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Update on Hypertension Research in 2021

Masaki mogi, tatsuya maruhashi, yukihito higashi, takahiro masuda, daisuke nagata, michiaki nagai, kanako bokuda, atsuhiro ichihara, yoichi nozato, keisuke narita, satoshi hoshide, atsushi tanaka, koichi node, yuichi yoshida, hirotaka shibata, kenichi katsurada, masanari kuwabara, takahide kodama, keisuke shinohara, kazuomi kario.

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Corresponding author.

Received 2022 Jun 1; Accepted 2022 Jun 3; Issue date 2022.

This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

In 2021, 217 excellent manuscripts were published in Hypertension Research. Editorial teams greatly appreciate the authors’ contribution to hypertension research progress. Here, our editorial members have summarized twelve topics from published work and discussed current topics in depth. We hope you enjoy our special feature, “Update on Hypertension Research in 2021”.

Keywords: Hypertension Research, Up-to-date, 2021

Usefulness of vascular function tests for cardiovascular risk assessment and a better understanding of the pathophysiology of atherosclerosis in hypertension (see Supplementary Information  1 )

Vascular function tests and vascular imaging tests are useful for assessing the severity of atherosclerosis. Since vascular dysfunction and vascular morphological alterations are closely associated with the maintenance and progression of atherosclerosis, vascular tests may provide additional information for cardiovascular risk assessment (Fig.  1 ) [ 1 – 5 ]. Measurement of the ankle-brachial index (ABI) has been performed not only for screening for peripheral artery disease but also for cardiovascular risk assessment in clinical practice [ 6 ]. However, the ABI method does not always provide reliable data because the ABI value is falsely elevated despite the presence of occlusive arterial lesions in the lower extremities of patients with noncompressible lower limb arteries, which can lead to incorrect cardiovascular risk assessment [ 7 – 9 ]. Tsai et al. [ 10 ] reported that a combination of an ABI value <0.9 and an interleg ABI difference ≥0.17 was more useful for predicting all-cause mortality and cardiovascular mortality than was an ABI value <0.9 alone. Therefore, attention should be given not only to the ABI value but also to the interleg ABI difference for more precise cardiovascular risk assessment. Sang et al. [ 11 ] conducted a systematic review and meta-analysis to investigate the usefulness of brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, for risk assessment and showed that higher baPWV was significantly associated with a higher risk of cardiovascular events, cardiovascular mortality, and all-cause mortality in patients with a history of coronary artery disease or stroke.

Vascular function tests and vascular imaging tests for the assessment of cardiovascular risk. CV cardiovascular

Vascular tests are also useful to achieve a better understanding of the underlying pathophysiology of cardiac disorders. Harada et al. [ 12 ] reported that short stature defined as height <155.0 cm was associated with low flow-mediated vasodilation (FMD), an index of endothelial function, in Japanese men, supporting the association between short stature and high risk of cardiovascular events [ 13 ]. Cassano et al. [Supplementary Information  1 - 1 ] reported that low levels of endothelial progenitor cells (EPCs) at baseline were associated with impaired endothelial function assessed by the reactive hyperemia index (RHI) and impaired arterial stiffness assessed by carotid-femoral PWV (cfPWV) at baseline and that EPC levels at baseline were also associated with longitudinal changes in RHI and cfPWV three years after the initiation of antihypertensive drug treatment in patients with hypertension. Murai et al. [Supplementary Information  1 - 2 ]. reported that a higher area under the curve value of insulin during a 75-g oral glucose tolerance test, but not insulin sensitivity indices, was significantly associated with higher baPWV in young Japanese subjects aged <40 years. Miyaoka et al. [ 14 ] reported that baPWV and central systolic blood pressure were significantly associated with renal microvascular damage assessed by using renal biopsy specimens in patients with nondiabetic kidney disease. Vila et al. [Supplementary Information  1 - 3 ] reported that carotid intima-media thickness (IMT) was significantly greater in male patients with autoimmune disease than in age-matched male controls without autoimmune disease, supporting a role for immune-mediated inflammation in the pathogenesis of atherosclerosis. Li et al. [Supplementary Information  1 - 4 ] showed in a cross-sectional study that increased carotid IMT was significantly associated with cognitive impairment assessed by the Mini-Mental State Examination in Chinese patients with hypertension, especially patients who were ≥60 years of age and patients with low high-density lipoprotein cholesterol levels (<40 mg/dL).

Vascular function is profoundly affected by habitual behavior. Fryer et al. [Supplementary Information  1 - 5 ] reported that central arterial stiffness and peripheral arterial stiffness assessed by cfPWV and PWV β were more deteriorated by uninterrupted prolonged sitting (180 min) combined with prior high-fat meal consumption (61 g fat, 1066 kcal) than by uninterrupted prolonged sitting combined with prior low-fat meal consumption (10 g fat, 601 kcal) in healthy nonsmoking male subjects, suggesting that high-fat meal consumption should be avoided before uninterrupted prolonged sitting to prevent the progression of arterial stiffening. Yamaji et al. [ 15 ] reported that endothelial function assessed by FMD and vascular smooth muscle function assessed by nitroglycerine-induced vasodilation of the brachial artery were more impaired in patients without daily stair climbing activity than in patients who habitually climbed stairs to the ≥3 rd floor among patients with hypertension. Funakoshi et al. [ 16 ] reported that eating within 2 h before bedtime ≥3 days/week was associated with the development of hypertension defined as blood pressure ≥140/90 mmHg or initiation of antihypertensive drug treatment during an average follow-up period of 4.5 years in the general Japanese population, suggesting that avoiding late dinners may be helpful for preventing the development of hypertension. These findings indicate the importance of lifestyle modifications for maintaining vascular function and preventing the development of hypertension and the progression of atherosclerosis.

(TM and YH)

Keywords : vascular function, endothelial function, arterial stiffness, carotid intimathickness, ankle-brachial index.

Advances in hypertension management for better renal outcomes (See Supplementary Information 2 )

In chronic kidney disease (CKD) patients, hypertension is a risk factor for end-stage renal disease (ESRD), cardiovascular events and mortality. Thus, the prevention and appropriate management of hypertension in CKD patients are important strategies for preventing ESRD and cardiovascular disease (Fig.  2 ).

Advantages of hypertension in CKD. CKD chronic kidney disease, GFR glomerular filtration rate, MR mineralocorticoid receptor, SGLT2 sodium–glucose cotransporter 2

Risk factors for hypertension

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that is mainly secreted by the liver. Circulating FGF21 levels are reported to be increased in CKD patients, while higher circulating FGF21 levels were reported to be associated with all-cause mortality in ESRD patients [ 17 , 18 ]. Additionally, Matsui et al. reported that higher circulating FGF21 levels partially mediate the association of elevated BP and/or aortic stiffness with renal dysfunction in middle-aged and older adults [ 19 ]. A study by Funakoshi et al. showed that eating before bed was correlated with the future risk of developing hypertension in the Iki Epidemiological Study of Atherosclerosis and Chronic Kidney Disease [Supplementary Information  2 - 1 ].

Prognostic markers

Several promising prognostic markers for renal and cardiovascular outcomes have been suggested. Matsukuma et al. reported that a higher urinary sodium-to-potassium ratio was independently associated with poor renal outcomes in patients with CKD [Supplementary Information  2 - 2 ]. Chinese hypertensive patients with higher albumin-to-creatinine ratios had a significantly increased risk of first ischemic stroke [Supplementary Information  2 - 3 ]. The number of nephrons in hypertensive patients was significantly lower than that in controls [ 20 ]. Tsuboi et al. suggested the usefulness of methods to estimate the total nephron count and single nephron GFR in living patients, which helped to tailor patient care depending on age or disease stage as well as to predict the response to therapy and the disease outcome [ 21 ].

Mineralocorticoid receptor (MR) blockers (e.g., esaxerenone) are used in the treatment of essential hypertension and hyperaldosteronism. Recently, a new MR antagonist, finerenone, has been introduced as a treatment for CKD patients with type 2 diabetes. However, hyperkalemia has been recognized as a potential side effect during treatment with MR blockers. A recent review article by Rakugi et al. suggested that being aware of at-risk patient groups, choosing appropriate dosages, and monitoring serum potassium during therapy are required to ensure the safe clinical use of these agents [Supplementary Information  2 - 4 ].

The clinical use of sodium–glucose cotransporter-2 inhibitors (SGLT2is) has recently been expanded to nondiabetic patients with CKD and heart failure as well as diabetic patients [ 22 , 23 ]. Several novel findings regarding the renal protective properties of SGTL2is were reported in 2021. In a real-world registry study of Japanese type 2 diabetes patients with CKD, SGLT2is were associated with significantly better kidney outcomes in comparison to other glucose-lowering drugs, irrespective of the presence or absence of proteinuria [ 24 ]. Kitamura et al. reported that the addition of metformin to SGLT2is blunts the decrease in eGFR but that the coadministration of RAS inhibitors ameliorates this response [Supplementary Information  2 - 5 ]. Thomson and Vallon reported that (1) SGLT2i treatment reduces glomerular capillary pressure that is mediated through tubuloglomerular feedback (TGF) and (2) the TGF response to SGLT2is involves preglomerular vasoconstriction and postglomerular vasorelaxation [ 25 ].

SGLT2is have an antihypertensive effect, which is greater in subjects with higher salt sensitivity and BMI [ 26 – 28 ]. Furthermore, the degree of BP change in patients undergoing SGLT2i therapy depends on the baseline BP; a larger reduction is observed in patients with higher baseline BP, and a smaller reduction or slight increase is observed in patients with lower baseline BP [ 29 ]. These BP regulation mechanisms may partially depend on body fluid homeostasis by SGLT2is. SGLT2is ameliorate fluid retention through osmotic diuresis and natriuresis but are associated with a low rate of hypovolemia [ 30 – 33 ], which is evident by the compensatory upregulation of renin and vasopressin levels [ 33 – 35 ]. These fluid homeostatic mechanisms exerted by SGLT2is may contribute to the stabilization of BP. Moreover, recent clinical studies have shown that SGLT2is reduce BP without changes in urinary sodium and fluid excretion or plasma volume [ 35 – 37 ], suggesting the role of other factors, such as the inhibition of the sympathetic nervous system, restoration of endothelial function, and reduction of arterial stiffness [ 38 , 39 ].

(TM and DN)

Keywords : fibroblast growth factor 21, nephron number, mineralocorticoid receptor blocker, SGLT2 inhibitor, fluid homeostasis.

Hypertension and heart disease-focusing on the relationship with HFpEF (See Supplementary Information 3 )

With the increasing longevity of ‘Westernized’ populations, heart failure (HF) in the elderly has become a problem of growing scale and complexity worldwide [ 40 ].

Stages of HF are classified from A to D [ 41 ]. HF patients are also divided into patients with preserved ejection fraction (EF) (HFpEF), those with mildly reduced EF and those with reduced EF (HFrEF). Persistent hypertension and increased arterial stiffness in stage A HF result in left ventricular (LV) hypertrophy (LVH), at which point it is classified as stage B HF. Although the etiology of HFpEF is diverse, patients with HFpEF have been reported to have a high prevalence of hypertension, which is closely associated with increased arterial stiffness, LVH and diastolic LV dysfunction [ 41 ].

In adult Sprague–Dawley rats, a novel flavoprotein, renalase, was increased in hypertrophic cardiac tissue, and recombinant renalase improved cardiac function and suppressed myocardial fibrosis in the HF model [ 42 ]. In stroke-prone spontaneously hypertensive rats, carboxypeptidase X 2 (Cpxm2) was identified as a locus that affects LV mass. Analysis of endomyocardial biopsies from LVH patients showed significant upregulation of CPXM2 expression [ 43 ]. In this way, basic research applied to humans has shown in detail the pathophysiology of LVH.

Left atrial (LA) enlargement (LAe) is also associated with HFpEF [ 44 ]. In response to proinflammatory mediators, microvascular endothelial cells become inappropriately activated, resulting in microvascular endothelial dysfunction, perpetuating the inflammatory process and LA fibrosis [ 45 ]. Manifestations of these mechanisms have been related to LAe, which can be detected prior to the incidence of atrial fibrillation. Sympathetic overdrive from the central autonomic network, including the insular cortex, causes LA-pulmonary vein (PV) border fibrosis. LA-PV border fibrosis was suggested to originate from local inflammation triggered by preganglionic fibers ending in ganglionated plexi [ 45 , 46 ].

In the SPRINT study, intensive BP management was not associated with LA abnormalities defined based on ECG [ 47 ]. Although LA volume (LAV) according to body surface area was recommended to assess LA size [ 48 ], LAV indexed for height 2 was shown to be more sensitive for detecting subclinical hypertensive organ damage in females [ 49 ]. In the ARIC study, the minimum but not the maximum LAV index was significantly associated with the risk of incident HFpEF or death [ 50 ].

In the 2021 European Society of Cardiology guidelines for the treatment of HFrEF, angiotensin receptor/neprilysin inhibitor (ARNI) and sodium–glucose cotransporter 2 inhibitor (SGLT2i) are newly recommended for first-line treatment. In contrast, no guideline-directed treatment has been shown to convincingly reduce mortality and morbidity in HFpEF patients [ 44 ].

BP control is important to prevent adverse events in HFpEF patients with high BP. In a randomized study of hypertension patients, a significant reduction in systolic blood pressure (BP) (SBP) and diastolic BP was observed during daytime and nighttime in the ARNI group compared to the placebo group [ 51 ]. ARNI was also associated with reduced BP in patients with refractory hypertension with HFpEF [ 52 ]. In the PARAGON-HF trial, a decrease in pulse pressure, a marker of large arterial stiffness, during ARNI run-in was associated with a significant improvement in the prognosis of HFpEF [ 53 ]. On the other hand, the SACRA study showed that a significant reduction in BP occurred after adding SGLT2i to existing antihypertensive and antidiabetic agents in nonsevere obese diabetic elderly with uncontrolled nocturnal hypertension [ 54 ]. Recently, in the EMPEROR-Preserved Trial, SGLT2i improved the prognosis of patients with HFpEF [ 55 ]. From the above, it is suggested that reducing nighttime BP and improving diurnal BP patterns improves the prognosis of HFpEF [ 56 , 57 ].

Accumulated evidence from basic and clinical studies suggests that hypertension is a crucial risk factor for HFpEF (Fig.  3 ). These data may contribute to future studies aimed at elucidating the more detailed pathophysiology of HFpEF in hypertension research and the development of therapeutic agents and/or strategies that improve the prognosis of HFpEF in hypertension.

A scheme of the relationship between hypertension and HFpEF. The dysregulation of the central autonomic network is associated with enhanced sympathetic nervous system activity in hypertension linked to HFpEF via left atrial remodeling, left ventricular hypertrophy and increased arterial stiffness. HFpEF heart failure with preserved ejection fraction, LA left atrium, PV pulmonary vein

Keywords : heart failure with preserved ejection fraction, arterial stiffness, leftventricular hypertrophy, diastolic left ventricular dysfunction, left atrial remodeling.

Up-to-date preeclampsia knowledge; what we should know for mother and child (See Supplementary Information 4 )

Diagnostic criterion.

In 2017, the American College of Cardiology/American Heart Association hypertension treatment guidelines identified hypertension as blood pressure (BP) ≥ 130/80 mmHg. The reference BP for hypertension during pregnancy as specified in international guidelines [e.g., the International Society for the Study of Hypertension in Pregnancy guidelines (ISSHP) [ 58 ] and the American College of Obstetricians and Gynecologists guidelines (ACOG) [ 59 , 60 ]] is ≥140/90 mmHg. A large number of studies have examined the incidence of PE and fetal outcomes according to BP levels. The meta-analysis of these studies has shown that BP ≥ 120/80 mmHg, particularly ≥130/80 mmHg, in early pregnancy is also associated with increased maternal and perinatal risks and proposed new BP categories of <120/80 mmHg (normal), 120–129/<80 mmHg (high normal), and 130–139/80–89 mmHg (elevated) for pregnant women [ 61 ].

Prognostic tools

The predictive value of BP and other clinical characteristics for PE is relatively low [ 62 , 63 ]. Soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio testing resulted in reduced unnecessary hospitalization [ 64 , 65 ]. Circulating cell-free DNA (cfDNA) and human suppression of tumorigenesis 2 (ST2) were increased in individual with gestational hypertension (GH) and PE and served as diagnostic biomarkers [Supplementary Information  4 - 1 ]. Nocturnal hypertension was a significant predictor of early-onset PE in high-risk pregnancies [ 66 ]. BP variability was higher in pregnant women with hypertensive disorders and was significantly associated with left ventricular mechanics [Supplementary Information  4 - 2 ]. Including these factors in multivariate models may improve the detection rates of PE and may identify women who could benefit from preventive interventions (Fig.  4 ).

Schematic presentation of the topics of preeclampsia 2021. HTN hypertension, PE preeclampsia, BP blood pressure, cfDNA cell-free DNA, ST2 human suppression of tumorigenesis 2, sFlt-1 soluble fms-like tyrosine kinase-1, PIGF placental growth factor, PRES posterior reversible encephalopathy syndrome, AKI acute kidney injury, ACE angiotensinogen converting enzyme, Ang angiotensin

The ISSHP recommends that BP ≥ 140/90 mmHg should be treated, with a goal BP of 110–140/85 mmHg, while the ACOG recommends antihypertensive medications when BP ≥ 160/110 mmHg, with goal BP below this threshold (Fig.  4 ). Systolic BP (sBP) < 130 mmHg within 14 weeks of gestation reduced the risk of developing early-onset superimposed PE in women with chronic hypertension [ 67 ]. The Chronic Hypertension and Pregnancy (CHAP) project also showed that BP control to <140/90 was associated with a reduction in composite adverse outcomes, with no significant increase in small for gestational age infants [ 68 ].

Long-term outcomes

PE is linked to major chronic diseases such as hypertension, type 2 diabetes mellitus, dyslipidemia, and cardiovascular disease (Fig.  4 ). The American Heart Association lists hypertension during pregnancy as a major cardiovascular risk factor and recommends that affected women undergo cardiovascular risk screening within 3 months after giving birth [ 69 ]. Since many cardiovascular risk factors are modifiable and related to lifestyle, all women with prior PE should be followed up by physicians even after the resolution of PE.

COVID-19 and Pregnancy

Pregnancy could potentially affect the susceptibility to and severity of COVID-19. Severe cases of COVID-19 present with PE-like symptoms. PE mimicry by COVID-19 was confirmed following the alleviation of preeclamptic symptoms without delivery of the placenta [ 70 ]. In COVID-19, angiotensin-converting enzyme 2 (ACE 2) function decreases, and subsequently, angiotensin II (Ang) activity increases [ 71 ]. Similar to PE, COVID-19 results in an increase in the sFlt-1/PlGF ratio due to pathologic Ang II/Ang (1-7) imbalance [ 72 ] (Fig.  4 ). Most experts believe that SARS-CoV-2 is likely to become endemic, and continued collection of data on the effects of COVID-19 during pregnancy is needed.

Further investigation is needed to decrease PE-related maternal and fetal deaths and to reduce maternal risks for chronic diseases in later life. The participation of physicians is necessary to offer appropriate medical care to women with prior PE, and continued publications of issues regarding PE in Hypertension Research are expected.

(KB and AI)

Keywords : preeclampsia, gestational hypertension, chronic hypertension, soluble fms-like tyrosine kinase 1, placental growth factor.

Appropriate blood pressure assessment methods for the prevention of hypertension complications (See Supplementary Information 5 )

Blood pressure (BP) values can vary and fluctuate widely depending on the method and the environment of blood measurement. Via appropriate measurement and interpretation of BP values, hypertension can be correctly diagnosed, treated and guided [ 73 ]. To give an example, appropriate body posture is important for accurate BP measurement. Wan et al. [Supplementary Information  5 - 1 ] demonstrated that BP levels measured with the back in an unsupported position were 2.3/1.0 mmHg higher than those measured with the back in a supported position. Glenning et al. [Supplementary Information  5 - 2 ] demonstrated the feasibility of measuring diastolic blood pressure by the onset of the fourth Korotkoff phase (K4), when K5 is undetectable under exercise conditions in children and adolescents. In recent years, a variety of BP measurement devices and techniques have appeared, and accumulating evidence has shown the feasibility, reproducibility, and usefulness of these devices [ 74 , 75 ]. Kario et al. [ 76 ] demonstrated the relationship between BP by a newly released wrist-cuff oscillometric wearable BP device and left ventricular hypertrophy. They concluded the feasibility and usefulness of wearable BP devices to detect masked daytime hypertension. Automated office blood pressure (AOBP) measurement includes recording of several BP readings using a fully automated oscillometric sphygmomanometer with the patient resting alone in a quiet place, thereby potentially minimizing the white-coat effect. The most comprehensive meta-analysis [ 77 ] reported that AOBP is equivalent to home BP (HBP), but the diagnostic value and viability of AOBP are still controversial. Lee et al. [ 78 ] assessed the diagnostic accuracies of two AOBP machines and manual office blood pressure measurements (MOBP) in Chinese individuals and clarified the lower diagnostic significance of AOBP than that of MOBP. Recent studies strongly recommended the wide use of self-measured HBP [ 79 ] because HBP has better reproducibility than office BP (OBP), improves adherence to treatment, enables us to detect high-risk populations and has prognostic value for cardiovascular disease (CVD) events [ 80 – 82 ]. Both elevated morning and nocturnal BP values and disrupted circadian BP rhythm assessed by each BP measurement method or devices are associated with worsened cardiovascular outcomes (Fig.  5 ). Zhan et al. [ 83 ] demonstrated that HBP monitoring improved treatment adherence and BP control in stage 2 and 3 hypertension. Hoshide et al. [ 84 ] demonstrated the association of nighttime BP assessed by HBP and CVD events, independent of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, in the Japanese clinical population. Narita et al. [Supplementary Information  5 - 3 ] demonstrated that the elevated difference between morning and evening systolic BP was associated with a higher incidence of CVD events in the J-HOP study. Narita et al. [Supplementary Information  5 - 4 ] also demonstrated that treatment-resistant hypertension diagnosed by HBP monitoring was associated with increased CVD risk independent of cardiovascular damage in the same Japanese cohort. Oliveira et al. [Supplementary Information  5 - 5 ] demonstrated that the SAGE score calculated by systolic BP, age, fasting blood glucose and estimated glomerular filtration rate was associated with pulse wave velocity measured by oscillometric devices and concluded that a SAGE score ≥8 could be used to identify a high risk of CVD events. ABPM is currently regarded as the reference method for hypertension diagnosis in children and pregnancy. Salazar et al. [Supplementary Information  5 - 6 ] demonstrated nocturnal hypertension assessed by ABPM as a significant predictor of early-onset preeclampsia/eclampsia in high-risk pregnant women in a cohort study in Argentina. ABPM also helped us to notice abnormal circadian patterns in BP, which are associated with increased circulating volume, largely determined by salt sensitivity and salt intake. Understanding these pathogenic mechanisms under conditions of nocturnal hypertension and heart failure suggests several new antihypertensive pharmacotherapies, including sodium–glucose cotransporter 2 inhibitors, angiotensin receptor neprilysin inhibitors and mineralocorticoid receptor antagonists [ 56 , 85 , 86 ]. Kario et al. [Supplementary Information  5 - 7 ] demonstrated the effect of esaxerenone, a highly selective mineralocorticoid receptor blocker, for improving nocturnal hypertension and NT-proBNP levels. Esaxerenon could be an effective treatment option, especially for nocturnal hypertensive patients with a riser pattern.

Methods of measuring variable blood pressure and evaluating factors associated with the prognosis of cardiovascular disease

Keywords : hypertension management, BP measurement devices, BP variability, home BP, cardiovascular disease

Considering frailty and exercise in the management of hypertension and hypertensive organ damage (See Supplementary Information 6 )

Frailty is defined as physiological decline and a state of vulnerability to stress and results in adverse health outcomes [ 87 ]. Frailty consists of multiple domains, such as physical, social, and psychological factors. Cognitive decline is one of the factors related to frailty, and blood pressure (BP) control significantly reduced dementia or cognitive decline in a meta-analysis [ 88 ]. However, in the elderly population above 80 years, the positive effect of antihypertensive therapy for preventing dementia was not proven [ 89 – 91 ].

A systematic review and meta-analysis of the prevalence of mild cognitive impairment (MCI) among hypertensive patients was conducted by Quin et al. The prevalence of MCI was 30% in a sample of 47,179 hypertensive patients. Heterogeneity was seen due to ethnicity, study design (cross-sectional or cohort study), and cognition assessment tools [ 92 ]. Li. et al. investigated the association between carotid intima thickness (CIMT) and cognitive function in hypertensive patients [Supplementary Information  6 - 1 ]. CIMT was significantly and negatively associated with MMSE scores in people aged ≥60 years but not in those aged <60 years.

BP guidelines in various countries suggest that BP management should be carried out in the context of frailty or end of life, and careful observation, including personalized BP control among elderly individuals, is essential (Fig.  6 ). A total of 535 patients with hypertension (age 78 [ 70 – 84 ] years, 51% men, 37% with frailty) were prospectively followed for 41 months, and mortality associated with frailty and BP was evaluated by Inoue et al. [ 93 ]. Frailty was assessed by the Kihon checklist. Among 49 patients who died, mortality rates were lowest in those with systolic BP < 140 mmHg and nonfrailty and highest in those with systolic BP < 140 mmHg and frailty. The results indicate that frail patients have a higher risk of all-cause mortality than nonfrail patients, and BP should be managed considering frailty status, which is in line with previous reports [ 94 ]. Our latest study showed that in patients with preserved MMSE scores, higher BP was associated with cognitive impairment, and those with MMSE scores below 24 points had the opposite results [ 95 ]. Elderly individuals with hearing impairment have higher rates of hospitalization, mortality, falls, frailty, dementia, and depression. Miyata et al. performed a study using data from medical records from health checkups: higher SBP levels were associated with an increased risk of objective hearing impairment at 1 kHz [Supplementary Information  6 - 2 ].

Hypertension management in frail patients. ADL activities of daily living, IADL instrumental activities of daily living

In the era of technical advancement, people are spending less time being active, which leads to cardiovascular risks, including hypertension. However, guidelines emphasize the importance of nonpharmacological strategies such as lifestyle modification and exercise to prevent diseases [ 96 ].

Sardeli et al. compared types of exercise that are beneficial to health. The study compared the effects of aerobic training (AT), resistance training (RT), and combined training (CT) in hypertensive older adults aged >50 years. There were extensive health benefits associated with exercise training, and CT was the most effective intervention at improving a wide spectrum of health conditions, including cardiorespiratory fitness, muscle strength BMI, fat mass, glucose, TC and TGs [ 97 ]. J Almeida et al. showed that isometric handgrip exercise training reduced systolic BP in treated hypertensive patients [Supplementary Information  6 - 3 ]. Stair climbing and vascular function were assessed by Yamaji et al. There was a significant difference in nitroglycerine-induced vasodilatation between the group with no habits of climbing stairs and the other groups with two or more climbing habits [Supplementary Information  6 - 4 ].

The safety of resistance training was studied by Hansford et al who concluded that isometric resistance training (IRT) was safe and led to a potentially clinically meaningful reduction in BP [Supplementary Information  6 - 5 ].

Keywords : physical and social frailty, elderly, cognitive function, resistance training, cardiorespiratory function

Blood pressure variability—therapeutic target for the prevention of cardiovascular disease (See Supplementary Information 7 )

In the past three decades, there have been many reports on the associations of various parameters of blood pressure (BP) variability with increased risk of cardiovascular disease (CVD) events; these parameters include short-term BP variability (BPV), i.e., beat-by-beat BPV and ambulatory BPV, abnormality of nocturnal BP dipping pattern, and mid- to long-term BPV, i.e., day-by-day BPV, visit-to-visit BPV, and seasonal variations in BP [ 98 – 106 ]. In addition, BPV has been associated with the progression of endovascular organ damage related to heart failure, chronic kidney disease, and cognitive function [ 107 – 111 ] [Supplementary Information  7 - 1 ]. Several factors that are associated with abnormal BPV [ 112 ], as well as environmental factors such as cold or warm temperatures and seasonal changes in climate, increase fluctuations in BP. Individual intrinsic factors, such as sympathetic nervous tone, arterial stiffness, physical activity, and mental stress, also contribute to elevated BPV. According to evaluations of BPV abnormalities, out-of-office BP measurements, such as ambulatory and home BP monitoring, are needed. To evaluate nighttime BP levels, home BP monitoring devices equipped with a function for nighttime BP readings and new wrist-type nocturnal BP monitoring devices are available [ 76 ]. Although there are issues regarding measurement accuracy, cuffless BP monitoring devices, for example, those using pulse transit time, may be used to estimate nighttime BP levels [Supplementary Information  7 - 2 ]. Such cuffless BP devices can also evaluate beat-by-beat BPV. Moreover, by using the multisensor-equipped ambulatory BP monitoring device developed by our research group, it is possible to evaluate BPV associated with changes in temperature, physical activity, and/or atmospheric pressure [ 113 ].

Based on the mechanism(s) underlying a given patient’s BPV abnormality, several methods may be considered for the management of that abnormality (Fig.  7 ). For example, improving excessive sympathetic nervous system activation may be useful in the management of BPV abnormalities [ 114 ], and renal denervation has been reported to decrease ambulatory BPV [ 115 ]. Abnormal nocturnal BP dips may be treated by decreasing nighttime BP. In patients with sleep apnea, improving sleep quality and implementing continuous positive airway pressure are recognized to be useful for nighttime BP control [ 116 ]. Moreover, early adjustment of antihypertensive drugs has been reported to be useful in suppressing seasonal variations in BP, leading to a decreased risk of CVD events [ 99 ]. Furthermore, housing conditions and room temperature are closely related to BP levels, and adaptive control of room temperature would be useful to suppress winter increases in BP [ 117 , 118 ]. In clinical practice, we must not forget that BPV parameters are interrelated. For instance, frequent evaluation of BP levels and adjustment of antihypertensive drugs can suppress visit-to-visit BPV, which in turn leads to the suppression of seasonal variations in BP.

Current and future perspectives in the management of blood pressure variability. Short- and long-term BP variability is associated with CVD event risk independent of each BP level. Out-of-office BP measurements, such as ABPM and home BP monitoring, and other new BP devices are useful for evaluating the various types of BP variability. To suppress BP variability, several management methods, including new antihypertensive medications, chronotherapy, housing condition, and sympathetic nervous denervation, are considered. ABPM ambulatory blood pressure monitoring, ABPV ambulatory blood pressure variability, ARNI angiotensin receptor neprilysin inhibitor, BP blood pressure, BPV blood pressure variability, CVD cardiovascular disease, ICT information and communication technology, SGLT2i sodium–glucose cotransporter 2 inhibitor

Over the next decade, more data on how to manage and control BPV need to be accumulated. Additionally, future studies should be conducted to verify whether the different types of BVP management are useful in preventing CVD events.

(KN, SH and KK)

Keywords : blood pressure variability, out-of-office blood pressure monitoring, cardiovascular disease prevention, wearable blood pressure monitoring device, environmental factors.

Optimal therapy and clinical management of obesity/diabetes (See Supplementary Information 8 )

Obesity/diabetes is a major comorbidity in patients with hypertension, and these conditions often share common pathological conditions, such as insulin resistance and the risk of cardiovascular diseases (CVD). One of the biggest highlights of recent years in the area of obesity/diabetes has been the remarkable benefits of newer glucose-lowering agents seen in large-scale clinical trials on cardiorenal outcomes (Fig.  8 ), followed by the relevant clinical guideline updates and the expansion of the clinical application of those agents [ 119 ]. In particular, sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists are now preferentially recommended in patients with type 2 diabetes (T2D) and specific cardiorenal risk, independent of diabetes status or background use of metformin [ 120 ]. It is noteworthy, of course, that those agents reduced the risk of cardiorenal events, and their multifaceted effects beyond hypoglycemic effects are also attracting clinical attention. In a review series ‘New Horizons in the Treatment of Hypertension’ in Hypertension Research, Tanaka and Node [ 121 ] discussed the modest effects of those agents on blood pressure (BP)-reduction and the clinical perspectives. They also proposed a new-normal style care for diabetes and its complications using such evidence-based agents with multidisciplinary effects, partly aiming at reduced polypharmacy and avoidance of its possible harm. This action will improve the quality of hypertension care in patients with obesity/diabetes; however, a substantial population with treated hypertension still has inadequate blood pressure control, which is recognized as resistant hypertension (RH). Due to the difficulty in distinguishing true RH from pseudo-RH due to nonadherence, little is known about the clinical characteristics of true RH. Chiu et al. from Boston [Supplementary Information  8 - 1 ] reported a notable prevalence (26.6%) of true RH in patients with T2D registered in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Blood Pressure trial and identified several independent predictors, such as higher baseline BP, higher number of baseline antihypertensives, macroalbuminuria, chronic kidney disease, and history of stroke. Moreover, patients with true RH exhibited poorer prognosis than those without, suggesting an emerging need for effective screening and intensified treatment for patients with true RH.

Schematic presentation of the topic ‘Obesity/Diabetes’ in 2021

The BP treatment goal in patients with diabetes and hypertension is less than 130/80 mmHg [ 122 ], and intensified BP control was associated with reduced stroke risk [ 123 – 125 ]. Intensive lipid-lowering therapy is also recommended for patients with T2D at risk of CVD [ 126 ]; however, an original EMPATHY study investigating the effect of intensive lipid-lowering therapy (target of low-density lipoprotein cholesterol [LDL-C] < 70 mg/dL) on cardiovascular outcomes failed to show the clinical benefits of intensive statin therapy in patients with T2D, diabetic retinopathy, elevated LDL-C levels, and no known CVD [ 127 ]. In a subanalysis of the EMPATHY study, Shinohara et al. [ 128 ] revealed for the first time that intensive statin therapy was associated with a reduced risk of cardiovascular events compared with standard therapy (target of ≥100 to <120 mg/dL) in a subgroup with baseline BP ≥ 130/80 mmHg but not in another subgroup with baseline BP < 130/80 mmHg. Their findings suggest that baseline BP is also a possible determinant of the target LDL-C in that patient population, although the precise reasons for the difference in the clinical benefits of intensive statin therapy between subgroups according to baseline BP levels are still uncertain.

Obesity is a crucial global health concern across generations. Obesity and insulin resistance cause several cardiometabolic disorders, including hypertension, and increase the risk of subsequent CVD. Hence, further actions against obesity and cardiometabolic disorders are urgently needed for individuals of all generations [ 129 , 130 ]. In this context, Fernandes et al. from Brazil [Supplementary Information  8 - 2 ] revealed for the first time that Ang-(1-7) and des-Arg9BK metabolites were novel biological markers of adolescent obesity and relevant cardiovascular risk profiles, such as elevated BP, lipids, and inflammation. Thu et al. from Singapore [Supplementary Information  8 - 3 ] found a positive association between accumulated visceral adipose tissue and systolic BP in midlife-aged women, independent of burdens of inflammatory markers. Intriguingly, Haze et al. [ 131 ] clearly demonstrated that an increased ratio of visceral-to subcutaneous fat volume was an independent risk factor for renal dysfunction in Japanese patients with primary aldosteronism. These findings should highlight the clinical importance and the need for further research to explore surrogate markers of obesity in the care of hypertension and its related conditions (Fig.  8 ).

Finally, we briefly introduce some exciting progress in vascular function in the area of “Obesity/Diabetes” (Fig.  8 ). Murai et al. [ 132 ] elegantly showed that postload hyperinsulinemia was independently associated with increased arterial stiffness as assessed by brachial-ankle pulse wave velocity (PWV) in young medical students at Jichi Medical University. Given the close pathological relationship between hyperinsulinemia and most CVDs, including heart failure [ 133 , 134 ], their findings suggest that hyperinsulinemia-induced vascular failure is one of the key drivers of that pathological link. Interestingly, Fryer et al. from the UK [Supplementary Information  8 - 4 ] also found that arterial stiffness as assessed by carotid-femoral PWV was exacerbated by the consumption of a high-fat meal relative to a low-fat meal prior to 180 min of uninterrupted sitting. Importantly, arterial stiffness testing could accurately reflect even such a combination of unfavorable behaviors, and thus vascular function assessment has the potential to reflect a wide spectrum of cardiovascular risk and provide a clinical opportunity for better risk stratification and optimal modification [ 135 ]. We look forward to accumulating and consolidating evidence of vascular function tests and further applying them to actual cardiovascular care [ 136 ].

(AT and KN)

Keywords : glucose-lowering agent, resistant hypertension, statin, surrogate marker, vascular function

A new era of progress in primary aldosteronism treatment: mineralocorticoid receptor antagonists, a new aldosterone assay, and a clinical practice guideline (See Supplementary Information 9 )

A hot topic in 2021 was advances in the treatment of mineralocorticoid receptor (MR)-associated hypertension [ 137 ], particularly primary aldosteronism (PA). The nonsteroidal MR antagonist (MRA) esaxerenone is now widely used in Japan. Kario et al. [ 138 ] reported that esaxerenone reduced nocturnal blood pressure in patients with essential hypertension, according to ambulatory blood pressure assessment and N-terminal pro-brain natriuretic peptide assays. Yoshida et al. [ 139 ] reported that MRAs such as esaxerenone improved quality of life in PA patients. Ito et al. [ 140 ] reported that add-on treatment using esaxerenone with maximal tolerable doses of a renin-angiotensin system (RAS) inhibitor reduced the urinary albumin-creatinine ratio in patients with type 2 diabetes mellitus (ESAX-DN), suggesting a renoprotective effect against diabetic nephropathy. Several clinical studies of another nonsteroidal MRA, finerenone (FIDELIO-DKD [ 141 ], FIGARO-DKD [ 142 ], and FIDELITY [ 143 ]), have shown its renoprotective effect against diabetic nephropathy as well as cardiovascular events, particularly hospitalization for heart failure in patients with type 2 diabetes and chronic kidney disease. Although there are no reports of clinical studies on finerenone for PA, finerenone may be used in the future for type 2 diabetes patients with PA, as obesity, glucose intolerance, and sleep apnea are common complications in patients with PA [ 144 ]. Similarly, sodium–glucose cotransporter 2 inhibitors (SGLT2i) have been demonstrated to improve the prognosis of cardiovascular disease and chronic kidney disease in individuals with type 2 diabetes (EMPA-REG OUTCOME [ 145 ], DECLARE–TIMI 58 [ 146 ], DAPA-HF[ 147 ], and DAPA-CKD [ 22 ]). As steroidal MRAs such as spironolactone and eplerenone are effective in the treatment of mild to severe stages of heart failure (RALES, EPHESUS [ 148 ], and EPHESUS-HF [ 149 ]), combined treatment with MRA and SGLT2i, in addition to an RAS inhibitor, may be a novel effective treatment for cardiac and renal protection in type 2 diabetic patients (Fig.  9 ). Second, radiofrequency ablation of macroscopic adrenal tumors [ 150 – 152 ] has been reported as an alternative treatment for PA to lower blood pressure and plasma aldosterone levels. This treatment has been covered by health insurance providers in Japan since April 2022, but long-term outcomes need to be validated.

Potential drug therapy regimen. Combined administration of an MRA and an SGLT2i may afford cardiac and renal protection. MRA mineralocorticoid receptor antagonist, SGLT2i sodium–glucose cotransporter 2 inhibitor

Another hot topic was the launch of serum aldosterone measurement using a chemiluminescent enzyme immunoassay (CLEIA), which utilizes a two-step sandwich method. Previously, low aldosterone levels may have been measured incorrectly [ 153 ]. The new CLEIA figures are closely correlated with liquid chromatography/tandem mass spectrometry values; the new assay is more accurate than the previous radioimmunoassay, which overestimated serum aldosterone levels [ 154 – 156 ]. Thus, the Japan Endocrine Society issued a Primary Aldosteronism Clinical Guideline in 2021 [ 157 ]. The CLEIA method is also used to measure urinary aldosterone levels; Ozeki et al. [ 158 ] proposed a PA diagnostic cutoff of ≥3 μg/day for the oral salt loading test. The CLEIA method is currently available only in Japan.

Exosomes may serve as biomarkers of MR activity. Ochiai-Homma et al. [ 159 ] focused on pendrin, a Cl – /HCO3 – exchanger that is only expressed by renal intercalated cells. In a rat model, the pendrin level in the urinary exosome was reduced by therapeutic interventions favored for PA patients; the urinary level was correlated with the renal level. This model may help to elucidate the pathophysiology of PA-induced organ injury [ 160 ].

Finally, Haze et al. [Supplementary Information  9 - 1 ], Segawa et al. [Supplementary Information  9 - 2 ], Nishimoto et al. [Supplementary Information  9 - 3 ], Chen et al. [Supplementary Information  9 - 4 ], and Liu et al. [Supplementary Information  9 - 5 ] have conducted intriguing clinical studies regarding PA.

(YY and HS)

Keywords : mineralocorticoid receptor-associated hypertension, mineralocorticoid receptor antagonist, hypertension, primary aldosteronism, chemiluminescent enzyme immunoassay

Advances in renal denervation for treating hypertension: current evidence and future perspectives (See Supplementary Information 10 )

It is well established that renal denervation (RDN) decreases blood pressure (BP) in various models of hypertension in animals and in humans [ 161 – 165 ]. Here, we reviewed studies related to RDN published in Hypertension Research in 2021 (Fig.  10 ). The antihypertensive effect of RDN is mediated by interrupting both the efferent outputs from the brain to the kidney and the afferent inputs from the kidney to the brain, suppressing systemic sympathetic outflow [ 165 , 166 ]. In basic research, there are two methods of RDN: total RDN (TRDN) performed by surgical cutting of renal nerves to ablate both efferent and afferent nerves and selective afferent RDN (ARDN) performed via capsaicin application to renal nerves to specifically ablate afferent nerves expressing capsaicin receptors [ 167 , 168 ]. Katsurada et al. [ 169 ] reviewed previous reports that address the different effects of TRDN and ARDN in different animal models of hypertension, suggesting potentially complicated and diversified origins of hypertension. The potential therapeutic effects of TRDN and ARDN have also been reported in animal models of heart failure [ 170 ].

Topics on renal denervation. BP blood pressure, RDN renal denervation

In clinical practice, radiofrequency, ultrasound, and alcohol-based RDN devices have been developed as second-generation catheter devices and evaluated in randomized control trials. Ogoyama et al. [ 171 ] reported a meta-analysis of nine randomized sham-controlled trials of RDN that showed that RDN significantly reduced a range of office, home and 24 h BP parameters in patients with resistant, uncontrolled, and drug-naïve hypertension. There were no significant differences in the magnitude of BP reduction between radiofrequency-based and ultrasound-based devices.

The Global SYMPLICITY Registry (GSR) is a prospective all-comer registry to evaluate the safety and efficacy of RDN in a real-world population [ 172 ]. The overall GSR has enrolled over 2700 patients, and more than 2300 of these have now been followed for 3 years [ 173 ]. GSR Korea is a Korean registry substudy of GSR ( N  = 102) [ 174 ]. Kim et al. [Supplementary Information  10 - 1 ] reported the 3-year follow-up outcomes from the GSR Korea showing that RDN led to sustained reductions in office systolic BP at 12, 24 and 36 months (−26.7 ± 18.5, −30.1 ± 21.6, and −32.5 ± 18.8 mmHg, respectively) without safety concerns. Recently, the efficacy and safety of second-generation radiofrequency RDN up to 36 months have been reported [ 175 ].

The REQUIRE trial by Kario et al. [Supplementary Information  10 - 2 ] is the first trial of ultrasound RDN in Asian patients from Japan and South Korea with hypertension receiving antihypertensive therapy. The study findings were neutral for the primary endpoint, with similar reductions in 24 h systolic BP at 3 months in the RDN (−6.6 mmHg) and sham control groups (−6.5 mmHg). Although BP reduction after RDN was similar to other sham-controlled studies [ 161 , 162 , 164 , 176 ], the sham group in this study showed much greater reduction. Unlike RADIANCE-HTN TRIO that used an ultrasound catheter system to measure its primary endpoint, REQUIRE did not standardize medications or measure medication adherence, which may lead to increased variability in BP outcome; moreover, REQUIRE was not a double-blind study, which may result in a substantial bias. Another important factor is that 32.4% of patients showed hyperaldosteronism in the REQUIRE trial. Patients with primary aldosteronism have decreased sympathetic nerve activity and are likely to respond poorly to RDN [ 177 ]. The lessons from REQUIRE will enable us to design a follow-up trial to make a definitive evaluation of the effectiveness of RDN in Asian patients with hypertension.

Another topic is the patient preference for RDN. Kario et al. [Supplementary Information  10 - 3 ] conducted a nationwide web-based survey in Japan and reported that preference for RDN was expressed by 755 of 2392 Japanese patients (31.6%) and was higher in males, in younger patients, in those with higher BP, in patients who were less adherent to antihypertensive drug therapy, in those who had antihypertensive drug-related side effects, and in those with comorbid heart failure. This should be taken into account when making shared decisions about antihypertensive therapy.

Keywords : renal nerves, hypertension, renal denervation, patient preference, heart failure

Hot topics in uric acid research: the difficulties of managing hyperuricemia (See Supplementary Information 11 )

The mechanisms linking hyperuricemia, arteriosclerosis, hypertension, chronic kidney disease, and cardiovascular disease are becoming clearer (Fig.  11 ) [ 178 – 181 ]. However, it remains unclear whether treatment of hyperuricemia improves these diseases. Some recent topics of uric acid research are introduced below.

Mechanisms linking hyperuricemia and arteriosclerosis, hypertension, chronic kidney disease, and cardiovascular disease. ATP adenosine triphosphate, CKD chronic kidney disease

First, urate-lowering treatment with allopurinol, a xanthine oxidase (XO) inhibitor, did not slow the decline in eGFR compared with placebo in either the PERL (Preventing Early Renal Loss in Diabetes) trial [ 182 ] or CKD-FIX (Controlled Trial of Slowing of Kidney Disease Progression from the Inhibition of Xanthine Oxidase) [ 183 ]. These results were similar to the results of FEATHER (Febuxostat Versus Placebo Randomized Controlled Trial Regarding Reduced Renal Function in Patients with Hyperuricemia Complicated by Chronic Kidney Disease Stage 3) from Japan [ 184 ]. Moreover, the PRIZE (Program of Vascular Evaluation Under Uric Acid Control by the Xanthine Oxidase Inhibitor Febuxostat: Multicenter, Randomized, Controlled) study showed that febuxostat did not delay the progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia [ 185 ]. These results suggest the difficulties of managing hyperuricemia for preventing chronic kidney disease (CKD) and/or arteriosclerosis.

Second, FAST (the Febuxostat versus Allopurinol Streamlined Trial) showed that febuxostat was noninferior to allopurinol therapy with respect to the primary cardiovascular endpoint, all-cause or cardiovascular deaths [ 186 ]. The results of FAST were different from the results of the CARES (The Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities) trial [ 187 ], and the authors summarized that regulatory advice to avoid the use of febuxostat in patients with cardiovascular disease should be reconsidered and modified [ 186 ].

In Hypertension Research 2021, several important articles on uric acid research were published. Mori et al. reported that a high serum uric acid level is associated with an increase in systolic blood pressure in women but not in men in subjects who underwent annual health checkups [ 188 ]. Their group also reported that a low uric acid level is a significant risk factor for CKD over 10 years in only women, and an elevated UA level increases the risk of CKD in both sexes [Supplementary Information  11 - 1 ]. Moreover, Li et al. reported that elevated serum uric acid levels in subjects without stroke, coronary heart disease, and medication for hyperuricemia or gout aged 40–79 years were independent predictors of total stroke, especially ischemic stroke, in women but not in men in a 10-year cohort study [Supplementary Information  11 - 2 ]. These results suggested the possibility that both hyperuricemia and hypouricemia in women could be associated with a higher risk for hypertension, CKD, and stroke than those in men.

Azegami et al. reported a prediction model of high blood pressure in young adults aged 12–13 years followed up for an average of 8.6 years. The results showed that uric acid was an important predictor of high blood pressure [ 189 ].

Kawasoe et al. reported that high (4.1–5.0, 5.1–6.0, and >/=6.1 mg/dL) and low (</=2.0 mg/dL) serum uric acid levels were significantly associated with an increased prevalence of high blood pressure compared to 2.1–4.0 mg/dL serum uric acid in subjects who underwent health checkups [ 190 ]. The results were compatible with a previous report stratified by sex [ 191 ]. Serum uric acid levels and the risks for diseases are largely different between men and women, and it is desirable to conduct every analysis by sex when conducting uric acid research.

Furuhashi et al. reported that plasma xanthine oxidoreductase (XOR) activity was associated with hypertension in 271 nondiabetic subjects in the Tanno–Sobetsu Study [ 192 ]. Kusunose et al. reported that additional febuxostat treatment in patients with asymptomatic hyperuricemia for 24 months might have potential prevention effects on impaired diastolic dysfunction in the subanalysis of the PRIZE study [ 193 ]. These reports suggested the potential direct antioxidant effects of the treatment as reflected in serum uric acid levels as well as its xanthine-oxidase-lowering properties in tissue [Supplementary Information  11 - 3 ]. Whether the preferential use of xanthine oxidoreductase XO inhibitors becomes a new therapeutic strategy for the prevention of cardiovascular disease in patients with asymptomatic hyperuricemia awaits further high-quality trials [Supplementary Information  11 - 4 ].

Finally, Nishizawa et al. reported a mini review article focusing on the relationship between hyperuricemia and CKD or cardiovascular diseases, and they summarized that high-quality and detailed clinical and basic science studies of hyperuricemia and purine metabolism are needed [Supplementary Information  11 - 5 ].

(MK and TK)

Keywords : uric acid, cardiovascular disease, chronic kidney disease, arteriosclerosis, xanthine oxidase

Basic research: elucidation of the “mosaic” pathogenesis of hypertension (See Supplementary Information 12 )

The pathogenesis of hypertension is multifactorial and highly complex, as described by the “mosaic theory” of hypertension. Basic research plays critical roles in elucidating the “mosaic” pathogenesis of hypertension and developing its treatment (Fig.  12 ).

Topics in basic research. Each ref. number indicates the reference paper cited in the text. AT1R angiotensin type 1 receptor, EV extracellular vesicles, KO knockout, RAS renin-angiotensin system, Snx1 soring nexin 1, SIRT6 sirtuin 6, TWIST1 twist-related protein 1

In the field of the brain and autonomic nervous system, Chen et al. demonstrated that mild cold exposure elicits autonomic dysregulation, such as increased sympathetic activity, decreased baroreflex sensitivity, and poor sleep quality, causing blood pressure (BP) elevation in normotensive rats [ 194 ]. This finding may have critical implications for cardiovascular event occurrence at low ambient temperatures. In addition, Domingos-Souza et al. showed that the ability of baroreflex activation to modulate hemodynamics and induce lasting vascular adaptation is critically dependent on the electrical parameters and duration of carotid sinus stimulation in spontaneously hypertensive rats (SHRs) [ 195 ], proposing a rationale for improving baroreflex activation therapy in humans. Although only normotensive and hypertensive rats were used in these two studies, without comparing the two strains, previous studies have shown that neuronal function and activity in the cardiovascular sympathoregulatory nuclei, including the nucleus tractus solitarius and rostral ventrolateral medulla, which are involved in baroreflex regulation, are different between normotensive and hypertensive rats [ 196 , 197 ]. Further studies comparing normotensive and various hypertensive animal models would be interesting.

In the kidney, Kasacka et al. showed that the activity of the Wnt/β-catenin pathway is increased in SHRs and two-kidney, one-clip (2K1C) hypertensive rats, while it is inhibited in deoxycorticosterone acetate (DOCA)-salt rats according to kidney immunohistochemistry [ 198 ]. The intrarenal renin-angiotensin system (RAS) is also involved in BP regulation. In renal damage with an impaired glomerular filtration barrier, liver-derived angiotensinogen filtered through damaged glomeruli regulates intrarenal RAS activity [ 199 ]. Matsuyama et al. further showed that the glomerular filtration of liver-derived angiotensinogen depending on glomerular capillary pressure causes circadian rhythm of the intrarenal RAS with in vivo imaging using multiphoton microscopy [ 200 ]. Fukuda and his colleagues have shown that complement 3 (C3) is a primary factor that activates intrarenal RAS [Supplementary Information  12 - 1 , 2 ]. Otsuki and Fukuda et al. additionally demonstrated that TWIST1, a transcription factor that regulates mesodermal embryogenesis, transcriptionally upregulates C3 in glomerular mesangial cells from SHRs [ 201 ].

The RAS in the vascular system, as well as in other organ systems, plays a major role in BP regulation. Soring nexins (SNXs) are cellular sorting proteins that can regulate the expression and function of G protein-coupled receptors (GPCRs) [Supplementary Information  12 - 3 , 4 , 5 ]. Liu C et al. demonstrated that SNX1 knockout mice exhibit hypertension through vasoconstriction mediated by increased expression of AT1R, a GPCR mediating most of the effects of angiotensin II (Ang II), within the arteries [ 202 ]. Moreover, in vitro studies suggest that SNX1 sorts arterial AT1R for proteasomal degradation. These findings indicate that SNX1 impairment increases arterial AT1R expression, leading to vasoconstriction and hypertension. Liu X et al. found that sirtuin 6 (SIRT6) expression is downregulated in the aortae of aged rats and showed that SIRT6 knockdown enhances Ang II-induced vascular adventitial aging by activating the NF-κB pathway in vitro [ 203 ]. This study suggests that SIRT6 may be a biomarker of vascular aging and that activating SIRT6 can be a therapeutic strategy for delaying vascular aging.

Several reports indicate the potential treatment for hypertension and the associated organ damage. Narita et al. showed that rivaroxaban exerts a protective effect against cardiac hypertrophy by inhibiting protease-activated receptor-2 signaling in renin-overexpressing hypertensive mice [Supplementary Information  12 - 6 ]. In addition, the efficacy of nebivolol (a third-generation β-blocker), maximakinin (a bradykinin agonist peptide extracted from the skin venom of toad), and Pinggan-Qianyang decoction (a traditional Chinese medicine) were also shown in hypertensive animal models [Supplementary Information  12 - 7 , 8 , 9 ]. In animal models of gestational hypertension, melatonin and crocin have each exhibited an antihypertensive effect [Supplementary Information  12 - 10 , 11 ].

Studies investigating extracellular vesicles (EVs) have increased. Ochiai-Homma et al. showed that pendrin in urinary EVs can be a useful biomarker for the diagnosis and treatment of primary aldosteronism, which was supported by studies using a rat model of aldosterone excess [ 159 ]. Another report indicated that pulmonary arterial hypertension induces the release of circulating EVs with oxidative content and alters redox and mitochondrial homeostasis in the brains of rats [Supplementary Information  12 - 12 ]. Studies on the role of gut microbiota in BP regulation have also been accumulating. Wu et al. demonstrated that captopril has the potential to rebalance the dysbiotic gut microbiota of DOCA-salt hypertensive rats, suggesting that the alteration of the gut flora by captopril may contribute to the hypotensive effect of this drug [ 204 ]. Moreover, important basic studies, including review papers, have been reported in Hypertension Research. See Supplementary Information.

Keywords : autonomic nervous system, kidney, vascular system, renin-angiotensin system, extracellular vesicles, gut microbiota.

Supplementary information

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The authors declare no competing interests.

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The online version contains supplementary material available at 10.1038/s41440-022-00967-4.

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Hypertension: Current trends and future perspectives

Affiliation.

• 1 Department of Renal Medicine, Royal Infirmary of Edinburgh & University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, UK.
• PMID: 33733505
• DOI: 10.1111/bcp.14825

Hypertension is a significant and increasing global health issue. It is a leading cause of cardiovascular disease and premature death worldwide due to its effects on end organs, and through its associations with chronic kidney disease, diabetes mellitus and obesity. Despite current management strategies, many patients do not achieve adequate blood pressure (BP) control. Hypertension-related cardiovascular mortality rates are rising in tandem with the increasing global prevalence of chronic kidney disease, diabetes mellitus and obesity. Improving BP control must therefore be urgently prioritised. Strategies include utilising existing antihypertensive agents more effectively, and using treatments developed for co-existing conditions (such as sodium-glucose cotransporter 2 inhibitors for diabetes mellitus) that offer additional BP-lowering and cardiovascular benefits. Additionally, novel therapeutic agents that target alternative prohypertensive pathways and that offer broader cardiovascular protection are under development, including dual angiotensin receptor-neprilysin inhibitors. Nonpharmacological strategies such as immunotherapy are also being explored. Finally, advancing knowledge of the human genome and molecular modification technology may usher in an exciting new era of personalised medicine, with the potential to revolutionise the management of hypertension.

Keywords: diabetes; hypertension; kidney disease; treatments.

© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

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• Research Support, Non-U.S. Gov't
• Antihypertensive Agents / pharmacology
• Antihypertensive Agents / therapeutic use
• Blood Pressure
• Cardiovascular Diseases* / drug therapy
• Diabetes Mellitus* / drug therapy
• Diabetes Mellitus, Type 2* / drug therapy
• Hypertension* / drug therapy
• Hypertension* / epidemiology
• Antihypertensive Agents

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• SCAF/19/02/CSO_/Chief Scientist Office/United Kingdom

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• Review Article
• Published: 15 October 2021

Annual reports on hypertension research 2020

• Masaki Mogi 1 ,
• Yukihito Higashi 2 , 3 ,
• Kanako Bokuda 4 ,
• Atsuhiro Ichihara 4 ,
• Daisuke Nagata 5 ,
• Atsushi Tanaka 6 ,
• Koichi Node 6 ,
• Yoichi Nozato 7 ,
• Koichi Yamamoto 7 ,
• Ken Sugimoto 8 ,
• Hirotaka Shibata 9 ,
• Satoshi Hoshide 10 ,
• Hitoshi Nishizawa 11 &
• Kazuomi Kario 10  

Hypertension Research volume  45 ,  pages 15–31 ( 2022 ) Cite this article

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In 2020, 199 papers were published in Hypertension Research. Many excellent papers have contributed to progress in research on hypertension. Here, our editorial members have summarized eleven topics from published work and discussed current topics in depth. We hope you enjoy our special feature, Annual Reports on Hypertension Research.

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Update on Hypertension Research in 2021

2023 update and perspectives

Hypertension research 2024 update and perspectives: basic research

Hot topics on vascular function in hypertension, 2020.

(See Supplementary Information  1 )

Several methods for assessment of vascular function including endothelial function, vascular smooth muscle function, arterial stiffness, and biochemical markers have been used in patients with hypertension (Fig.  1 ) [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]. These methods have been established as markers for the grade of atherosclerosis, markers for efficacy of interventions, tools for evaluating mechanisms of atherosclerosis, and predictors of cardiovascular outcomes in cardiovascular disease (CVD) including hypertension (Fig.  1 ) [ 8 , 9 , 10 , 11 , 12 ].

Methods for assessment of vascular function (top) and clinical efficacy of assessment of vascular function (bottom). FMD indicates flow-mediated vasodilation, ezFMD enclosed-zone FMD, RHI reactive hyperemia index, NID nitroglycerine-induced vasodilation, baPWV brachial-ankle pulse wave velocity, cfPWV carotid-femoral PWV, CAVI cardio-ankle vascular index, AI augmentation index, TBI toe brachial pressure index, ABI ankle-brachial pressure index, IMT intima media thickness

There were many reports on “vascular function and hypertension” in Hypertension Research in 2020 alone. Liu et al. [ 13 ] demonstrated a significant association of higher brachial-ankle pulse wave velocity (baPWV) as an index of arterial stiffness with a higher frequency of the presence of carotid plaque in patients with hypertension, particularly in relatively young patients. Maruhashi et al. [ 14 ] showed that measurement of baPWV is a predictor of cardiovascular events in hypertensive patients with coronary artery disease with controlled blood pressure (BP) of <130/80 mmHg, suggesting that a BP target of <130/80 mmHg is appropriate for the treatment of hypertensive patients with coronary artery disease. Tomiyama et al. ( Supplementary Information 1–1 ) showed that the SAGE score calculated from age, office systolic BP, fasting blood glucose, and estimated glomerular filtration rate (eGFR) is useful for predicting baPWV in patients with hypertension. In addition, elevation of BP contributes, at least in part, to microvascular dysfunction ( Supplementary Information 1–2 ). The association between quality of sleep and vascular function in patients with hypertension remains unclear. Hu et al. ( Supplementary Information 1–3 ) reported that poor sleep quality was associated with higher arterial stiffness measured by baPWV in patients with hypertension. It has also been reported that measurement of carotid-femoral PWV reveals different hypertension phenotypes including white-coat hypertension, resistant hypertension and nonresistant hypertension ( Supplementary Information 1–4 ). Interestingly, it has been shown that high BP-induced alteration of shear stress reduces antithrombotic effects through a decrease in nitric oxide bioavailability in human conduit arteries, leading to an increase in risk of arterial thrombosis [ 15 ].

In fields other than hypertension, Fukumoto et al. ( Supplementary Information 1–5 ) showed that smoking cessation improved flow-mediated vasodilation as an index of macrovascular endothelial function but not reactive hyperemic index as an index of microvascular endothelial function, suggesting that attention should be paid to the effects of smoking on endothelial function in vessels of different sizes. Maruhashi et al. [ 16 ] confirmed that vascular function, including endothelial function, vascular smooth muscle function and arterial stiffness, is continuously impaired throughout life with aging. Harada et al. ( Supplementary Information 1–6 ) showed that vascular dysfunction plays a critical role in the decrease in skeletal muscle mass, leading to cardiovascular events. Also, microcirculatory dysfunction assessed by digital capillary density and high normal ankle-brachial pressure index independently contributes to advancement of chronic kidney disease stages (Supplementary Information 1–7 , 1–8 ). The advanced glycation end products (AGEs)/soluble receptor for AGEs pathway is associated with arterial stiffness in the general population ( Supplementary Information 1–9 ).

Next year and also in the next decade, we would like to pay attention to publications concerning “vascular function and hypertension” in Hypertension Research. Accumulation of data on vascular function in hypertension would enable more specific conclusions concerning the roles of vascular function in the pathophysiology, maintenance, and development of hypertension to be drawn.

Preeclampsia update

(See Supplementary Information  2 )

No effective treatment that attenuates the progression of preeclampsia (PE) has been established. New trials and cohort studies have provided insights into the development of preventive care and diagnostic and prognostic tools, and reports regarding these issues have also been published in Hypertension Research.

Pathogenesis

The two-stage paradigm of poor early placental development followed by systemic endothelial dysfunction and severe maternal organ injury is an effective model to frame the pathogenesis of PE (Fig.  2 ) [ 17 ]. Vangrieken et al. ( Supplementary Information 2–1 ) investigated the effect of placental hypoxic-conditioned medium on intraluminal-induced contraction and endothelial barrier integrity in chorionic arteries, and have demonstrated a link between factors secreted by placental cells in response to hypoxia and vascular abnormalities.

Topics on preeclampsia, 2020. PE preeclampsia, BP blood pressure, sFlt-1 soluble fms-like tyrosine kinase-1, sENG soluble endoglin, PRES posterior reversible encephalopathy syndrome, AKI acute kidney injury, CsA cyclosporin A, CKD chronic kidney disease

Preventive care

The strongest risk factors for PE are history of PE and chronic hypertension. Li et al. showed associations between high preconception BP level and an increase in risk of gestational hypertension and PE, indicating the importance of preconception BP control. Some risk factors are amendable to pre-pregnancy modifications [ 18 ]. Li et al. ( Supplementary Information 2–2 ) demonstrated that different subclasses of saturated fatty acids show diverse effects on the risk of pregnancy-induced hypertension, and suggested that dietary saturated fatty acids may be a novel means by which to decrease BP during pregnancy.

Diagnostic and prognostic tools

To make an early prediction of PE before diagnosis, Yue et al. ( Supplementary Information 2–3 ) developed a nomogram that incorporates BMI, BP, uterine artery ultrasound parameters, and serological indicators for the early prediction of PE in pregnant Chinese women. Also, recently, the Fetal Medicine Foundation proposed a Bayes theorem-based model to predict preterm PE. Goto et al. investigated the diagnostic accuracy of the model and showed that the model is feasible in the Japanese population [ 19 ].

Once diagnosed, PE is often a progressive condition and maternal organ function deteriorates with time. Chen et al. ( Supplementary Information 2–4 ) have reported that crocin alleviates inflammatory and oxidative stress in placental tissues, thereby protecting against gestational hypertension (Fig.  2 ). Li et al. ( Supplementary Information 2–5 ) explored the efficacy of troxerutin and found that it reduces BP and the expression of vasodilation converting enzyme, angiotensin, urinary protein, and pro-inflammatory cytokines while increasing the expression of anti-inflammatory cytokines (Fig.  2 ).

Magnesium sulfate reduces the risk of an eclamptic seizure, but its mechanism of action is poorly understood. Li et al. ( Supplementary Information 2–6 ) have shown that prophylactic magnesium sulfate decreases BP and attenuates the postpartum effects of PE. Huang et al. ( Supplementary Information 2–7 ) have shown that the maternal hyperinflammatory response in PE lowers the eclampsia-like seizure threshold [ 20 ] and found that administration of a well-known immunosuppressive agent, cyclosporin A (CsA), effectively attenuated PE manifestation, and eclampsia-like seizure severity and improved subsequent pregnancy outcomes in a rat model (Fig.  2 ).

Long-term outcomes

PE confers an increased risk of major chronic diseases in later life including many cardiovascular complications [ 21 ], diabetes [ 22 ], chronic kidney disease [ 23 ], and also dementia [ 24 ]. Wagata et al. have shown that the association between hypertensive disorders in pregnancy (HDP) and later hypertension was stronger in younger women, implying that continuous follow-up after the postpartum period is important for women with a history of HDP for early detection of hypertension in later life [ 25 ].

The 2019 Maternal Mortality update from the WHO report indicated a major contribution of PE and eclampsia to worldwide maternal deaths. Much work is needed to decrease its morbidity and mortality, and this may be reported in Hypertension Research in the future.

Treatment of hypertensive patients during COVID-19 pandemic

(See Supplementary Information  3 )

During 2020, the coronavirus disease 2019 (COVID-19) pandemic has been the most defining global health crisis worldwide. Many reports related to this international public health emergency have been published in Hypertension Research. Presidents of the Japanese Society of Hypertension (JSH) have written communications about proposals for future hypertension treatment, conscious of the “new normal” during and after COVID-19. Shibata and JSH members also strived together to summarize and discuss the effects and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the effects of antihypertensive drugs, especially in relation to blockade of the renin–angiotensin system (RAS) [ 26 ]. The most downloaded article in 2020 was a short communication by Li et al. ( Supplementary information 3–1 ), demonstrating the association between COVID-19 and RAS inhibitors. On March 4, the date on which the communication was accepted, there was concern that ACE2, which is considered to be upregulated by RAS inhibitors, could promote the proliferation of COVID-19 and enhance its capability for infection. Kai et al. ( Supplementary Information 3–2 ) promptly reviewed the interactions between coronaviruses and ACE2, angiotensin II, and RAS inhibitors. This review was the second most downloaded article in 2020. Furuhashi et al. ( Supplementary Information 3–3 ) also commented on this topic around the same time. To address this question, Matsuzawa et al. clearly demonstrated that RAS inhibitors could be beneficial for the prevention of confusion in COVID-19 patients with hypertension [ 27 ]. Following assessment of the clinical studies, speculation about the safety of RAS inhibitors has diminished [ 28 , 29 ] (Fig.  3 ).

Topics on COVID-19

The next hot topic is the effect of hypertension and BP control on COVID-19 severity. Huang et al. ( Supplmentary Information 3–4 ) showed that COVID-19 patients with hypertension were more likely to have severe pneumonia and excessive inflammatory reactions compared with patients without hypertension. Ran et al. ( Supplmentary Information 3–5 ) also showed that BP control is independently associated with mortality and intensive care unit (ICU) admission. Hypertension has been identified as the most common comorbidity in COVID-19 patients and has shown an association with worse outcomes, possibly due to more advanced atherosclerosis and target organ damage, in a recent report [ 30 ]. More attention should be paid to avoiding SARS-CoV-2 infection in hypertensive patients in order to prevent severe COVID-19 disease (Fig.  3 ).

Finally, the COVID-19 pandemic has changed lifestyle factors and behaviors such as physical activity, dietary pattern, alcohol consumption and mental conditions, resulting in an increase in metabolic syndrome with body weight gain. These communicable disease-induced noncommunicable diseases [ 31 , 32 , 33 ] have been focused on in hypertension management during and after the COVID-19 pandemic and may be reported in Hypertension Research in the future (Fig.  3 ).

Treatment of CKD patients and therapeutic usefulness of SGLT2 inhibitors

(See Supplementary Information  4 )

The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guidelines for the Management of BP in Chronic Kidney Disease (CKD) [ 34 ] represents an update to the KDIGO 2012 guidelines. The updated guidelines include a chapter dedicated to standardized office BP (OBP) measurement for most patients with CKD, who do not undergo dialysis. With regard to recommendations for standardized OBP measurements, based on previous and new evidence, particularly the results of the Systolic Blood Pressure Intervention Trial (SPRINT) [ 35 ], these guidelines propose a systolic BP target of <120 mmHg. Renin–angiotensin system inhibitors (RASis) are recommended as first-line medication for patients with high BP and CKD accompanied by proteinuria. Although these guidelines include advice regarding salt reduction, reduction of salt intake is difficult in real-world practice. Yoshimura et al. [ 36 ] reported that excessive alcohol consumption enhanced the effect of salt intake on albuminuria. The benefit of salt restriction in reducing albuminuria is greater in patients who successfully limit alcohol consumption. Data regarding the addition of mineralocorticoid receptor antagonists (MRA) to RASis are unavailable in the headlines of the updated guidelines. However, finerenone (a selective MRA) was shown to significantly reduce the risk of CKD progression and cardiovascular events in patients with CKD with concomitant type 2 diabetes. [ 37 ] Wang et al. ( Supplementary Information 4–1 ) reported that an appropriate dose of spironolactone may improve endothelial function, as reflected by a lower prevalence of microalbuminuria in patients with primary aldosteronism, which suggests that in addition to their beneficial effects on the endothelium, MRAs may reinforce the cardio-renal protective effects of RASis. Zamami et al. ( Supplementary Information 4–2 ) proposed the application of the ankle-brachial index (ABI) as a useful tool for evaluation of CKD severity. ABI was positively correlated with biopsy-proven severity of renal small artery intimal thickening in patients with CKD, which indicates that an elevated ABI may predict renal small artery remodeling and a low eGFR. Based on quantitative nailfold video capillaroscopy assessment, Schoina et al. ( Supplementary Information 4–3 ) reported that capillary density progressively decreased with advancing CKD stage. The authors observed structural alterations in the microvasculature in parallel to arteriosclerosis in large and medium-sized arteries in patients with CKD, which supports the usefulness of capillary density as a predictor of CKD severity and the risk of cardiovascular events.

Independent of diabetes, sodium-glucose cotransporter-2 inhibitors (SGLT2is) have gained much attention in the field of nephrology in recent times. Although SGLT2is were originally introduced as antidiabetic agents, several studies have shown that these drugs improved cardiovascular and renal prognosis in patients with CKD [ 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. The mechanisms underlying SGLT2i activity include selective inhibition of SGLT2 expressed in the S1 segment of the proximal tubule, promotion of hypotensive activity, and improvement of glucose metabolism. SGLT2is also increase the quantity of sodium chloride delivered to the macula densa of the distal tubule and correct glomerular hyperfiltration by promoting contraction of the afferent arteriole via the tubuloglomerular feedback mechanism, which serves as a major contributor to the renoprotective effects of SGLT2is (Fig.  4 ) [ 45 ]. Furthermore, SGLT2is reduce adverse left ventricular remodeling and improve systolic function by switching cardiac metabolism from glucose consumption toward utilization of more energy-producing ketone bodies, free fatty acids, and branched-chain amino acids, which results in improved myocardial energetics and efficiency [ 46 , 47 ]. SGLT2i-induced sympathetic nerve inhibition was shown to be a critical contributor to the cardio-renal protective effects associated with SGLT2is in some nondiabetic animal models [ 48 , 49 ]. Compared with RASi monotherapy, combination therapy using SGLT2is and RASis was effective and well tolerated in patients with diabetes and could improve renal outcomes. However, this therapeutic approach was associated with an increased risk of hypoglycemia [ 50 ]. Kitamura et al. [ 51 ] reported that pre-treatment administration of metformin diminished the SGLT2i-induced reduction in eGFR, and addition of RASi therapy restored this response. This study highlights that SGLT2i-induced renal microvascular action may be mediated predominantly by post-glomerular vasodilatation as opposed to pre-glomerular vasoconstriction, which has been considered the primary underlying mechanism. Finally, the initial decrease in eGFR during the early stages of SGLT2i therapy was a concern expressed by several nephrologists, and Kohagura et al. ( Supplementary Information 4–4 ) showed that eGFR measured during the chronic phase after luseogliflozin administration remained stable regardless of the severity of the initial acute changes.

Mechanisms by which SGLT2 inhibitors might improve cardiac and renal function

Obesity/diabetes

(See Supplementary Information  5 )

Under the COVID-19 catastrophe, many people are likely forced to face various health problems caused by disordered eating habits and physical inactivity, leading to overweight/obesity, hypertension, and metabolic syndrome. At the same time, the baseline obesity/overweight and impaired metabolic conditions are also associated with adverse outcomes in patients infected with COVID-19 [ 52 , 53 , 54 ]. There is now a renewed need to focus on the clinical management of obesity/overweight and its association with hypertension (Fig.  5 ). Thu et al. ( Supplementary Information 5–1 ) demonstrated a strong association between the burden of visceral adipose tissue and systolic BP, independent of serum levels of inflammatory markers, in midlife Singaporean women. Intriguingly, among Japanese women, a history of hypertensive disorders of pregnancy was significantly associated with later development of hypertension even in younger generations, and overweight/obesity unfavorably enhanced that association [ 25 ]. Thus, it is obvious that overweight/obesity incrementally increases the level of BP and accelerates the risk of hypertension; this fact no longer needs a reference. To adjust or maintain an individual’s ideal body weight, it also goes without saying that comprehensive lifestyle modification, including exercise and diet, is essential. Regarding exercise-training, Clark et al. sought to determine an optimal practical program for reducing BP in men with overweight/obesity. They found that a series of high-intensity interval training was more effective for central and peripheral BP-lowering than was moderate-intensity continuous training, and those effects were more pronounced in overweight/obese subjects with higher baseline BP [ 55 ]. On the other hand, a higher frequency of alcohol consumption, which is also a current socio-physical problem, was associated with higher incidence of hypertension in nonobese men, but not women and overweight/obese men [ 56 ]. Importantly, although the relationship between alcohol intake and the development of hypertension and cardiovascular events is not necessarily a simple one [ 57 , 58 , 59 ], it is best not to drink, or for habitual drinkers to try to stay sober regardless of overweight/obesity and sex.

Topics on obesity/diabetes

Type 2 diabetes (T2D) and hypertension synergistically increase the risk of cardiovascular events and mortality. Imai et al. investigated the impact of hypertension stratified by diabetes status on the lifetime risk of cardiovascular death using a Japanese cohort of the EPOCH-JAPAN study. They found that hypertension and diabetes were associated with a markedly increased lifetime risk in a synergistic manner even at an earlier index age [ 60 ], suggesting the importance of social awareness and prevention of these factors from the younger generation. Thus, constant BP measurement/monitoring and comprehensive clinical management of relevant risk factors, including hypertension, are of importance especially in patients with T2D. Ushigome et al. examined the predictive impact of BP values measured at home on the first onset of major adverse cardiovascular events in Japanese patients with T2D with no previous history of CVD (KAMOGAWA-HBP study). They reported that a rise in morning systolic BP by 10 mmHg was independently associated with an increased risk of development of cardiovascular events (adjusted hazard ratio [HR] 1.14, 95% confidence interval 1.01 to 1.28), and HR in patients with morning systolic BP ≥ 135 mmHg was numerically larger than that in those with morning systolic BP < 125 mmHg [ 61 ]. However, it has long been controversial whether lower BP is associated with better outcomes in patients with T2D, although BP-lowering of 10 mmHg was associated with apparent clinical benefits in patients with T2D and baseline BP ≥ 140 mmHg [ 62 ]. On the basis of previous meta-analyses and the expected benefit on the risk of stroke in the Japanese population [ 63 , 64 , 65 ], the current JSH guidelines recommend a BP of less than 130/80 mmHg as a treatment target for OBP in patients with T2D complicated with hypertension [ 66 ]. Generally, in patients with hypertension complicated with atherosclerotic cardiovascular disease (ASCVD), careful attention should be paid to the decrease in organ perfusion associated with BP-lowering. Kai et al. examined whether lower BP levels independently contributed to the incidence of cardiovascular events in patients with T2D who underwent coronary revascularization (CREDO-Kyoto cohort-1 registry). They demonstrated that clinically-allowable levels of low BP were not associated with an increased risk of ASCVD and mortality [ 67 ], supporting the current clinical practice of BP-lowering in patients with T2D recommended by the JSH 2019 guidelines [ 66 ].

Finally, we would like to briefly introduce some exciting progress in exploratory and basic research in the area of “Obesity/Diabetes”. Gelžinský et al. investigated how to better depict the burden of advanced glycation end products (AGEs) related to arterial stiffness. They revealed that skin AGEs quantified by a noninvasive autofluorescence device and its ratio to the circulating concentration of soluble receptor for AGEs were strongly and independently associated with increased arterial stiffness assessed as aortic pulse wave velocity [ 68 ], suggesting that this simple method is clinically useful to assess “vascular age” and/or “vascular failure” [ 69 ]. Hirao et al. examined the effect of pharmacological blockade of vacuolar type H + -ATPase (V-ATPase) in a rat model of T2D. They newly found that blockade of V-ATPase by bafilomycin inhibited renal ammoniagenesis and gluconeogenesis and improved pancreatic insulin secretion and its sensitivity [ 70 ], shedding light on the pathophysiological role of V-ATPase as a novel therapeutic target in T2D. Heart failure is a common complication in patients with T2D, and this pathological condition requires novel therapeutic approaches beyond glucose-lowering therapy [ 71 ]. Wang et al. focused on the role of translocase of mitochondrial outer membrane 70 (Tom70) in the pathogenesis of diabetic cardiomyopathy. They first revealed that genetic rescue of Tom70 expression protected against mitochondrial dysfunction and improved the cardiac phenotype of diabetic cardiomyopathy in db/db mice [ 72 ], indicating that Tom70 may become an emerging therapeutic target specifically for diabetic cardiomyopathy.

Hypertension management

(See Supplementary Information  6 )

Given the importance of intensive BP treatment implicated in recent clinical trials including SPRINT [ 73 ], it is increasingly important to clarify how hypertensive patients need to be managed in clinical practice. In this context, recent studies have focused on the appropriate use and interpretation of home BP (HBP) [ 74 ] including self-measured BP (SMBP) and ambulatory BP (ABP), which enables us to detect a high-risk population and reduce cardiovascular risk [ 75 , 76 , 77 ]. We reviewed studies related to HBP and hypertension management that were published on hypertension research in 2020. The subjects of these studies can be categorized into “evaluation of BP values”, “assessment of cardiovascular risk”, and “treatment of hypertension” (Fig.  6 ).

Advantages of home BP monitoring

Regarding the evaluation of BP values, Kubozono et al. ( Supplementary Information 6–1 ) demonstrated that HBP was significantly correlated with room temperature. Asayama et al. ( Supplementary Information 6–2 ) revealed the current status of HBP and home pulse rate in relation to sex, age, and antihypertensive treatment status in the Japanese general population. Kadowaki et al. demonstrated that OBP measured with a sufficient rest time (st-OBP) was comparable to HBP at the population level [ 78 ]. Interestingly, smokers and obese men taking antihypertensive drugs had higher HBP than st-OBP, indicating that their BP levels are at risk of being underestimated. Gkaliagkousi et al. reported a novel method to detect masked hypertension in individuals with normal OBP using a combination of conventional brachial BP and aortic BP (central BP) measured in the office [ 79 ]. Sheng et al. shed light on the pathophysiology of BP and pulse variability in relation to the autonomic nervous system, and demonstrated that individuals with masked hypertension showed variability in BP and heart rate, and baroreflex sensitivity similar to that in those with sustained hypertension [ 80 ].

Regarding the assessment of cardiovascular risk, Ushigome et al. ( Supplementary Information 6–3 ) demonstrated that elevated morning BP is a future risk for cardiovascular events in a Japanese retrospective cohort study of type 2 diabetic patients. Manousopoulos et al. ( Supplementary Information 6–4 ) showed that ABP variability was positively associated with LVMI in CKD patients. Ramoshaba et al. ( Supplementary Information 6–5 ) demonstrated that masked hypertension was associated with retinal arteriolar narrowing in young healthy adults.

Regarding the treatment of hypertension, HBP monitoring has a beneficial effect on adherence and hypertension education. Zhang et al. reported that HBP measurement improved adherence and OBP control in a randomized controlled trial in Chinese subjects with stage 2 and 3 hypertension [ 81 ].

Vallée et al. ( Supplementary Information 6–6 ) reported factors that improved adherence to antihypertensive treatment in a cross-sectional study in the French general population including elderly individuals. Nishimura et al. ( Supplementary Information 6–7 ) revealed that although adherence was relatively high compared with that in Western countries, younger age, female sex, antihypertensive drug class, comorbid conditions, and types of medical institutions were associated with relatively low adherence. Nishigaki et al. ( Supplementary Information 6–8 ) and Yoshida et al. ( Supplementary Information 6–9 ) examined the gaps in perspectives on hypertension management between patients and physicians in the same panel-based, cross-sectional, observational study in Japan, and proposed a solution to the hypertension paradox. Nishigaki et al. demonstrated that perception of the amount of education provided by physicians on hypertension management was lower in patients than in physicians. Yoshida et al. demonstrated that, compared with specialist physicians, nonspecialists were less likely to provide adequate guidance on lifestyle modifications.

These reports support the importance of adequate HBP monitoring to improve hypertension management and reduce the risk of cardiovascular events and mortality.

Hypertension and frailty

(See Supplementary Information  7 )

The relationship between frailty and hypertension has been studied. Guidelines for the treatment of hypertension in various countries show that older hypertensive patients with frailty, especially impaired physical function and/or activities of daily living (ADL), should be individually evaluated for the target BP and the initiation of antihypertensive medication [ 66 , 82 ].

In Japan, the relationship between hypertension and frailty has been investigated mainly using cohort or cross-sectional studies. Here, we introduce three papers published in Hypertension Research in 2020 and discuss the relationship between frailty and BP or cardiovascular risk.

In the SONIC study, an ongoing prospective cohort conducted since 2010, the relationship between systolic BP and physical frailty or cognitive function was examined in groups aged 70 ± 1, 80 ± 1, and 90 ± 1 years ( Supplementary Information 7–1 ). Lower systolic BP was associated with a higher frequency of physical frailty in the 80-year-old group, but not in the 70- and 90-year-old groups, in subjects on antihypertensive medication; however, no association was found in the groups without antihypertensive medication. Besides, higher systolic BP was associated with lower cognitive function in the 70-year-old group, and lower systolic BP was associated with lower cognitive function in the 90-year-old group in subjects on antihypertensive treatment; however, no association was found in the 80-year-old group on antihypertensive treatment or all the groups without antihypertensive medication. In another report, greater variability of systolic BP was an independent risk factor associated with frailty status [ 83 ]. These results suggest the need to consider the pros and cons of antihypertensive treatment individually to prevent frailty and other geriatric syndromes in older adults.

In a cross-sectional study of the association between cardiovascular risk profile and frailty in the Nambu Cohort Study (mean age 78 years), 37% of cases of frailty were diagnosed using the Kihon Checklist score ( Supplementary Information 7–2 ). For every 10 mmHg increase in systolic BP, the risk of frailty decreased significantly by 17%. Moreover, the total number of cardiovascular risk profiles within the optimal range (systolic BP < 140/90 mmHg, LDL-cholesterol < 100 mg/dL and BMI < 25 kg/m 2 ) was significantly associated with the risk of frailty. These results suggest that a favorable cardiovascular risk profile, called “reverse metabolic syndrome”, might be a risk for frailty.

Sarcopenia is an essential component of frailty, and chronic diseases, including CVD, are a common cause of sarcopenia. However, there has been little clinical evidence on the mechanism of sarcopenia in patients with CVD. A retrospective cross-sectional study in the Kyushu area (mean age 72 years) showed an association among skeletal muscle mass reduction, endothelial function, and markers of advanced vascular damage in older patients with CVD ( Supplementary Information 7–3 ). Of cases of sarcopenia, 25.5% were diagnosed using the Asian Working Group for Sarcopenia criteria. Greater progression of arterial stiffness, shown by a higher arterial velocity pulse index (AVI), and more severe tissue damage, shown by a narrower bioelectrical phase angle (PA), were found in subjects with sarcopenia. Both AVI and PA, as well as gender, age, and presence of hypertension, were independently correlated with skeletal muscle index. These results suggest that advanced vascular damage, called “vascular aging”, may contribute to the development of sarcopenia, possibly through skeletal muscle tissue damage in patients with CVD.

The risk of development of CVD, such as elevated systolic BP or BP variability, high LDL-cholesterol, and obesity, should be controlled within the optimal range in non-older or robust older adults; however, in frail older adults, a favorable cardiovascular risk profile may act as an adverse prognostic factor, and in addition, advanced vascular damage is thought to be associated with sarcopenia. Therefore, especially in older patients with a long duration of hypertension or CVD, it is important to keep in mind that strict control of risk factors may lead to a poor prognosis through the progression of frailty. Therefore, it is strongly recommended to consider whether to prioritize antihypertensive treatment or frailty intervention based on the evaluation of frailty status (Fig.  7 ) [ 84 ].

Proposed management process for hypertension in frail older adults. Cited from ref. [ 84 ]

New chemiluminescent enzyme immunoassays for aldosterone measurement and nonsteroidal mineralocorticoid receptor antagonists in the diagnosis and management of primary aldosteronism

(See Supplementary Information  8 )

During 2020–2021, large numbers of papers regarding primary aldosteronism have been published in Hypertension Research and other journals. It is recommended that the diagnosis of primary aldosteronism (PA) is performed in a step-wise manner; screening, confirmatory testing and subtype testing. The biggest topic in Japan is the discontinuation of the previous radioimmunoassay for aldosterone measurement in March 2021, and the launch of alternative new chemiluminescent enzyme immunoassays (CLEIA) for aldosterone measurement. Nishikawa et al. [ 85 ], Ozeki et al. [ 86 ], and Teruyama et al. [ 87 ] demonstrated that the new CLEIA-plasma aldosterone concentration (PAC) is almost equal to the value obtained by LC–MS/MS; however, the CLEIA-PAC value was shown to be lower than the old RIA-PAC value. Therefore, these changes markedly affect PA diagnosis. The PA clinical practice guidelines 2021 will soon be published by the Japan Endocrine Society. When saline infusion test (SIT) is performed for confirmatory testing, Yamashita et al. ( Supplementary Information 8–1 ) showed that shortened SIT (1 L saline loading over 2 h) may be as useful as the standard SIT (2 L saline loading over 4 h) with a cutoff value of 66 pg/mL. In adrenal vein sampling, use of cosyntropin stimulation is controversial; however, Yatabe et al. ( Supplementary Information 8–2 ) showed that it improved the judgment of successful adrenal vein catheterization and outcome prediction. Nishimoto et al. [ 88 ] showed that immunohistochemical staining for aldosterone synthase revealed diverse PA pathology, and hypokalemia (<2.82 mEq/L) may independently predict a small PA lesion. PA is a clinically important disease because it is associated with a high prevalence of cardiovascular complications, such as abdominal aortic calcification, skin microvascular dysfunction, and microalbuminuria, as shown by Tuersun et al. ( Supplementary Information 8–3 ), Concistre et al. ( Supplementary Information 8–4 ), and Wang et al. ( Supplementary Information 8–5 ), respectively.

The next hot topic is the development of novel nonsteroidal mineralocorticoid receptor (MR) antagonists, esaxerenone and finerenone. Both MR antagonists showed high affinity as well as high selectivity for MR. Esaxerenone was approved in Japan in January 2019 for the treatment of hypertension. Ito et al. [ 89 ] showed that esaxerenone had sufficient antihypertensive effects and was well tolerated in hypertensive patients with moderate kidney dysfunction (eGFR 30-60 mL/min/1.73 m 2 ), as both monotherapy and add-on therapy to a RAS inhibitor. Satoh et al. [ 90 ] showed that esaxerenone is also a potent MR antagonist with favorable efficacy and safety profile in patients with hypertension and PA. Using a T2D mouse model, KK-Ay, Arai et al. [ 91 ] showed that esaxerenone plus olmesartan treatment ameliorated diabetic nephropathy without affecting systolic BP. Similarly, Ito et al. [ 92 ] showed that adding esaxerenone to existing RAS inhibitor therapy increased the likelihood of albuminuria returning to a normal level, suggesting renoprotective effects of esaxerenone in diabetic kidney disease, but careful monitoring of serum K level is needed. Bakris et al. [ 93 ] showed that administration of another nonsteroidal MR antagonist, finerenone, in patients with CKD and T2D resulted in lower risk of CKD progression and cardiovascular events than with placebo (FIDELIO-DKD). Sarafidis et al. [ 94 ] summarized mounting evidence from large outcome trials suggesting that sodium-glucose cotransporter-2 (SGLT2) inhibitors and MR antagonists can, apart from nephroprotection, offer significant cardioprotection in patients with CKD (Fig.  8 ).

Role of MR antagonists in primary aldosteronism and CKD with and without diabetes. Esaxerenone and finerenone have been developed as novel nonsteroidal MR antagonists. It is crucial to select an appropriate MR antagonist (steroidal or nonsteroidal) according to the disease state. Recent clinical trials showed that the combination of a renin–angiotensin system (RAS) inhibitor and a sodium-glucose cotransporter-2 (SGLT2) inhibitor with an MR antagonist may have benefit for renoprotection as well as cardiovascular protection. Each ref. number indicates the reference paper cited in the text

The last topic is the biology of MR activation in hypertension. Yokota et al. [ 95 ] showed a repressive role of CASZ1b in regulating MR-mediated transcriptional activity, as well as acting as a hypertension-associated protein. Wu et al. ( Supplementary Information 8–6 ) showed that sodium butyrate, one of the end products of complex carbohydrates generated by the gut microbiota, ameliorated deoxycorticosterone acetate/salt-induced hypertension, and renal damage by inhibiting the MR/SGK1 pathway.

Risk of blood pressure variability in diverse conditions

(See Supplementary Information  9 )

A large number of previous studies have shown that increased blood pressure variability (BPV) is associated with risk of target organ damage and worse cardiovascular outcome in the general, hypertensive and high-risk populations, independent of average BP level [ 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 ]. Generally, BPV has been classified into very short-term, short-term, mid-term and long-term BPV according to the measurement period. In 2020, Hypertension Research published a paper about BPV in diverse conditions (Fig.  9 ). In the first study, in acute ischemic stroke patients, high BP variability measured in the supine position every 4 h during the first 24 h of admission was associated with an unfavorable outcome within 30 days after onset ( Supplementary Information 9–1 ). Alexandrou et al. compared short-term BPV assessed by ABP monitoring (ABPM) in peritoneal dialysis (PD) patients with hemodialysis (HD) patients ( Supplementary Information 9–2 ). The results showed that there was no significant difference in short-term BPV between PD and HD patients.

Topics on blood pressure variability. BPV blood pressure variability, CKD chronic kidney disease, HT hypertension

Manousopoulos et al. reported that short-term BPV assessed by ABPM, but not mid-term BPV assessed by HBP monitoring (day-to-day home BPV), was associated with left ventricular mass index in CKD patients defined by eGFR < 60 ml/min/1.73 m 2 [ 107 ]. This result showed a discrepancy with a previous study [ 108 ]. The reason may be due to differences in the populations. The prevalence of diabetes was 53.3% and 9% in the present and previous study, respectively. For example, we previously reported that increased day-to-day home BPV was associated with reduced eGFR in individuals with diabetes, but not in those without [ 109 ]. Although increased day-to-day home BPV was associated with the risk of cardiovascular events independent of average home BP level [ 96 ], further study is needed to determine whether the clinical impact of day-to-day home BPV is different in high-risk populations such as individuals with diabetes or CKD or both.

Liu et al. reported that in pregnancy, increased long-term BPV assessed by OBP measured from 20 weeks of gestation onwards was associated with poor birth outcomes [ 110 ]. On the other hand, the association between the maternal HBP trajectory and lower infant birth weight showed a J-curve relationship [ 111 ]. Thus, even in pregnancy, management using office and out-of-office BP measurement is important.

Another topic is whether masked and white-coat hypertension, which are caused by BP variability between office and out-office BP measurements, have different pathological mechanisms, from the viewpoint of BPV, from sustained hypertension. Sheng et al. reported that masked, but not white-coat hypertension, showed a similar pattern of change in BP and heart rate variability and baroreceptor sensitivity assessed with a Finometer device to those in sustained hypertension [ 80 ]. This result confirms the previous study results that masked hypertension exerted a risk of poor cardiovascular outcome similarly to sustained hypertension [ 112 ]. Although beat-to-beat BP measurement is needed to estimate BPV accurately and reliably, there is no validated and simplified device that is available to use in clinical settings. In the future, the development of BP monitoring is expected in this field [ 113 , 114 ].

(See Supplementary Information  10 )

Serum uric acid level is regulated by renal excretion, extrarenal excretion in the gut and de novo synthesis in the liver. These are affected by the genetic predisposition for uric acid transporters (kidney and gut) and also by environmental factors. Hyperuricemia is the cause of gout and is also closely associated with the development of hypertension (Fig.  10 ) [ 115 , 116 ]. The mechanism by which uric acid is involved in hypertension is assumed to be endothelial dysfunction related to the crystal pathway (extracellular uric acid) and crystal-independent pathway (intracellular uric acid) [ 116 ].

Association of hyperuricemia with hypertension, gout, chronic kidney disease (CKD) and cardiovascular disease (CVD). Hyperuricemia is known to be the etiological mechanism of gout. In recent papers in Hypertension Research, elevated serum uric acid level was reported to be a risk factor for subsequent development of hypertension. Furthermore, elevated serum uric acid level has been reported to be associated with chronic kidney disease (CKD), and also potentially with cardiovascular disease (CVD). Each ref. number indicates the reference paper cited in the text

Recently, a cross-sectional study in Japanese subjects ( n  = 236,22) who underwent heath checkups demonstrated a J-shaped association between serum uric acid level and the prevalence of BP abnormalities ( Supplementary Information 10–1 ). It was also reported in Hypertension Research that hyperuricemia was a risk for developing hypertension independently of alcohol consumption (Saku study) ( Supplementary Information 10–2 ), and that elevated serum uric acid level in subjects aged 12–13 years was associated with elevated BP in young adults (Fig.  10 ) ( Supplementary Information 10–3 ). Some SNPs have been reported to be involved in the increase in serum uric acid by thiazide-like diuretics ( Supplementary Information 10–4 ). Taking these findings together, including those in previous papers, it is well established that elevated serum uric acid level is one of the risk factors for the subsequent development of hypertension. On the other hand, elevated plasma activity of xanthine oxidoreductase (XOR) was reported to be associated with hypertension independently of uric acid level ( Supplementary Information 10–5 ). Since patients with hyperuricemia comprise an etiologically heterogeneous population, there may be differences in its complications such as hypertension, depending on the subpopulation.

In Hypertension Research 2020, papers on the association of uric acid with CKD and CVD from cohort studies in the Japanese general population such as BOREAS-CKD2, CIRCS, and the Hisayama Study were published (Fig.  10 ) [ 117 , 118 , 119 ]. Elevated serum uric acid level was associated with a decline in renal function [ 117 ], was an independent predictor of total strokes in women [ 118 ], and was a risk for cardiovascular mortality [ 119 ]. The causality between serum uric acid and stroke was taken up as a topic in Hypertension Research ( Supplementary Information 10–6 ). Besides, serum uric acid level was high in adult patients with congenital heart disease showing high brachial-ankle pause wave velocity (baPWV) ( Supplementary Information 10–7 ). Basic studies are needed to elucidate the mechanism(s) of uric acid not only in hypertension but also in atherosclerosis. Accumulated evidence from epidemiological studies suggests that hyperuricemia is also a risk factor for CKD and CVD. However, the clinical significance of intervention for serum uric acid in CKD and CVD remains controversial. Further progress in clinical research is expected in the near future.

Progress in translational research: basic research

(See Supplementary Information  11 )

Basic research plays important roles in the progress of translational research (Fig.  11 ). First, in the heart, Peterson et al. demonstrated the enhancing effects of caspase recruitment domain family member 9 (Card9) on cardiac fibrosis and hypertrophy using a transverse aortic constriction model [ 120 ]. The authors previously reported a protective effect against ischemia and reperfusion injury through attenuation of acute inflammatory responses in mice without the Card9 gene [ 121 ], indicating Card9 to be a potential target in CVD [ 122 ]. On the other hand, another Card family member, Card6, is reported to be a novel cardioprotective factor via negative regulation of mitogen-activated protein kinase signaling [ 123 ]. “Cards” act as different master cards in cardiac disease.

Topics in basic research. Each ref. number indicates the reference paper cited in the text

In the kidney, Natarajan et al. reported the effects of acute hypoxia on renal epithelial cells, with enhanced mitochondrial function [ 124 ]. Young spontaneously hypertensive rats (SHR) show increased renal expression of key proteins for mitochondrial biogenesis and hypoxia-inducible factor (HIF)−1α compared to normotensive Wistar Kyoto rats. Increased mitochondrial metabolism could be a causal contributor to hypertension in SHR [ 125 ]. On the other hand, HIF-1α activation improves mitochondrial function in early CKD and has a beneficial effect on renal function, with lowered mitochondrial oxygen consumption [ 126 ]. Thus, the roles of HIF-1α have been focused on in both hypertension and CKD. Moreover, Kouyoumdzian et al. reported the effects of angiotensin II on the renal dopaminergic system [ 127 ]. They presented a clear schematic representation of this mechanism, showing the association between dopamine D1-like receptor (D1R) and angiotensin type 1 receptor (AT1R), focusing on the counteraction of the effects of dopamine and angiotensin II on sodium excretion. On the other hand, a role of the D1R and angiotensin type 2 receptor (AT2R) interaction in maintaining sodium ion transport has been reported [ 126 ]. Interestingly, AT2R stimulation was regulated by angiotensin III. There are marked interactions between dopamine receptors and angiotensin receptors. Morisawa et al. demonstrated the beneficial effects of renal denervation on salt-sensitive hypertension by reducing its effects on catabolism and cardiovascular energy expenditure [ 128 ]. Hypertension increases glucose utilization in cardiac muscle prior to the development of structural changes [ 129 ]. Renal denervation is expected to have not only BP-lowering effects but also BP-independent cardioprotective effects, with attenuation of the salt-derived catabolic state.

In the brain, Savic et al. ( Supplementary Information 11–1 ) showed possible roles of vasopressin, with an increase in gene expression of vasopressin and V1b receptor in the hypothalamic paraventricular nuclei in borderline hypertensive rats. Moreover, Cao et al. ( Supplementary Information 11–2 ) demonstrated that microinjection of urotensin II, a polypeptide molecule with neurohormone-like activity, into the rostral ventrolateral medulla increases sympathetic vasomotor tone. Such vasoactive peptides have also been highlighted in hypertension research to elucidate the central regulation of BP.

Jackson et al. ( Supplementary Information 11–3 ) demonstrated that neural suppression of miRNA-181a in the kidney increases renin expression, resulting in exacerbation of hypertension in BPH/2J mice. Moreover, Zhang et al. ( Supplementary Information 11–4 ) showed that an increased circulating level of miR-122 could be a potential risk factor for endothelial dysfunction in young hypertensive mice. MicroRNAs have been highlighted as future clinical biomarkers and therapeutic tools in hypertension.

Finally, Steppan et al. reported mouse strain-dependent differences in key vascular stiffness indices among inbred mouse strains such as C57BL/6J, 129S, and BL6/129S [ 130 ]. These baseline data may contribute to future animal studies in hypertension research. Moreover, much promising basic research has been reported in Hypertension Research. See Supplementary Information .

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Deparment of Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime, Japan

• Masaki Mogi

Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Hiroshima, Japan

Yukihito Higashi

Divivsion of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Hiroshima, Japan

Department of Endocrinology and Hypertension, Tokyo Women’s Medical University, Shinjuku, Tokyo, Japan

Kanako Bokuda & Atsuhiro Ichihara

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Hirotaka Shibata

Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan

Satoshi Hoshide & Kazuomi Kario

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Mogi, M., Higashi, Y., Bokuda, K. et al. Annual reports on hypertension research 2020. Hypertens Res 45 , 15–31 (2022). https://doi.org/10.1038/s41440-021-00766-3

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Received : 13 September 2021

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Published : 15 October 2021

Issue Date : January 2022

DOI : https://doi.org/10.1038/s41440-021-00766-3

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