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Aldosterone (Aldo) breakthrough is a well-known phenomenon that occurs in patients with long-term renin-angiotensin aldosterone system (RAAS) blockade using inhibitors of renin or angiotensin converting enzyme or angiotensin II type 1 receptor blockers. The blockade of the mineralocorticoid receptor (MR), an Aldo binding receptor, is effective in managing patients with resistant hypertension, defined as uncontrollable blood pressure despite the concurrent use of three antihypertensive drugs. In other words, MR inhibitors are not used as first-line antihypertensive drugs in most guidelines for hypertension management. Aldo breakthrough puts hypertensive patients at higher risk of cardiovascular disease and worsens future outcomes. This review discusses Aldo secretion and the mechanism of Aldo breakthrough, dependent or independent of the RAAS, with consideration of the pharmacological aspects of this phenomenon, as well as hypothetical views.

Direct factor Xa (FXa) inhibitors have been used as active oral anticoagulant agents to prevent stroke and deep vein thrombosis. Recently, the anti-inflammatory effects of FXa inhibitors have been expected to reduce the risk of future cardiovascular events via its effect on various signaling pathways through activation of protease-activated receptors (PARs) and non-PARs [1]. PARs are seven-transmembrane domain receptors that are activated by the specific proteolytic cleavage of the N-terminal extracellular domain by endogenous serine proteases, such as thrombin (which acts on PAR-1, -3, and -4) and trypsin, tryptase, factor VIIa, and FXa (which act on PAR-2), and the released N-terminal tail binds the receptor itself and induces intracellular signaling [2].

Circadian rhythms are physical, mental, and behavioral changes within sleep/wake cycles and hormonal activity during the 24-hour day and are closely related to cardiovascular events [1]. Multiple biochemical and physiological parameters, such as blood pressure, autonomic nervous system activity, and renin-angiotensin system (RAS) activity, exhibit circadian rhythms. Circadian rhythms and renal function have been studied for more than 150 years [2], and there has been a focus on the association of circadian rhythm disorders of renal function with hypertension, chronic kidney disease (CKD) and renal fibrosis [3]. Ohashi et al. studied the relation between circadian rhythms and renal damage, especially focusing on the intrarenal RAS, using various rodent models of renal injury [4, 5]. They previously contributed a review article to Hypertension Research reporting that an increase in the intrarenal angiotensinogen (AGT) level induced by augmented glomerular permeability affects circadian rhythms of the intrarenal RAS [6]. Here, the present study by Matsuyama and Ohashi et al. demonstrated that intrarenal RAS activity is influenced by the filtration of “liver-derived” AGT from damaged glomeruli due to disordered circadian fluctuations of glomerular capillary pressure [7].

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected more than seven million people worldwide, contributing to 0.4 million deaths as of June 2020. The fact that the virus uses angiotensin-converting enzyme (ACE)-2 as the cell entry receptor and that hypertension as well as cardiovascular disorders frequently coexist with COVID-19 have generated considerable discussion on the management of patients with hypertension. In addition, the COVID-19 pandemic necessitates the development of and adaptation to a “New Normal” lifestyle, which will have a profound impact not only on communicable diseases but also on noncommunicable diseases, including hypertension. Summarizing what is known and what requires further investigation in this field may help to address the challenges we face. In the present review, we critically evaluate the existing evidence for the epidemiological association between COVID-19 and hypertension. We also summarize the current knowledge regarding the pathophysiology of SARS-CoV-2 infection with an emphasis on ACE2, the cardiovascular system, and the kidney. Finally, we review evidence on the use of antihypertensive medication, namely, ACE inhibitors and angiotensin receptor blockers, in patients with COVID-19.

Despite the challenges associated with the coronavirus pandemic, the last 2 years have been active periods for hypertension research and initiatives in Asia. There are new hypertension guidelines from the World Health Organization that can be interpreted and applied locally. This is also the case for data from the latest Blood Pressure Lowering Treatment Trialists' Collaboration meta-analysis, which showed that greater reductions in systolic blood pressure (BP) are associated with lower risks of cardiovascular events. The randomized controlled Strategy of Blood Pressure Intervention in the Elderly Hypertensive study and the Salt Substitute and Stroke Study provide local data to inform practice. Other initiatives to help reduce high salt intake in Asia are also underway. Both drug-resistant and nocturnal hypertension are appropriate areas of focus in Asia, and there are an increasing number of pharmacological and non-pharmacological treatment options for these conditions. Digital therapeutics to promote uptake and implementation of lifestyle interventions are showing promise, and other digital-based strategies such as telemedicine, wearable BP monitors to detect beat-by-beat BP and artificial intelligence will no doubt become integral parts of future strategies to reduce the burden of hypertension and hypertension-related disease. A number of initiatives from the Hypertension Cardiovascular Outcome Prevention and Evidence in Asia Network and Japanese Society of hypertension are underway, and there is good reason for optimism regarding the ongoing and future management of hypertension in Asia based on these and the active research activities in the region.