 or more complications (Fig. 3 A). Among these, 22 cases manifested a triad of acute kidney impairment, severe retinopathy and concentric LVH (i.e., a∩b∩c, Fig. 3 B) and had a higher aldosterone concentration (321 [IQR: 218–553] pg/mL, Supplementary table 1 ). These observations lend support to the premise that aldosterone may be involved in the pathophysiology of the multiple organ injuries in hypertensive emergencies. Indeed, a strong correlation was noted between the number of complications and plasma aldosterone concentrations (Rs = 0.47, p = 0.002, Fig. 4 B). The fact that higher plasma aldosterone (≥ 250 pg/mL) is associated with 3 or more complications also indicates a close relationship between these two factors (Fig. 4 C). Hence, supernormal levels of aldosterone exert pathophysiological action on the cardiovascular system, resulting in endothelial dysfunction [ 5 ] and myocardial hypertrophy [ 20 ], and could be responsible for the development of multiple cardiovascular injuries. In contrast, concentric LVH and retinopathy were found more frequently than other target organ injuries among the patients with a single or two complications, who had lower plasma aldosterone than those with 3 or more complications (Supplementary Fig. 3). Hence, the organ damage in this subpopulation may be attributed largely to severe hypertension. Intriguingly, all cases with TMA were found among the subgroup with a triad of impaired renal function, severe retinopathy and concentric LVH (a∩b∩c in Fig. 3 B) and consequently had 4 complications. This subgroup could therefore be regarded as manifesting a severer form of hypertensive emergencies. Although aldosterone plays a pivotal role in the development of TMA (Fig. 2 and Supplementary Fig. 1) [ 7 , 21 ], there was found no difference in its concentration between the subgroup with TMA and that without TMA when evaluated among the population with the triad (Supplementary table 1 ). Since endothelial injury constitutes a major determinant of TMA, additional factors favoring endothelial damage may predispose this patient population to TMA under the high aldosterone milieu; smoking-related vascular injury could be a possible factor (Supplementary table 1 ) [ 23 , 24 ]. Limitation The results from our cross-sectional study contain several caveats to be mentioned. This study was conducted in a single medical center located in the suburbs of Tokyo and the patients enrolled in this study might have some bias that affected patient profiles. Indeed, 77.8% of the patients were aware of hypertension but only 21.4% received medical management (Table 1) and the rate of smoking habits (51.9%) was higher than that in the general population in Japan [ https://ganjoho.jp/public/pre_scr/cause_prevention/smoking/tobacco03.html ]. Furthermore, the incidence of cerebrovascular disease was relatively low even though the deceased cases were included (13.6% [= 8/59], Fig. 1 ). It requires more thorough evaluation to clarify whether the diverse patient profiles or the event rates affected our observations. Conclusion Acute severe hypertension causes deranged organ circulation and imposes a tremendous pressure burden on various organs. Furthermore, enhanced RAS during the establishment of this disorder could accelerate the progression of organ damage and may multiply the number of complications in hypertensive emergencies. Whether the preemptive treatment or early blockade with mineralocorticoid receptor antagonists alleviates the organ damage and accelerates the recovery from organ injuries awaits further investigations. Declarations Data availability statement The data used to support the findings of this study are available from the corresponding author on reasonable request. Acknowledgements The authors thank all the participants in this study. Authors’ contributions AM and KE participated in study design, data collection, analysis, and manuscript drafting. TH, YH and TH assised the data collection and interpretation. SI, KT, KY, KK and MS contributed to data analysis. NI and SF contributed to critical revision of this study. KH and TS contributed to the study design, implementation, analysis, drafting, and modification of the manuscipt. All authors have read and approved the final manuscript. Funding None. Ethical approval The study was approved by the Institutional Review Board and Ethics Committee of Tokyo Bay Urayasu-Ichikawa Medical Center with waiver of the requirement for obtaining informed consent (approval No. 726) and was conducted in accordance with the Declaration of Helsinki. Information from medical records was anonymized prior to final analysis. Competing interests No potential conflict of interest was reported by the authors. References Peixoto AJ. Acute severe hypertension. N Engl J Med. 2019; 381: 1843-1852. Doi: 10.1056/NEJMcp1901117. Shantsila A, Lip GYH. Malignant hypertenson revisited-does this still exist? Am J Hypertens 2017; 30: 543-549. van den Born BJ, Koopmans RP, van Montfrans GA. The renin-angiotensin system in malignant hypertension revisited: plasma renin activity, microangiopathic hemolysis, and renal failure in malignant hypertension. Am J Hypertens. 2007; 20: 900-906. Gosse P, Boulestreau R, Brockers C, Puel C, Rubin S, Cremer A. The pharmacological management of malignant hypertension. J Hypertens. 2020; 38: 2325-2330. Allingham MJ, Mettu PS, Cousins SW. Aldosterone as a mediator of severity in retinal vascular disease: evidence and potential mechanisms. Exp Eye Res 2019; 188: 107788. Doi: 10.1016/j.exer.2019.107788. Edelmann F, Tomaschitz A, Wachter R, Gelbrich G, Knoke M, Düngen HD, et al. Serum aldosterone and its relationship to left ventricular structure and geometry in patients with preserved left ventricular ejection fraction. Eur Heart J 2012; 33: 203-212. Akimoto T, Muto S, Ito C, Takahashi H, Takeda S, Ando Y, Kusano E. Clinical features of malignant hypertension with thrombotic microangiopathy. Clin Exp Hypertens 2011; 33: 77-83. Cremer A, Amraoui F, Lip GYH, Morales E, Rubin S, Segura J, et al. From malignant hypertension to hypertension-MOD: a modern definition for an old but still dangerous emergency. J Human Hypertens 2016; 30: 463-466. Gonzalez R, Morales E, Segura J, Ruilope LM, Praga M. Long-term renal survival in malignant hypertension. Nephrol Dial Transplant 2010; 25: 3266-3272. van den Born BJH, Honnebier UPK, Koopmans RP, van Montfrans GA. Microangiopathic hemolysis and renal failure in malignant hypertension. Hypertension 2005; 45: 246-251. Endo K, Hayashi K, Hara Y, Miyake A, Takano K, Horikawa T, et al. Impact of early initiation of renin-angiotensin blockade on renal function and clinical outcomes in patients with hypertensive emergency: a retrospective cohort study. BMC Nephrol 2023; 24(1):68. Doi: 10.1186/s12882-023-03117-1. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Asociation of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18: 1440-1463. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009; 53: 982-992. Dziedziak J, Zaleska-Zmijewska A, Szaflik JP, Cudnoch-Jedrzejewska A. Impact of arterial hypertension on the eye: a review of the pathogenesis, diagnostic methods, and treatment of hypertensive retinopathy. Med Sci Monit 2022; 28: e935135. Grossmann C, Gekle M. New aspects of rapid aldosterone signaling. Mol Cell Endocrinol 2009; 308: 53-62. Schmitz B, Brand SM, Brand E. Aldosterone signaling and soluble adenylyl cyclase-a nexus for the kidney and vascular endothelium. Biochim Biophys Acta 2014; 1842(12 Pt B): 2601-2609. Hashikabe Y, Suzuki K, Jojima T, Uchida K, Hattori Y. Aldosterone impairs vascular endothelial cell function. J Cardiovasc Pharmacol 2006; 47: 609-613. Farquharson CAJ, Struthers AD. Aldosterone induces acute endothelial dysfunction in vivo in humans: evidence for an aldosterone-induced vasculopathy. Clin Sci 2002; 103: 425-431. Mishima E, Funayama Y, Suzuki T, Mishima F, Nitta F, Toyohara T, Kikuchi K, Kunikata H, Hashimoto J, Miyazaki M, Harigae H, Nakazawa T, Ito S, Abe T. Concurrent analogous organ damage in the brain, eyes, and kidneys in malignant hypertension: reversible encephalopathy, serous retinal detachment, and proteinuria. Hypertens Res 2021; 44: 88-97. https://doi.org/10.1038/s41440-020-0521-2 Somanna NK, Yariswamy M, Garagliano JM, Siebenlist U, Mummidi S, Valente A, et al. Aldosterone-induced cardiomyocyte growth, and fibroblast migration and proliferation are mediated by TRAF3IP2. Cell Signal 2015; 27(10): 1928-1938. Doi: 10.1016/j.cellsig.2015.07.001. Chander PN, Roha R, Ranaudo J, Singh G, Zuckerman A, Stier CT Jr. Aldosterone plays a pivotal role in the pathogenesis of thrombotic microangiopathy in SHRSP. J Am Soc Nephrol 2003; 14: 1990-1997. Brilla CG, Weber KT. Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J Lab Clin Med 1992; 120: 893-901. Isles C, Brown JJ, Cumming AM, Lever AF, McAreavey D, Robertson JI, et al. Excess smoking in malignant-phase hypertension. Br Med J 1979; 1: 579-581. Messner B, Bernhard D. Smoking and cardiovascular disease -mechanisms of endothelial dysfunction and early atherogenesis. Arteriolscler Thromb Vasc Biol 2014; 34: 509-515. Table Table 1 is available in the Supplementary Files section. Additional Declarations There is NO conflict of interest to disclose. Supplementary Files Table.xlsx Table 1 Supplementaldatafile.pdf Supplementary information Supplementary table 1. Characteristics of patients with TMA among the group with a triad of kidney impairment, severe retinopathy and concentric LVH. Supplementary fig. 1. Impact of blood pressure and aldosterone on the development of various organ damage. Supplementary fig. 2. ROC curves determining the cut-off values for complications ≥3 vs aldosterone, systolic BP and diastolic BP. Supplementary fig. 3. Association between the incidence of organ injuries and the number of complications. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3713893","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":259860310,"identity":"04c5215e-9411-4cbb-a47c-23e5f81219ef","order_by":0,"name":"Toshihiko Suzuki","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBUlEQVRIie2RsUoDMRzGv+Mgt0RvzSHYV0gR6uirJFMXW4QuHaQcCHdLoWt9i3sDUyKZ7gEcz+VmxxNE/ZcqtkOujoL5TSHkl3zfP0Ag8DdhUMA5YM3hrg/+pVwATu0fPqIQOgeXx+7fcZWUbdNgMa42tYy6OabpIGfNC06n3ld4fSkV7OQ+dzcxrzHLCiTDNdjMq4hrJvS7maxgqzgqPnTlwM44GEX1KeNWKArGYGT0WkA/bJW3XkWNSIlVikeJE1IqRgr6lLreKnZIXZSlLnrtdJEtpb9LUpZt1mExkE9280wT06s760Q3d96J/SAMzG4VUST5/bF9pIfZb3+hBAKBwD/hE2ldT3KHgOSIAAAAAElFTkSuQmCC","orcid":"","institution":"Tokyo Bay Urayasu Ichikawa Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Toshihiko","middleName":"","lastName":"Suzuki","suffix":""},{"id":259860311,"identity":"ff00a8b7-2f7f-434f-a69b-28ea1d957b9e","order_by":1,"name":"Akihiro Miyake","email":"","orcid":"","institution":"Tokyo Bay Urayasu Ichikawa Medical 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Center","correspondingAuthor":false,"prefix":"","firstName":"Taro","middleName":"","lastName":"Hirai","suffix":""},{"id":259860315,"identity":"15c1a2a3-36e0-445b-8afe-f943c76a4da5","order_by":5,"name":"Yuki Hara","email":"","orcid":"","institution":"Tokyo Bay Urayasu Ichikawa Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Hara","suffix":""},{"id":259860316,"identity":"f814d0a5-dd69-4525-abd0-360102fb9f5d","order_by":6,"name":"Keisuke Takano","email":"","orcid":"","institution":"Tokyo Bay Urayasu Ichikawa Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Keisuke","middleName":"","lastName":"Takano","suffix":""},{"id":259860317,"identity":"fed54fc7-1880-4997-ad58-f594c55b94d1","order_by":7,"name":"Takehiro Horikawa","email":"","orcid":"","institution":"St Marianna University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Takehiro","middleName":"","lastName":"Horikawa","suffix":""},{"id":259860318,"identity":"acf71abb-6210-4f8d-bc78-0373f6e6347a","order_by":8,"name":"Kaede Yoshino","email":"","orcid":"","institution":"Tokyo Bay Urayasu Ichikawa Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Kaede","middleName":"","lastName":"Yoshino","suffix":""},{"id":259860319,"identity":"f13b2ccb-0cee-400d-962d-d465ccda10ec","order_by":9,"name":"Masahiro Sakai","email":"","orcid":"","institution":"Tokyo Bay Urayasu Ichikawa Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Masahiro","middleName":"","lastName":"Sakai","suffix":""},{"id":259860320,"identity":"ef6e9f46-59e8-49a8-8809-4dbaad0573a3","order_by":10,"name":"Koichi Kitamura","email":"","orcid":"","institution":"Tokyo Bay Urayasu Ichikawa Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Koichi","middleName":"","lastName":"Kitamura","suffix":""},{"id":259860321,"identity":"47ab8d7a-6ed2-4cdf-8567-a92e598952a3","order_by":11,"name":"Shinsuke Ito","email":"","orcid":"","institution":"Tokyo Bay Urayasu Ichikawa Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Shinsuke","middleName":"","lastName":"Ito","suffix":""},{"id":259860322,"identity":"35e4e1fb-0059-4193-ad4e-4e9cdda6cf5a","order_by":12,"name":"Naohiko Imai","email":"","orcid":"","institution":"St Marianna University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Naohiko","middleName":"","lastName":"Imai","suffix":""},{"id":259860323,"identity":"573beec8-a199-4136-999a-c2d4d0c00e33","order_by":13,"name":"Shigeki Fujitani","email":"","orcid":"","institution":"St Marianna University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Shigeki","middleName":"","lastName":"Fujitani","suffix":""}],"badges":[],"createdAt":"2023-12-06 08:45:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3713893/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3713893/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49238596,"identity":"0fb1293b-3f34-4973-894c-389d30bdd525","added_by":"auto","created_at":"2024-01-05 18:12:37","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":121034,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow diagram illustrating the enrollment of patients with hypertensive emergencies.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHFrEF; heat failure with reduced ejection fraction, c-LVH; concentric left ventricular hypertrophy, NSTEMI; non-ST elevation myocardial infarction.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3713893/v1/cf678ad4f5ca9bbffef347f1.jpg"},{"id":49240223,"identity":"fbd86890-3e1a-449c-8583-3bef5c47cf54","added_by":"auto","created_at":"2024-01-05 18:20:37","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":180938,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRelationships among systolic blood pressure, diastolic blood pressure and aldosterone in patients with various organ damage.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAld; aldosterone, SBP; systolic blood pressure, DBP; diastolic blood pressure, c-LVH; concentric left ventricular hypertrophy, TMA; thrombotic microangiopathy, HFrEF; heart failure with reduced ejection fraction.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3713893/v1/8c698c0f7128209c5f6c46d1.jpg"},{"id":49238598,"identity":"8ab17c23-fbdb-41e3-b940-9aa3846f9520","added_by":"auto","created_at":"2024-01-05 18:12:37","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":122092,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNumber of complications and the association among the complications.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLVH; left ventricular hypertrophy, TMA; thrombotic microangiopathy, HFrEF; heart failure with reduced ejection fraction.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3713893/v1/1a6a20872cc2bf1813a28106.jpg"},{"id":49238588,"identity":"49392a57-db93-4494-80a0-2fc95af5b8e7","added_by":"auto","created_at":"2024-01-05 18:12:37","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":135002,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAssociation between the number of complications and plasma aldosterone/blood pressure in patients with hypertensive emergency.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBP; blood pressure, SBP; systolic BP, DBP; diastolic BP.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3713893/v1/68a9c67914a52f96cd82ce54.jpg"},{"id":51852643,"identity":"8fd95353-4ef7-4592-b19a-2fe4b529a3ed","added_by":"auto","created_at":"2024-03-01 09:56:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":824898,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3713893/v1/9fccd001-4665-47a3-ba5d-d141e7af3d5b.pdf"},{"id":49238581,"identity":"76671bf5-37ba-4f4b-ad20-e896c58544e1","added_by":"auto","created_at":"2024-01-05 18:12:37","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":11344,"visible":true,"origin":"","legend":"Table 1","description":"","filename":"Table.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3713893/v1/01abf7ce085c99dab27900fe.xlsx"},{"id":49238599,"identity":"d2d60c72-07ad-4c58-a591-a7aae0620744","added_by":"auto","created_at":"2024-01-05 18:12:37","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":218074,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary table 1. Characteristics of patients with TMA among the group with a triad of kidney impairment, severe retinopathy and concentric LVH.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary fig. 1. Impact of blood pressure and aldosterone on the development of various organ damage.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary fig. 2. ROC curves determining the cut-off values for complications ≥3 vs aldosterone, systolic BP and diastolic BP.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary fig. 3. Association between the incidence of organ injuries and the number of complications.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Supplementaldatafile.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3713893/v1/2c355546a99640cfe4f99bac.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Role of aldosterone in various target organ damage in patients with hypertensive emergency: A cross-sectional study","fulltext":[{"header":"What is known about the topic","content":"\u003cul\u003e\n \u003cli\u003eIn hypertensive emergencies, markedly elevated blood pressure causes multiple target organ damage.\u003c/li\u003e\n \u003cli\u003eRenin-angiotensin-aldosterone system is markedly activated in most cases of this disorder.\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eWhat this study adds\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eAldosterone is closely associated with target organ damage.\u003c/li\u003e\n \u003cli\u003eHigher aldosterone concentrations may be associated with the number of damaged target organs.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eDespite the progress in diagnostic medicine and therapeutic pharmacology, uncontrolled severe hypertension remains a matter of great concern in emergency medicine. A variety of organ damage ensues following the development of acute severe hypertension, including cerebral hemorrhage, heart failure, retinopathy and acute kidney impairment. Although the pathophysiology of organ injuries in hypertensive emergencies is attributed in large part to absolute levels and the pace of the changes in blood pressure (BP) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], other factors may also contribute to the development of organ damage [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Because the renin-angiotensin-aldosterone system (RAS) is activated in these patients [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], it is reasonably surmised that RAS shares the responsibility for the organ damage with acute severe hypertension [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Nevertheless, there have been few studies that attempt to scrutinize comprehensively the role of RAS and BP in the pathophysiology of acute organ damage in hypertensive emergencies [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere are reported various incidence rates of acute target organ injuries among patients with hypertensive emergencies [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In patients with malignant hypertension, a subset of hypertensive emergencies, high-grade hypertensive retinopathy is observed, and renal functional impairment is reported to be common, with 63% of the patients manifesting this feature at the time of the presentation [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Furthermore, acute vascular endothelial damage could elicit thrombotic microangiopathy (TMA), which is characterized by fragmented erythrocytes and hemolytic anemia and is reported to be present in 25\u0026ndash;44% of patients with malignant hypertension [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Left ventricular hypertrophy (LVH) is also observed frequently, which occurs most often in combination with other complications [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Although these observations imply that the patients with hypertensive emergencies possess multiple target organ injuries, it remains unknown which factors (e.g., BP or aldosterone) are associated more closely with the occurrence of multiple organ injuries.\u003c/p\u003e \u003cp\u003eIn the present study, we attempted to characterize the severe hypertension-induced injuries of various organs, including the kidney, heart, retina, and micro-vessels, in patients with hypertensive emergencies. Because RAS is recognized to be markedly activated in this disorder, we evaluated whether the augmented aldosterone was associated with or additively contributed to the development of these complications in patients with acute severe hypertension.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe aim of this cross-sectional study is to characterize various target organ damage induced by acute severe hypertension in patients with hypertensive emergencies, with special reference to plasma aldosterone levels. The study is a subanalysis of our original investigation that evaluated the effects of RAS inhibitors and other antihypertensive drugs on the temporal changes in renal function and prognosis in patients with hypertensive emergencies [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The Review Board and Ethics Committee of Tokyo Bay Urayasu-Ichikawa Medical Center approved the protocol of this study and waived the requirement for obtaining informed consent because of the retrospective nature of this study (approval No. 726). The opt-out information was shown in the following URL (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://tokyobay-mc.jp/opt_out/\u003c/span\u003e\u003cspan address=\"https://tokyobay-mc.jp/opt_out/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The study was conducted to conform to the principles of the Declaration of Helsinki and was registered at UMIN (ID#; UMIN000047340). Information from medical records was anonymized prior to final analysis.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population and design\u003c/h2\u003e \u003cp\u003eDuring the period between April 2012 and August 2020, seventy-seven patients visited the emergency department of Tokyo Bay Urayasu-Ichikawa Medical Center, presenting with severe hypertension (systolicBP\u0026thinsp;\u0026ge;\u0026thinsp;180 mmHg and/or diastolic BP\u0026thinsp;\u0026ge;\u0026thinsp;120 mmHg) and the associated complications (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Among them, eighteen patients were transferred to other hospitals for further assessment and the treatment of severe hypertension, and five patients died upon admission; the causes of the death were brainstem hemorrhage (age\u0026thinsp;=\u0026thinsp;64.5 [IQR: 60.8\u0026ndash;73.8] y/o, n\u0026thinsp;=\u0026thinsp;4) and aortic dissection (n\u0026thinsp;=\u0026thinsp;1). Ultimately, 54 patients were eligible for further evaluation.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAt the time of admission, BP and laboratory data, including serum creatinine, hemoglobin A1c, hematocrit, urine protein/creatinine ratio, plasma renin activity, and aldosterone, were evaluated. Plasma aldosterone was measured with a traditional radioimmunoassay method.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eHypertensive emergency-associated organ damage\u003c/h2\u003e \u003cp\u003eThe hypertensive emergency-associated organ damage was evaluated upon admission. They included cardiac complications (heart failure with ejection fraction (EF) less than 40% [HFrEF], LVH, myocardial infarction), impaired renal function (estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e or requirement for dialysis therapy), high-grade hypertensive retinopathy, cerebral complications (infarction, encephalopathy) and TMA. EF was assessed with cardiac ultrasound and hypertensive retinopathy was evaluated with Scheie\u0026rsquo;s classification, with grade 3 or 4 as high-grade retinopathy. Concentric LVH was defined according to the standard criteria [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. TMA was determined based on the standard criteria (i.e., microangiopathic hemolytic anemia and thrombocytopenia [less than 15x10\u003csup\u003e4\u003c/sup\u003e/mm\u003csup\u003e3\u003c/sup\u003e]). eGFR was assessed using the formula adapted to the Japanese population [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eeGFR\u0026thinsp;=\u0026thinsp;194\u0026times;age\u003csup\u003e\u0026minus;\u0026thinsp;0.287\u003c/sup\u003e\u0026times;serum creatinine\u003csup\u003e\u0026minus;\u0026thinsp;1.094\u003c/sup\u003e (\u0026times;0.739, if female)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe results are expressed as the median [lower quartile-upper quartile: IQR]. The comparison between two groups was made with the Mann-Whitney U test, and the data among 3 or more groups were compared with the Kruskal-Wallis test, followed by the Steel-Dwass post-hoc test. The chi-square or Fisher\u0026rsquo;s exact test was used to compare categorical variables, including the number of patients. Odds ratios (ORs) for each target organ damage were calculated in association with systolic BP, diastolic BP or plasma aldosterone. The relationship between the number of organ damage and various parameters, including plasma aldosterone concentration, systolic BP and diastolic BP, was analyzed using the Spearman's rank correlation test. Furthermore, the cut-off values of these parameters for 3 or more versus 2 or less organ injuries were determined, using the receiver operating characteristic (ROC) analysis. Then, logistic regression analysis was applied with inclusion of these parameters as independent variables and the adjusted OR for 3 or more complications was calculated. Statistical analyses were performed using the John Macintosh Project (JMP) statistical software (version 16, SAS Institute Inc., Cary, NC, USA). Statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eA. Patient characteristics\u003c/h2\u003e \u003cp\u003eAmong the 54 patients enrolled in this study, approximately three-quarters of the patients were male and a half of the population had a smoking habit (Table\u0026nbsp;1). Although 77.8% of the patients were aware of having hypertension, only 21.4% of these subjects had been receiving antihypertensive treatment. Most of the patients were deemed to have essential hypertension but had no evidence of primary aldosteronism, renal vascular stenosis, or CKD, based on previous medical information and clinical examination [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Mild anemia and slightly elevated LDH were observed. Although the median value of the platelet count remained within the normal range, a quarter of the patients manifested the values less than 15x10\u003csup\u003e4\u003c/sup\u003e/mm\u003csup\u003e3\u003c/sup\u003e. eGFR was moderately to severely reduced; five patients commenced hemodialysis therapy upon admission (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Both plasma renin activity and aldosterone concentrations were elevated.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eB. Target organ damage on admission\u003c/h2\u003e \u003cp\u003eAmong 54 survivors on admission, 3 patients suffered cerebral infarction (BP\u0026thinsp;=\u0026thinsp;204 [IQR: 201\u0026ndash;225]/128 [IQR: 124\u0026ndash;129] mmHg, age\u0026thinsp;=\u0026thinsp;48.0 [IQR: 46.5\u0026ndash;54.5] y/o) and hypertensive encephalopathy developed in 1 patient (BP\u0026thinsp;=\u0026thinsp;260/170 mmHg, age\u0026thinsp;=\u0026thinsp;54 y/o, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThirty patients (i.e., 55.6%) had moderately to severely impaired renal function (i.e., eGFR\u0026thinsp;\u0026lt;\u0026thinsp;30 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e or need for dialysis therapy, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). In these patients, neither systolic nor diastolic BP differed from that in patients with eGFR\u0026thinsp;\u0026ge;\u0026thinsp;30 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e. Plasma aldosterone was higher in patients with eGFR\u0026thinsp;\u0026lt;\u0026thinsp;30 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e though it did not reach a statistical significance (279 [IQR: 144\u0026ndash;484] vs. 165 [IQR: 108\u0026ndash;289] pg/mL, p\u0026thinsp;=\u0026thinsp;0.085).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSevere hypertensive retinopathy (H3/H4) was observed in 34 patients (i.e., 79.1%, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). These patients manifested higher diastolic BP (p\u0026thinsp;=\u0026thinsp;0.042) and elevated plasma aldosterone concentrations (313 [IQR: 173\u0026ndash;504] vs. 131 [IQR: 99\u0026ndash;164] pg/mL) and their systolic BP tended to be higher than that in patients with retinopathy H1/H2 (p\u0026thinsp;=\u0026thinsp;0.081). Similarly, the patients with concentric LVH (n\u0026thinsp;=\u0026thinsp;37) had higher aldosterone (285 [IQR: 150\u0026ndash;466] vs. 163 [IQR: 120\u0026ndash;197] pg/mL) and showed a higher tendency of systolic BP than those with no concentric LVH (p\u0026thinsp;=\u0026thinsp;0.069, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003eFive patients (i.e., 9.3%) were diagnosed with TMA and had higher plasma aldosterone (321 [IQR: 298\u0026ndash;591] vs 201 [IQR: 116\u0026ndash;331] pg/mL) whereas the BP was nearly the same as in patients without TMA (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD). Ten patients (i.e., 19.2%) manifested a feature of HFrEF (EF\u0026thinsp;\u0026lt;\u0026thinsp;40%), but neither systolic BP, diastolic BP nor plasma aldosterone differed between the patients with HFrEF and those with EF\u0026thinsp;\u0026ge;\u0026thinsp;40% (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE). Finally, there were observed diverse incidence rates among these five target organ complications (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eThe association between the target-organ damage and various parameters (systolic BP, diastolic BP, and aldosterone) was assessed, using the value approximate to the median for each parameter as a cut-off value. Thus, retinopathy and concentric LVH were associated with higher diastolic BP (\u0026ge;\u0026thinsp;140 mmHg) and systolic BP (\u0026ge;\u0026thinsp;220 mmHg), respectively, and both complications had higher associations with aldosterone (\u0026ge;\u0026thinsp;250 pg/mL, Supplementary Fig.\u0026nbsp;1). Reduced eGFR (\u0026lt;\u0026thinsp;30 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e) was marginally associated with aldosterone, but not with BP. Similarly, aldosterone\u0026thinsp;\u0026ge;\u0026thinsp;250 pg/mL was the only parameter that significantly affected the incidence of TMA. HFrEF had no association with BP or aldosterone.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eC. Association between BP/aldosterone and the number of complications\u003c/h2\u003e \u003cp\u003eThe patients with hypertensive emergencies suffered multiple organ injuries (number of complications\u0026thinsp;=\u0026thinsp;2.0 [IQR: 1.0\u0026ndash;3.0]) when admitted to our hospital. Twenty-three patients (i.e., 42.6%) had 3 or more complications (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA), among whom 22 cases had a triad of severe kidney impairment, severe retinopathy and concentric LVH (a\u0026cap;b\u0026cap;c, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). Of note, this population included all cases with TMA (n\u0026thinsp;=\u0026thinsp;5), who had a longer history of smoking habits but similar levels of BP and aldosterone, compared with the remaining population (Supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe relationship between systolic/diastolic BP and the number of complications in each patient was depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA. There was no difference in systolic or diastolic BP among the 4 groups with a single or multiple complications (p\u0026thinsp;=\u0026thinsp;0.441 and p\u0026thinsp;=\u0026thinsp;0.225, for systolic and diastolic BP, respectively). In contrast, plasma aldosterone was higher in patients who had 3 or 4 complications than in those with a single complication (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB); a positive correlation was found between these two parameters (Rs\u0026thinsp;=\u0026thinsp;0.47).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eROC analysis showed that the cut-off values for aldosterone, systolic BP and diastolic BP in association with 3 or more versus 1 or 2 complications were 257 pg/mL, 219 mmHg and 143 mmHg, respectively (Supplementary Fig.\u0026nbsp;2). The presence of 3 or more complications was strongly associated with higher plasma aldosterone concentrations (\u0026ge;\u0026thinsp;250 pg/mL), but not with systolic (\u0026ge;\u0026thinsp;220 mmHg) or diastolic BP (\u0026ge;\u0026thinsp;140 mmHg, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eHypertensive emergencies represent a form of acute severe hypertension with multiple organ damage and should bring about poor prognosis unless appropriately treated. Cardiac, renal and retinal disease are the commonly observed complications and traditionally, an acute and marked elevation in BP is recognized to be responsible for the development of these organ injuries. There is proposed, however, an additional thesis that enhanced aldosterone activity may play a substantial role in the pathogenesis of the acute organ injuries in hypertensive emergencies [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. We therefore attempted to characterize the clinical features underlying the acute hypertensive organ damage, based on the levels of BP and aldosterone.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eHypertensive emergencies and organ damage\u003c/h2\u003e \u003cp\u003eThe present study demonstrated that the incidence of each complication varied depending on the target organs among our patients with hypertensive emergencies (i.e., 55.6%, 79.1%, 71.2%, 9.3%, and 19.2% for kidney impairment, severe retinopathy, concentric LVH, TMA, and HFrEF, respectively, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Whereas we arbitrarily defined some of these complications, the differences in the incidence of the complications should be attributed to the diverse vulnerability of the organs to BP and aldosterone. Of note, although the patients with brainstem hemorrhage were not included for detailed evaluation because they died very early upon admission, their higher age (64.5 [IQR: 60.8\u0026ndash;73.8] vs. 46.0 [IQR: 41.0\u0026ndash;51.0] y/o) but similar systolic (219 [IQR: 209\u0026ndash;226] vs. 221 [IQR: 200\u0026ndash;236] mmHg) and diastolic BP (130 [IQR: 111\u0026ndash;142] vs. 140 [IQR: 127\u0026ndash;156] mmHg) were worthy of further investigation.\u003c/p\u003e \u003cp\u003eSevere retinopathy constitutes a pivotal aspect in the pathological process of malignant hypertension, a major subset of hypertensive emergencies. Evidence has been accumulated that aldosterone, acting as a humoral mediator, contributes to the development of retinopathy through vascular endothelial dysfunction and retinal inflammation [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In the present study, we found that the patients with severe retinopathy had higher aldosterone levels along with diastolic BP (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Furthermore, higher aldosterone concentrations (\u0026ge;\u0026thinsp;250 pg/mL) were strongly associated with severe retinopathy (OR\u0026thinsp;=\u0026thinsp;34.2 [95%CI: 1.83-638.38], Supplementary Fig.\u0026nbsp;1). Although acute severe hypertension-induced organ damage is recognized as the consequence of the organ ischemia and/or the hyperperfusion-induced capillary leakage attributed to disrupted blood flow autoregulation [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], elevated aldosterone levels may also act in concert with the hemodynamic factor to cause severe retinopathy.\u003c/p\u003e \u003cp\u003eIn addition to the classic action on renal electrolyte and body fluid balance, excess aldosterone may exert deleterious effects on various organs [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The present study revealed that higher plasma aldosterone was associated with severe kidney impairment (eGFR\u0026thinsp;\u0026lt;\u0026thinsp;30 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e) and the development of TMA (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Supplementary Fig.\u0026nbsp;1). Moreover, aldosterone, along with systolic BP, contributed to the development of concentric LVH. Because aldosterone causes endothelial dysfunction [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], acute complications of TMA, kidney impairment and severe retinopathy may be relevant to the previous reports showing aldosterone-mediated endothelial injury independent of renin or angiotensin [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Furthermore, aldosterone could play an important role as a factor promoting hypertrophic changes in cardiomyocytes [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] and may be responsible partly for the development of concentric LVH [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Elevated aldosterone may therefore facilitate multiple organ injuries under the milieu of acute severe hypertension.\u003c/p\u003e \u003cp\u003eOf note, the present study showed that both kidney impairment and TMA were associated with elevated aldosterone, but neither systolic nor diastolic BP differed between the presence and the absence of these complications (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD and Supplementary Fig.\u0026nbsp;1). In this regard, Akimoto et al. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] found higher aldosterone levels in patients with TMA than in those without TMA. An experimental study also revealed that aldosterone played a crucial role in the pathogenesis of TMA, independently of hypertension, in stroke-prone spontaneously hypertensive rats [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Interestingly, van den Born et al. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] demonstrated a close relationship between TMA and renal dysfunction in patients with malignant hypertension. They also showed that RAS activation was associated with enhanced microangiopathic damage and renal dysfunction [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In concert, it is reasonably inferred that aldosterone could participate in the development of microangiopathy and accelerate the progression of kidney impairment.\u003c/p\u003e \u003cp\u003eWe observed 10 cases with heart failure with reduced EF (\u0026lt;\u0026thinsp;40%). Although chronic exposure to excess aldosterone was associated with collagen accumulation in the myocardium [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], no difference in plasma aldosterone concentration was found between the subgroup with EF\u0026thinsp;\u0026lt;\u0026thinsp;40% and that with EF\u0026thinsp;\u0026ge;\u0026thinsp;40% (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE). Other factors such as hypertension history, the presence of diabetes and reduced eGFR did not differ between these populations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eNumber of complications and BP/aldosterone\u003c/h2\u003e \u003cp\u003eThe present study showed that 37 patients (i.e., 68.5%) had multiple organ injuries at the time of admission, and as many as 23 cases (i.e., 42.6%) possessed 3 or more complications (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Among these, 22 cases manifested a triad of acute kidney impairment, severe retinopathy and concentric LVH (i.e., a\u0026cap;b\u0026cap;c, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB) and had a higher aldosterone concentration (321 [IQR: 218\u0026ndash;553] pg/mL, Supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). These observations lend support to the premise that aldosterone may be involved in the pathophysiology of the multiple organ injuries in hypertensive emergencies. Indeed, a strong correlation was noted between the number of complications and plasma aldosterone concentrations (Rs\u0026thinsp;=\u0026thinsp;0.47, p\u0026thinsp;=\u0026thinsp;0.002, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB). The fact that higher plasma aldosterone (\u0026ge;\u0026thinsp;250 pg/mL) is associated with 3 or more complications also indicates a close relationship between these two factors (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC). Hence, supernormal levels of aldosterone exert pathophysiological action on the cardiovascular system, resulting in endothelial dysfunction [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] and myocardial hypertrophy [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], and could be responsible for the development of multiple cardiovascular injuries. In contrast, concentric LVH and retinopathy were found more frequently than other target organ injuries among the patients with a single or two complications, who had lower plasma aldosterone than those with 3 or more complications (Supplementary Fig.\u0026nbsp;3). Hence, the organ damage in this subpopulation may be attributed largely to severe hypertension.\u003c/p\u003e \u003cp\u003eIntriguingly, all cases with TMA were found among the subgroup with a triad of impaired renal function, severe retinopathy and concentric LVH (a\u0026cap;b\u0026cap;c in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB) and consequently had 4 complications. This subgroup could therefore be regarded as manifesting a severer form of hypertensive emergencies. Although aldosterone plays a pivotal role in the development of TMA (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Supplementary Fig.\u0026nbsp;1) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], there was found no difference in its concentration between the subgroup with TMA and that without TMA when evaluated among the population with the triad (Supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Since endothelial injury constitutes a major determinant of TMA, additional factors favoring endothelial damage may predispose this patient population to TMA under the high aldosterone milieu; smoking-related vascular injury could be a possible factor (Supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eLimitation\u003c/h2\u003e \u003cp\u003eThe results from our cross-sectional study contain several caveats to be mentioned. This study was conducted in a single medical center located in the suburbs of Tokyo and the patients enrolled in this study might have some bias that affected patient profiles. Indeed, 77.8% of the patients were aware of hypertension but only 21.4% received medical management (Table\u0026nbsp;1) and the rate of smoking habits (51.9%) was higher than that in the general population in Japan [\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://ganjoho.jp/public/pre_scr/cause_prevention/smoking/tobacco03.html\u003c/span\u003e\u003cspan address=\"https://ganjoho.jp/public/pre_scr/cause_prevention/smoking/tobacco03.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e]. Furthermore, the incidence of cerebrovascular disease was relatively low even though the deceased cases were included (13.6% [=\u0026thinsp;8/59], Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). It requires more thorough evaluation to clarify whether the diverse patient profiles or the event rates affected our observations.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAcute severe hypertension causes deranged organ circulation and imposes a tremendous pressure burden on various organs. Furthermore, enhanced RAS during the establishment of this disorder could accelerate the progression of organ damage and may multiply the number of complications in hypertensive emergencies. Whether the preemptive treatment or early blockade with mineralocorticoid receptor antagonists alleviates the organ damage and accelerates the recovery from organ injuries awaits further investigations.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used to support the findings of this study are available from the corresponding author on reasonable request. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank all the participants in this study. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAM and KE\u003csup\u003e \u003c/sup\u003eparticipated in study design, data collection, analysis, and manuscript drafting. TH, YH and TH assised the data collection and interpretation. SI, KT, KY, KK and MS contributed to data analysis. NI\u003csup\u003e \u003c/sup\u003eand SF\u003csup\u003e \u003c/sup\u003econtributed to critical revision of this study. KH and TS\u003csup\u003e \u003c/sup\u003econtributed to the study design, implementation, analysis, drafting, and modification of the manuscipt. All authors have read and approved the final manuscript. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Institutional Review Board and Ethics Committee of Tokyo Bay Urayasu-Ichikawa Medical Center with waiver of the requirement for obtaining informed consent (approval No. 726) and was conducted in accordance with the Declaration of Helsinki. Information from medical records was anonymized prior to final analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo potential conflict of interest was reported by the authors.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePeixoto AJ. Acute severe hypertension. N Engl J Med. 2019; 381: 1843-1852. Doi: 10.1056/NEJMcp1901117.\u003c/li\u003e\n\u003cli\u003eShantsila A, Lip GYH. Malignant hypertenson revisited-does this still exist? Am J Hypertens 2017; 30: 543-549.\u003c/li\u003e\n\u003cli\u003evan den Born BJ, Koopmans RP, van Montfrans GA. The renin-angiotensin system in malignant hypertension revisited: plasma renin activity, microangiopathic hemolysis, and renal failure in malignant hypertension. Am J Hypertens. 2007; 20: 900-906.\u003c/li\u003e\n\u003cli\u003eGosse P, Boulestreau R, Brockers C, Puel C, Rubin S, Cremer A. The pharmacological management of malignant hypertension. J Hypertens. 2020; 38: 2325-2330.\u003c/li\u003e\n\u003cli\u003eAllingham MJ, Mettu PS, Cousins SW. Aldosterone as a mediator of severity in retinal vascular disease: evidence and potential mechanisms. Exp Eye Res 2019; 188: 107788. Doi: 10.1016/j.exer.2019.107788. \u003c/li\u003e\n\u003cli\u003eEdelmann F, Tomaschitz A, Wachter R, Gelbrich G, Knoke M, D\u0026uuml;ngen HD, et al. Serum aldosterone and its relationship to left ventricular structure and geometry in patients with preserved left ventricular ejection fraction. Eur Heart J 2012; 33: 203-212. \u003c/li\u003e\n\u003cli\u003eAkimoto T, Muto S, Ito C, Takahashi H, Takeda S, Ando Y, Kusano E. Clinical features of malignant hypertension with thrombotic microangiopathy. Clin Exp Hypertens 2011; 33: 77-83.\u003c/li\u003e\n\u003cli\u003eCremer A, Amraoui F, Lip GYH, Morales E, Rubin S, Segura J, et al. From malignant hypertension to hypertension-MOD: a modern definition for an old but still dangerous emergency. J Human Hypertens 2016; 30: 463-466. \u003c/li\u003e\n\u003cli\u003eGonzalez R, Morales E, Segura J, Ruilope LM, Praga M. Long-term renal survival in malignant hypertension. Nephrol Dial Transplant 2010; 25: 3266-3272.\u003c/li\u003e\n\u003cli\u003evan den Born BJH, Honnebier UPK, Koopmans RP, van Montfrans GA. Microangiopathic hemolysis and renal failure in malignant hypertension. Hypertension 2005; 45: 246-251.\u003c/li\u003e\n\u003cli\u003eEndo K, Hayashi K, Hara Y, Miyake A, Takano K, Horikawa T, et al. Impact of early initiation of renin-angiotensin blockade on renal function and clinical outcomes in patients with hypertensive emergency: a retrospective cohort study. BMC Nephrol 2023; 24(1):68. Doi: 10.1186/s12882-023-03117-1. \u003c/li\u003e\n\u003cli\u003eLang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography\u0026rsquo;s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Asociation of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18: 1440-1463. \u003c/li\u003e\n\u003cli\u003eMatsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009; 53: 982-992.\u003c/li\u003e\n\u003cli\u003eDziedziak J, Zaleska-Zmijewska A, Szaflik JP, Cudnoch-Jedrzejewska A. Impact of arterial hypertension on the eye: a review of the pathogenesis, diagnostic methods, and treatment of hypertensive retinopathy. Med Sci Monit 2022; 28: e935135. \u003c/li\u003e\n\u003cli\u003eGrossmann C, Gekle M. New aspects of rapid aldosterone signaling. Mol Cell Endocrinol 2009; 308: 53-62. \u003c/li\u003e\n\u003cli\u003eSchmitz B, Brand SM, Brand E. Aldosterone signaling and soluble adenylyl cyclase-a nexus for the kidney and vascular endothelium. Biochim Biophys Acta 2014; 1842(12 Pt B): 2601-2609.\u003c/li\u003e\n\u003cli\u003eHashikabe Y, Suzuki K, Jojima T, Uchida K, Hattori Y. Aldosterone impairs vascular endothelial cell function. J Cardiovasc Pharmacol 2006; 47: 609-613.\u003c/li\u003e\n\u003cli\u003eFarquharson CAJ, Struthers AD. Aldosterone induces acute endothelial dysfunction in vivo in humans: evidence for an aldosterone-induced vasculopathy. Clin Sci 2002; 103: 425-431. \u003c/li\u003e\n\u003cli\u003eMishima E, Funayama Y, Suzuki T, Mishima F, Nitta F, Toyohara T, Kikuchi K, Kunikata H, Hashimoto J, Miyazaki M, Harigae H, Nakazawa T, Ito S, Abe T. Concurrent analogous organ damage in the brain, eyes, and kidneys in malignant hypertension: reversible encephalopathy, serous retinal detachment, and proteinuria. Hypertens Res 2021; 44: 88-97. https://doi.org/10.1038/s41440-020-0521-2\u003c/li\u003e\n\u003cli\u003eSomanna NK, Yariswamy M, Garagliano JM, Siebenlist U, Mummidi S, Valente A, et al. Aldosterone-induced cardiomyocyte growth, and fibroblast migration and proliferation are mediated by TRAF3IP2. Cell Signal 2015; 27(10): 1928-1938. Doi: 10.1016/j.cellsig.2015.07.001.\u003c/li\u003e\n\u003cli\u003eChander PN, Roha R, Ranaudo J, Singh G, Zuckerman A, Stier CT Jr. Aldosterone plays a pivotal role in the pathogenesis of thrombotic microangiopathy in SHRSP. J Am Soc Nephrol 2003; 14: 1990-1997. \u003c/li\u003e\n\u003cli\u003eBrilla CG, Weber KT. Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J Lab Clin Med 1992; 120: 893-901. \u003c/li\u003e\n\u003cli\u003eIsles C, Brown JJ, Cumming AM, Lever AF, McAreavey D, Robertson JI, et al. Excess smoking in malignant-phase hypertension. Br Med J 1979; 1: 579-581. \u003c/li\u003e\n\u003cli\u003eMessner B, Bernhard D. Smoking and cardiovascular disease -mechanisms of endothelial dysfunction and early atherogenesis. Arteriolscler Thromb Vasc Biol 2014; 34: 509-515. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3713893/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3713893/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHypertensive emergency is a critical disease that causes multiple organ injuries. Although the renin-angiotensin-aldosterone system (RAS) is enormously activated in this disorder, whether the RAS contributes to the development of the organ damage has not been fully elucidated. This cross-sectional study was conducted to characterize the association between RAS and the organ damage in patients with hypertensive emergencies. We enrolled 54 patients who visited our medical center with acute severe hypertension and multiple organ damage between 2012 and 2020. Upon admission, the hypertensive damage was evaluated, including severe kidney impairment (eGFR less than 30 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e, SKI), severe retinopathy, concentric left ventricular hypertrophy (c-LVH), thrombotic microangiopathy (TMA) and heart failure with reduced ejection fraction (HFrEF). Among 54 patients, 30, 34 and 37 cases manifested SKI, severe retinopathy and c-LVH, respectively. Each population with these organ injuries had higher plasma aldosterone concentrations than the remaining subset but exhibited variable difference in systolic or diastolic blood pressure. Twenty-two patients had a triad of SKI, severe retinopathy and c-LVH, among whom 5 patients manifested TMA. Furthermore, the number of the damaged organs was correlated with plasma aldosterone levels (Spearman’s coefficient=0.47), with a strong association between plasma aldosterone (≥250 pg/mL) and 3 or more complications (odds ratio=8.49 [95%CI: 2.37-30.46]). In conclusion, in patients with hypertensive emergencies, a higher aldosterone level not only contributed to the development of the organ damage but also was associated with the number of damaged organs in each patient.\u003c/p\u003e","manuscriptTitle":"Role of aldosterone in various target organ damage in patients with hypertensive emergency: A cross-sectional study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-05 18:12:32","doi":"10.21203/rs.3.rs-3713893/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"75d67d95-9a34-4987-af12-d22325f61848","owner":[],"postedDate":"January 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":27443402,"name":"Health sciences/Medical research"},{"id":27443403,"name":"Health sciences/Diseases/Cardiovascular diseases/Hypertension"}],"tags":[],"updatedAt":"2024-07-23T11:18:16+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-05 18:12:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3713893","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3713893","identity":"rs-3713893","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}