Encounter with hypertension

I was born in 1946 in Maebashi City, Gunma Prefecture, Japan. My mother died from a hypertensive disorder of pregnancy at the age of 36 years when I was just 8 years of age. She suffered from malignant hypertension and renal failure. At that time, there was no available antihypertensive treatment. My father was a doctor of internal medicine, but he just looked on with folded arms. This might have been the formative experience and trauma that motivated me to engage in the world of hypertension research.

Age of junior residents

I graduated from Tohoku University School of Medicine in 1971 and spent two and a half years as a junior resident at Yuri General Hospital, Honjo, Akita Prefecture. At that time, the Yuri-Honjo area had the highest incidence of hypertensive cerebral bleeding in Japan. Patients with severe hypertension were common. Dr. Shojiro Izumi, Director; Dr. Masashi Itoh, Associate Director, and many medical staff of the Yuri General Hospital, pushed forward with practice prevention and epidemiological surveys of hypertension, in which I also participated. I am surprised that self-measurement of BP using a mercury sphygmomanometer and stethoscope had already been introduced in their epidemiological surveys.

At that time, there was no effective treatment for hypertension, especially severe hypertension. Many hypertensive patients died of stroke, congestive heart failure, and renal insufficiency. I had the option of a path as a neurologist. However, after encountering the serious and miserable situations of young to middle-aged patients who suffered from irreversible conditions, I chose a path to prevent stroke, that is, hypertension medicine.

Age of postgraduate school

In 1974, I was admitted to the Second Department of Medicine, Tohoku University School of Medicine, chaired by Professor Kaoru Yoshinaga. Because I was interested in circulatory regulation, he dispatched me to the Second Department of Pharmacology, chaired by Prof. Norio Taira, who was an expert and authority in cardiovascular pharmacology. He provided me with a theme regarding venous return. This task helped me notice that BP had phasic and tonic regulatory mechanisms [1]. This sparked my interest in BP variability. I began my clinical research in 1976 with the supervision of Prof. Kaoru Yoshinaga. He assigned me a task related to the clinical pharmacology of diuretics. I performed self-measurement of BP at home (home BP [HBP]) using a semiautomatic aneroid sphygmomanometer as a tool for clinical pharmacology. This experience persuaded me to apply HBP as a tool for research in the clinical science of hypertension based on its outstanding characteristics, particularly high measurement frequency, unified measurement conditions and high reproducibility of the measurement value.

Before and after study abroad

In 1984, I was invited by Prof. Colin Johnston, Department of Medicine, Monash University, Melbourne. Based on my experience in the Department of Pharmacology in Sendai, I started my experiment on cardiovascular autonomic control. Since Prof. Colin Johnston kept Brattleboro rats, hereditary vasopressin-deficient rats, I used these rats to examine the effect of vasopressin on baroreflex control of BP. Baroreflex sensitivity decreased in vasopressin-deficient rats through attenuation of vagal function, which led to high BP variability [2]. After returning to Japan, I continued my experiments using Brattleboro rats and found that centrally administered vasopressin induced BP stabilization through facilitation of the parasympathetic nerve system [3]. Furthermore, centrally administered vasopressin induced hypotensive and bradycardic effects in spontaneously hypertensive rats [4].

Circadian BP variation and nocturnal BP

Based on these experimental results, BP variability has become the focus of attention in hypertension research and practice. Circadian BP variation is an important factor that affects BP variation. At that time, devices for ambulatory BP monitoring (ABPM) using an upper arm cuff were introduced in Japan. However, these devices were too large, heavy, and noisy. Intermittent cuff inflation significantly disturbed sleep. To overcome these shortcomings of conventional ABPM devices, we developed a finger volume-oscillometric device capable of performing ABPM [5]. Using this device, circadian BP variations in several forms of secondary hypertension were studied. The most important finding of these studies was the loss or reversal of normal nocturnal dipping of BP and high nocturnal BP in Cushing’s syndrome [6]. The effect of excess glucocorticoids on circadian BP variation was subsequently confirmed by the effect of exogenously administered glucocorticoids [7]. These variations in circadian BP were later labeled ‘nondipper’ and ‘inverted dipper (riser)’, which led to hypertensive cardiovascular target organ damage and events. These studies were presented at the 12th Annual Meeting of the International Society of Hypertension, Kyoto, in 1988. I concluded that advanced cardiovascular damage in Cushing’s syndrome might be partly due to nocturnal hypertension. This was the beginning of our focus on nocturnal BP. Simultaneously, I observed and reported that high BP in the morning (morning hypertension) was accompanied by nocturnal hypertension as well as nondipping. Although it was a later development, I explored the possibility of measuring nocturnal BP using an HBP measurement (HBPM) device, which led to the publication “Device for the self-measurement of BP that can monitor BP during sleep” in 2001 [8]. Furthermore, this exploration progressed to the development of a “home nocturnal BP monitoring system using a wrist-cuff device” in 2018 that did not disturb nocturnal sleep [9]. In addition to Cushing’s syndrome, I studied circadian BP variation in essential hypertension, pheochromocytoma, primary aldosteronism, hyperthyroidism, renovascular hypertension, renal insufficiency, preeclampsia, and autonomic failure. These observations were reported in the State-of-the-Art lecture at the 13th Annual Meeting of the International Society of Hypertension, Montreal in 1990 [10]. This transmission of information across the world brought about communication among international researchers in the field of BP measurements. Later, this research group held the 8th International Consensus Conference on Blood Pressure Monitoring in Sendai in 2001 (Supplementary Fig. 1).

The Ohasama study

Through my experience over 15 years of engaging in clinical science and practice of hypertension, I noticed the clinical significance of HBPM and ABPM. However, around the 1980s, the clinical significance of HBP received little attention. Professor Shigeaki Hinohara, a legendary doctor of clinical medicine in Japan, often told us that when he started his research on HBP in the 1970s, the Ministry of Health and Welfare, Japan, warned him not to make patients self-monitor their BP at home. They told him that BP measurements are medical practice and that patients should not measure their BP by themselves. Around the same time, I started to measure HBP in the general population and in hypertension clinics. At that time, many physicians told me that patients should not measure their own BP at home, and many study participants reported to me that they were scolded by family doctors, “Don’t measure BP by yourself at home”.

Almost 30 years ago, I contributed to a paper on HBP in the American Heart Association Journal. One of the reviewers commented, “What is home BP? Home has no BP”, indicating very low awareness of HBPM in that era.

In 1986, Dr. Kenichi Nagai, Director of Ohasama Prefectural Hospital, Ohasama, Iwate prefecture, who was my classmate at Tohoku University School of Medicine, asked me how to increase health awareness and preventive awareness regarding hypertension among Ohasama inhabitants. I suggested that he make the Ohasama inhabitants measure HBP. Obtaining HBPM devices and encouraging them to measure HBP was the challenge. Nothing ventured, nothing gained. I called a person responsible for the marketing of Omron Life Science Co. LTD　(Present Omron Health care Co. Ltd) and asked him to support our project. He offered us 300 semiautomatic electrical sphygmomanometer devices (Omron HEM401C).

At that time, Ohasama Town had a population of 8000 people. The movement of people in Ohasama Town was small. The Ohasama Prefectural Hospital was the sole medical institute in this area. Young and active public health nurses and the highly conscious local administration of Ohasama encouraged us. Furthermore, Ohasama inhabitants had a strong interest in HBPM, since at that time, they were aware that the stroke incidence in Ohasama was very high and that hypertension was an important cause of stroke.

In 1987, the HBPM devices were distributed to each household. Each member of the household over 12 years of age measured their own BP and recorded it in a log book. The inhabitants of Ohasama continued their BP measurements for 35 years, and their outcomes were followed up over these periods. Simultaneously, ABPM was initiated. However, ABPM was aborted after 12 years because it was too burdensome for public health nurses to visit and apply devices to each individual. ABPM received unfavorable criticism from the inhabitants. These findings suggest that ABPM is difficult to introduce widely into general clinical practice. In contrast, the Ohasama Study shed light on the high feasibility and utility of HBPM.

First in the world achievements from the Ohasama study

The prognostic significance of ambulatory blood pressure (ABP) was first reported by Dr. Dorothee Perloff (San Francisco, CA, USA) and colleagues in 1983 through a prospective analysis of 1076 hypertensive patients.

The Tecumseh Blood Pressure Study in Michigan, USA, was a pioneering epidemiological survey of BP based on HBPM. Although the Tecumseh Blood Pressure Study started in the 1970s, HBPM was introduced in the 1980s, and participants were followed up for three years. The first observation was reported in 1990 by Dr. AD Mejia and colleagues as ‘normative data on BP self-determination’. This study included normotensive subjects aged 18-42 years old. The Ohasama Study started in 1986 and followed up with the participants for 35 years. The Ohasama Study included the general population of Ohasama aged between 7 and 98 years, and the normative value of HBP was first reported in 1993 [11],; thus, the following results reported from the Ohasama Study were largely the first epidemiological findings of HBP.

Reference values of HBP and ABP

In 1993, the reference values of HBP and ABP were first reported in the Ohasama Study [11, 12]. These were the results of the cross-sectional analysis.

Around that time, I did not have the ability to analyze prospective data statistically. However, young and talented people were recruited for the Ohasama Study projects; these members are shown in Supplementary Table 1. Many doctoral and postdoctoral fellows from the Department of Clinical Pharmacology, Tohoku University, which I have chaired since 1999, have joined this project.

The first and most important results of the Ohasama Study were reported in 1997 [13], followed by a report in 1998 [14]. In the latter study, 1491 individuals aged ≥40 years in Ohasama without a history of stroke were followed up for an average of 10.6 years. HBP could be used to predict stroke incidence, whereas conventional BP values obtained during health examinations could not. HBP ≥ 135/85 mmHg significantly increased the relative hazard of stroke incidence (Supplementary [15] Fig. 2), and these values were referred to as the hypertensive level. These reports were cited in The Sixth Report of the Joint National Committee, 1997, USA; World Health Organization-International Society of Hypertension Guideline, 1999; European Society of Hypertension/European Society of Cardiology Guidelines for Management of Arterial Hypertension 2007 and 2013; British Guidelines for management of Hypertension 2011; and Japanese Society of Hypertension Guidelines 2004, 2014 and 2019. Thereafter, a normal BP level of <125/85 mmHg was reported in the Ohasama Study. These values are now the basis of reference values for hypertension and normotension based on HBP in the International Hypertension Guidelines. Thus, the Ohasama Study has been recognized worldwide.

Barriers to implementation of the Ohasama Study

During the 35 years of the Ohasama Study, we faced several crises related to the continuation of the study. The largest one was a 1999 press report by a major newspaper that reported that the Ohasama Study analyzed genes without permission from study participants. This was the top newspaper article. Certain unfavorable persons treated me like a criminal, while many colleagues defended me. We obtained informed consent from the residents after explaining that their remaining blood samples were stored for future research. However, the explanation sheets did not include the term “gene”. At that time, there were no official ethical guidelines for genetic research in Japan; thus, the need for specific informed consent for genetic research was not introduced. Many newspaper reporters visited Ohasama for follow-up coverage. Many residents of Ohasama told reporters, “We acknowledge the researchers of the Ohasama Study since they are supporting our health. We received an explanation of their genetic analysis”.

Thus, the Ohasama Study was saved and continues to date. I thank the many supporters and residents of Ohasama from the bottom of my heart.

Differential prognostic significance among ABP, HBP and clinical BP

Finally, we wanted to determine which BPM, HBP, ABP, or clinical BP (CBP) provided the most useful information for the diagnosis and treatment of hypertension. Few studies have directly compared the usefulness of ABP, HBP, and CBP. In 2005, Dr. Robert Sega (Milano, Italy) and colleagues first reported from the Pressioni Arteriose Monitorate eLovo Associazione (PAMELA) study that the risk of death increased with a given increase in HBP or ABP rather than CBP, but the overall ability to predict death was not greater for HBP and ABP than for CBP. In the PAMELA study, the average of only two HBP measurements was used. In the Ohasama Study, 49 HBP measurements were averaged over four weeks. As a result, the clinical indications for ABPM and HBPM overlapped, and the clinical significance of each method for predicting target organ damage might differ for different organs [16].

Contribution to international and domestic joint research

Data on HBP and ABP were provided for international and domestic joint research. I greatly appreciate Prof. Jan Staessen (Leuven, Belgium), who organized the International Database of Ambulatory Blood Pressure in relation to Cardiovascular Outcome (IDACO) (Supplementary references 1) and the International Database of Home Blood Pressure in relation to Cardiovascular Outcome (IDHOCO) meta-analyses (Supplementary references 2). These meta-analyses established firm evidence for the clinical significance of HBP and ABP. I acknowledge that the results of the IDACO and IDHOCO meta-analyses corroborated many results of the Ohasama Study. The Asia Pacific Cohort Studies Collaboration (APCSC) (Supplementary references 3), Blood Pressure Lowering Treatment Trialist’s Collaboration (BPLTTC) (Supplementary references 4), ambulatory blood pressure international (ABP-International) study (Supplementary references 5), prospective study collaboration (Supplementary references 6), Chronic Kidney Disease Prognosis Consortium (Supplementary references 7), Evidence for Cardiovascular Prevention from Observational Cohort in Japan (EPOCH-JAPAN) (Supplementary references 8), and the Japan Arteriosclerosis Longitudinal Study (JALS) (Supplementary reference 9) are international and domestic joint studies. I am proud that the Ohasama Study could contribute to such global efforts.

White-coat hypertension and masked hypertension

Pressor response and hypertension in response to the medical environment have been well recognized for a long time. Prof. Thomas G Pickering (New York, USA) termed this “white-coat hypertension” in 1988. The diagnosis of white-coat hypertension cannot be discussed without BP measurement outside the clinic.

Whether white-coat hypertension is harmful or innocent remains unclear. The Ohasama Study demonstrated that white-coat hypertension was a transitional condition to hypertension, suggesting that white coat hypertension carried a poor cardiovascular prognosis [17]. In fact, we demonstrated in a meta-analysis of four cohorts that white-coat hypertension was not a benign condition for stroke in the long term [18].

In 1996, we reported a prognostic significance for mortality among white-coat and “reverse white-coat hypertension” [19]. The term “reverse white-coat hypertension” was later referred to as “masked hypertension” by Prof. Thomas G Pickering in 2002.

The term “masked hypertension” is unmatched when compared to “reverse white-coat hypertension.” The Ohasama Study first demonstrated that masked hypertension was associated with a high risk for all-cause mortality [19] and cardiovascular/stroke mortality [20]. We also demonstrated first that the risk of silent cerebrovascular lesions is higher with masked hypertension than with sustained normotension [21]. In an international hypertension meeting, Professor Thomas G Pickering mentioned that the Ohasama Study first reported a high risk of masked hypertension. I was impressed with his sense of fairness.

The diagnoses of white-coat hypertension and masked hypertension are diverse based on the differential out-of-clinic BP measurements. The impact of partial white-coat hypertension (either home or ambulatory normotension with clinical hypertension) and partially masked hypertension (either home or ambulatory hypertension with clinical normotension) is comparable to that of completely masked hypertension (both home and ambulatory hypertension with office normotension) or sustained hypertension [22].

The Japan Home versus Office Measurement Evaluation (J-HOME) study first reported the prevalence and predictive factors of treated white-coat hypertension and treated masked hypertension in a real-world larger-scale observational study [23]. Similar survey results are listed in Supplementary references 10.

Circadian BP variation, nocturnal BP and morning BP in the Ohasama Study

Prof. Eoin O’Brien (Dublin, Ireland) and colleagues first noticed in 1988 that people with nondipping nocturnal BP, nondippers, have a higher risk of cerebrovascular complications than people with normal circadian BP variation, dippers. In 1990, Prof. Kazuyuki Shimada (Kouchi, Japan) and colleagues reported the risk of nocturnal hypertension for silent cerebrovascular disease. Around the same time, I reported disturbed circadian variation in BP in several forms of secondary hypertension [6, 7, 10], that is, nondipping and inverted dipping of nocturnal BP. Therefore, the investigation of circadian and nocturnal BP variations was of urgent interest in the Ohasama Study. The first report from the Ohasama Study was focused on the relationship between nocturnal BP and silent cerebrovascular lesions in elderly subjects [24]. We observed that in women with multiple lacunar infarctions, the amplitude of the nocturnal fall of systolic BP was greater than that in women without lacunar infarction [24]. The greater amplitude of nocturnal fall of BP was a real finding. This apparently excessive fall in nocturnal BP might be equivalent to the term “extreme dipper”. Nocturnal hypotension has long been considered the “sine qua non” of extreme dippers. First, we concluded that excessive falls in nocturnal BP and resulting inappropriately low nocturnal BP levels were responsible for the risk of silent cerebrovascular lesions. However, in our analysis, we did not adjust the amplitude of the nocturnal BP fall to the nocturnal BP level as well as the daytime BP level. The daytime and nocturnal BP levels in subjects with lacunar infarction were higher than those in subjects without lacunar infarction [24].

The following results from the Ohasama Study demonstrated that extreme dipping was a benign condition when compared to nondipping and inverted dipping [25]. The mortality risk was highest among inverted dippers, followed by nondippers; there was no difference in mortality between extreme dippers and dippers [25].

Nondipper and inverted dipper

A very high risk for mortality of inverted dippers was first reported epidemiologically from the Ohasama Study [25]. We also reported that a diminished nocturnal fall in BP was a risk factor for cardiovascular mortality independent of the overall BP load during a 24-h period in the general population [26]. However, it is also logically derived that nocturnal BP levels in nondippers with 24-h normotension are relatively higher than those in dippers with 24-h normotension.

Extreme dipper

Looking back on this experience, we epidemiologically reported that women with daytime systolic BP ≥140 mmHg and extreme dipping had higher nocturnal BP than those with daytime systolic BP <120 mmHg and normal dipping [27] (Supplementary Fig. 3). When daytime systolic BP was high, nocturnal BP was also high, even when these participants had extreme dipping (Fig. 1). In other words, the risk of extreme dipping behavior in hypertensive subjects was not necessarily due to an excessive nocturnal fall of BP/excessively low nocturnal BP levels but might be, at least in part, due to a high level of either or both nocturnal and daytime BP.

Fig. 1

Circadian blood pressure variation among women with different daytime systolic blood pressure (SBP) levels in the Ohasama study. As daytime ambulatory blood pressure levels increased, the amplitude of nocturnal blood pressure decrease increased. A substantial number of subjects with high daytime blood pressure had an extreme dipping pattern of circadian blood pressure variation, while nocturnal blood pressure levels were hypertensive

Nocturnal hypertension

Assessing this phenomenon, it is true that nondippers and inverted dippers seem to have a high risk of mortality and morbidity from cardio- and cerebrovascular diseases. It is also true that high nocturnal BP levels might be responsible for the high risk of mortality and morbidity associated with cardio- and cerebrovascular diseases. Even in extreme dippers with daytime hypertension, high nocturnal BP levels might partly be responsible for their high risk. The high predictability of cardio- and cerebrovascular risk of nocturnal BP was first reported in the systolic hypertension in Europe (Syst-Eur) study by Prof. Jan Staessen and others in 1999. The Ohasama Study clearly demonstrated that the total cardio- and cerebrovascular mortality risk was significantly associated with elevated nocturnal systolic BP [28, 29]. The Ohasama Study was the main source of the IDACO database, which demonstrated the high prognostic accuracy of nighttime ABP [30, 31].

Morning BP

The remaining topics of circadian BP variation were morning BP, morning surges, and morning hypertension. Looking back, a motive for why I drew attention to the circadian variation of BP in Cushing’s syndrome was very high morning BP just after awaking in patients with this syndrome [6]. We were the first to observe differential characteristics of morning and evening HBP. In subjects in the Ohasama Study, the morning HBP was higher than the evening HBP [32]. Interestingly, the use of antihypertensive medication in the morning was positively associated with the difference between morning HBP and evening HBP, indicating that an insufficient duration of action of antihypertensive drugs contributed to the high morning BP [33]. This observation led me to introduce HBP as a tool for assessing the clinical pharmacology of antihypertensive drugs.

In 2001, we reported that the risk of cardiovascular mortality was higher in subjects with large positive differences between morning and evening HBP than in subjects with small or negative differences, indicating that when morning HBP was relatively or absolutely higher than evening HBP, the risk of cardiovascular mortality was high [34]. We also demonstrated that morning hypertension determined by HBPM, which indicates hypertension specifically observed in the morning, was a good predictor of stroke, particularly among individuals using antihypertensive medication [35], suggesting again that insufficient duration of antihypertensive drug action was responsible for the morning hypertension [34]. Finally, we reported that risk stratification in international hypertension guidelines has stronger predictive power when based on morning HBP than on clinic BP [36, 37].

Morning surge

A remarkable rise in BP in the early morning has been referred to as the morning surge. Many historical studies have indicated that cardio- and cerebrovascular events occur more frequently in the early morning, when the morning surge of BP develops. A pioneering study by Dr. Iwao Kuwajima (Tokyo, Japan) in 1995 reported that the magnitude of the morning surge in BP after rising from bed was related to the severity of hypertensive target organ damage. Thereafter, the risk of morning surge for cardio- and cerebrovascular diseases has been widely reported. However, the risk of morning surge differs among definitions, age, race, and pathophysiological conditions of the disease. For example, in the Ohasama Study, morning surge was not associated with a risk of cerebral infarction, but an increased risk of cerebral hemorrhage was observed in subjects with a large morning pressor surge [38].

The IDACO meta-analysis, which included data from the Ohasama Study, demonstrated that only an extreme morning surge conveyed a risk for cardiovascular events [39]. The mechanical and dynamic impact of extreme morning surges on vasculature may cause cardiovascular events. We have shown that the product of the rate of rise of morning surge (dp/dt, the slope of morning rise of BP) and amplitude of morning surge (ΔBP) are independent risk factors for predicting cardiovascular events and stroke [40].

A remarkable rise in BP in the early morning, the morning surge, may produce a large difference between morning BP level and nocturnal BP level; thus, subjects with a morning surge may have low nocturnal BP and/or high morning BP, and therefore, morning surge should occur in dippers, including extreme dippers and/or subjects with morning hypertension. The Ohasama Study demonstrated that dippers and extreme dippers had a lower risk than nondippers and inverted dippers [25, 26]. The morning surge should have a steep slope of the pressor phenomenon from nighttime during sleep to the morning after rising. However, the Ohasama Study demonstrated that high morning BP relative to average daytime BP occurred in subjects with a loose or negative slope of the pressor phenomenon, indicating that high morning BP was observed in nondippers and inverted dippers. In contrast, in subjects with a steep slope of the pressor phenomenon, dippers and extreme dippers had minimal morning high BP (Fig. 2). These observations suggest that the risk of morning hypertension reflects the risk of nondippers and/or inverted dippers. Furthermore, nondippers and inverted dippers had relatively or absolutely high nocturnal BP.

Fig. 2

Relation between slopes of morning pressor response seen from preawakening to postawakening period and the difference between morning blood pressure levels in subjects treated with antihypertensive drugs in the Ohasama study. Subjects with a steep slope of morning pressor response, such as extreme dippers, had relatively low morning blood pressure when compared to daytime ambulatory blood pressure. In other words, morning hypertension is rather rare in extreme dippers

There are many concepts related to the risk of cardio- and cerebrovascular disease in relation to pathological circadian BP variation, such as nondipper, inverted dipper, extreme dipper, morning surge, and morning hypertension. What is the principle of the unification of these concepts? Considering the results of the Ohasama Study in a comprehensive way, high nocturnal BP is postulated to be a common risk factor for mortality and morbidity of cardio- and cerebrovascular diseases among pathological circadian BP variations.

Clinical significance of differential BP indices

Many previous studies have demonstrated the clinical significance of isolated systolic hypertension, isolated diastolic hypertension, pulse pressure, and double products. We also focused on these indices based on HBP and ABP epidemiologically. Thus, our findings are novel in this field. The risk of isolated systolic hypertension assessed by HBP had a significantly higher relative hazard than that of normotension, while isolated diastolic hypertension carries a low risk of cerebrovascular mortality, similar to that found in subjects with normotension [41]. This result was later confirmed by the IDACO meta-analysis [42]. In contrast, the Ohasama Study demonstrated that pulse pressure assessed by ABPM was a weak predictor of stroke when compared to systolic ABP [43]. Finally, we found that the double product (product of home systolic BP and home pulse rate) had a predictive value for mortality [44].

BP variability

My motivation to research hypertension started with my interest in BP variability. Physical materials are relatively resistant to continuous stress levels but are more susceptible to intermittent stress. Therefore, it might be expected that individuals with an increased lability of BP would suffer from more cardiovascular diseases.

Short-term BP variation

To the best of our knowledge, the relationship between short-term variability (every 30 min) and target organ damage was first reported in 1987 by Prof. Gianfranco Parati (Milano, Italy) and colleagues. However, this result was derived from a cross-sectional analysis, and the cause-effect relationship between BP variability and target organ damage was unclear. The prognostic significance of short-term BP variability was first reported in the Ohasama Study [45]. The BP and heart rate variabilities obtained every 30 min by ABPM were independent predictors of cardiovascular mortality in the general population. We subsequently reported that ABP variability was closely associated with carotid artery alterations [46]. This result was later confirmed by the IDACO meta-analysis [47].