Hypertension is the most common condition associated with cardiovascular disease (CVD; population attributable fraction of 22.3%) and a known risk factor for mortality [1]. The prevalence of hypertension continues to rise in China, where the number of people with hypertension is expected to reach ~300 million by 2025 [2]. For decades, hypertension was defined as a baseline systolic blood pressure (SBP)/diastolic blood pressure (DBP) of at least 140/90 mmHg [1]. While SBP of 130–139 mmHg and DBP of 80–89 mmHg were previously defined as "pre-hypertensive," they were redefined as stage I hypertension in the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines [3]. The ACC/AHA guidelines recommend initiating antihypertensive therapy in patients with SBP ≥130 or DBP ≥80 mmHg to reduce the risk of CVD and cardiovascular events [4]. Indeed, several studies have shown that lowering the SBP to <130 mmHg reduces the risk of fatal outcomes such as myocardial infarction, stroke, and heart failure [5]. However, evidence based on several randomized controlled trials suggested that it was more beneficial to treat patients with office blood pressure (BP) ≥140/90 mmHg, leaving the definition of hypertension unchanged (office SBP ≥140 mmHg and/or DBP ≥90 mmHg) [6]. Moreover, some scholars speculated that the lower BP suggested in the 2017 ACC/AHA guidelines might lead to over-treatment [7]. Whether this "pre-hypertensive" stage differs from the normal and/or hypertensive stage remains unclear, requiring further clarification of the characteristics of individuals with pre-hypertension.

Atherogenesis is a key manifestation of target organ morphological damage, which commonly manifests as coronary heart disease leading to myocardial infarction, cerebrovascular disease leading to stroke and other complications, and biomechanical damage, which manifests as arteriosclerosis. The carotid intima-media thickness (cIMT), measured non-invasively by ultrasonography, is considered a morphological surrogate of early atherosclerosis. Studies have shown that elevated cIMT was associated with obesity, hypertension, and cardiovascular events [8,9]. However, due to the low spatial resolution of current vascular ultrasound probes, cIMT measurements include the intima and media layers together. However, the atherosclerosis process primarily involves the intima layer. Therefore, an increase in cIMT may be primarily due to medial hypertrophy caused by hypertension or aging rather than atherosclerosis-induced intimal hyperplasia [10]. According to current guidelines, risk assessment with cIMT for primary prevention is no longer recommended since research confirmed that the cIMT was inferior to the coronary artery calcification and ankle-brachial index in a medium- to high-risk cohort [11].

Carotid-femoral pulse wave velocity (cfPWV) correlates well with cardiovascular risk factors and mortality and is considered the gold standard for measuring arterial stiffness [12]. The European guidelines include cfPWV in the management of arterial hypertension [13], but its accuracy is limited by the error introduced by the distance and the timing algorithm used. Ultrafast pulse wave velocity (ufPWV) is a novel ultrafast ultrasonographic technique, which directly photographs (>2,000 frames/s) the propagation of the pulse wave to calculate pulse wave velocity in real time [14]. Unaffected by the evaluation error introduced by the distance between measurement points, ufPWV can more accurately characterize the biomechanical properties of the arterial wall and the effect of vascular aging or genetic defects [14]. Moreover, it is an effective and user-friendly alternative for carotid stiffness evaluation in normal individuals and those with relatively early atherosclerosis [15]. Studies have shown that pulse wave velocity-beginning of systole (PWV-BS) and pulse wave velocity-end of systole (PWV-ES) measurements using the ufPWV technique were positively correlated with BP, possibly due to an increase in arterial stiffness linked to hypertension [16]. The authors’ previous studies have shown that ufPWV measurements were an independent predictor of atherosclerosis in patients with hypertension and that PWV-ES could quantitatively evaluate arterial stiffness in healthy individuals, even in those with normal cIMT [17,18]. However, no study has focused on arterial stiffness as quantified with ufPWV in the pre-hypertensive (PHT) population.

Therefore, the aim of this study was to utilize the cIMT and ufPWV to assess the morphological and biomechanical properties of the carotid wall as evaluation of arteriosclerotic characteristics in a PHT population.

The results of this study showed that the PHT population was distinctive, with remarkably distinct ufPWV values from healthy individuals and those with hypertension, even when the cIMT was normal and the results were adjusted for age. Furthermore, the present findings indicate that ufPWV could be used for quantitative evaluations of the carotid stiffness in the PHT population, and suggest that biomechanical alterations of atherosclerotic arteries might occur earlier than morphological alterations. The 2017 ACC/AHA guidelines indicated that the prevalence of hypertension had increased observably, and a significant portion of adults taking antihypertensive medicines are recommended for more intensive BP reduction regimens [19]. However, multiple CVD studies have demonstrated that the risk reduction benefit of the target BP stated in the 2017 ACC/AHA guidelines (130/90 mmHg) was lower than the target in the Chinese hypertension guidelines (140/90 mmHg) [20]. Moreover, patients with diabetes or chronic kidney disease and people aged ≥60 years might not benefit from lower BP targets and, instead, experience dizziness and cognitive impairment [5,20]. Besides, a recent study in African-Caribbean males aged ≥65 years showed that arterial stiffness, quantified by brachial-ankle pulse wave velocity, was markedly higher in PHT individuals than in NBP individuals but indistinguishable from patients with HT [21]. The authors’ previous studies have shown that increases in PWV-ES assessed by ufPWV were consistently synchronized with age, even in a young population of 30–39 years old [18]. In summary, a PHT population exists and has different carotid stiffness measured by ufPWV from NBP individuals. The PHT group deserves more attention and specific hypertension management guidelines. Of course, more data and validation of this technique are needed before guidelines can be formulated.

Atherosclerosis is a life-long and multifactorial disease. Besides hypertension, aging is a key risk factor that could drive atherosclerosis development and progression [22,23]. Previous studies have shown that age and high BP were independently associated with the PWV, and measurements of cfPWV showed that age was an important predictor of aortic stiffening [24,25]. ufPWV is an effective, user-friendly alternative for assessing carotid stiffness at a relatively early atherosclerotic stage [15]. Consistent with this stance, the authors’ previous studies have shown that carotid stiffness, measured by ufPWV, was strongly correlated with age and that PWV-ES performed better than PWV-BS at assessing age-related atherosclerosis [18]. These findings are probably due to the following reasons [26,27]: (1) regional PWV-ES can technically be more accurately estimated than PWV-BS; (2) PWV-ES represents the arterial stiffness at the systole phase, which is more effective and sensitive to changes in arterial stiffness due to age and related diseases; and (3) early systolic expansion powered by left ventricular ejection might hinder the detection of minute differences in wall stiffness. This study showed that the standardized coefficients of age in the multivariable linear analyses of PWV-BS and PWV-ES were both notably higher than those of other cardiovascular risk factors, such as sex, SBP and DBP, indicating that aging was a dominant driver of carotid stiffening. Furthermore, PWV-ES in the PHT group was notably higher than in the normal-cIMT NBP group, indicating that ufPWV may be a promising tool for evaluating atherosclerosis progression in a younger population than has been previously done.

Carotid intima thickening is considered an early indicator of atherosclerosis and a target organ for damage caused by hypertension. The cIMT value of patients with hypertension is markedly higher than that in healthy volunteers [28–30]. Studies have shown that the carotid stiffness, measured by ufPWV, was positively correlated with cIMT [15,31]. The authors’ previous results demonstrated that cIMT and PWV-ES were higher in patients with hypertension than in healthy people, and changes in cIMT appeared to lag behind PWV-ES when measurements were made with ufPWV [18,32]. These previous findings also demonstrated that arterial stiffening was highly accelerated in the early stages and slowed down thereafter, seemingly reaching an upper limit [18]. This finding could explain the more apparent arterial stiffness differences in participants with normal cIMT (<0.050 cm) in this study, showing a unique ufPWV value when assessing early arteriosclerosis linked to pre-hypertension. This study showed that with an increase in BP, a larger proportion of the population had increased cIMT. The proportion of patients with increased cIMT when using ufPWV in the PHT group was prominently higher than in the NBP and HT groups, confirming that the arterial morphology and stiffness in the PHT population were distinctive. This finding agrees with the aim of the ACC/AHA guideline to merge prevention and treatment, proposing a goal for the category formerly accepted as pre-hypertension [3,7]. However, the question of whether intensive therapy is appropriate for the PHT population remains controversial, requiring further verification and validation in future studies.

There were some limitations to this study. First, there were considerably fewer patients in the PHT group than in the other two groups due to its smaller range of BP. Second, patients with atherosclerosis often have multiple coexisting risk factors that simultaneously affect their disease progression. Therefore, it is usually difficult to control for all the confounding factors. Third, this was a retrospective study that did not screen patients through an age-matching process. Furthermore, atherosclerosis is a life-long disease in which numerous factors play various roles. Some factors that might affect the cIMT and carotid stiffening were not considered in this retrospective study (e.g., perimenopause, family history, lifestyle, and work style). Fourth, the PWV-BS and PWV-ES were measurements representing the arterial stiffness, performed at two time points in the cardiac cycle rather than average values of the arteries of interest, so they may be lower than the values measured when using the cfPWV technology. Therefore, a larger sample in a multi-center prospective cohort study could further explore this approach in the future.

In conclusion, the cIMT (representing morphological) and carotid stiffness (representing biomechanical properties) of patients with PHT were distinctive from those in the NBP and HT groups. ufPWV may be used for the early evaluation of arteriosclerosis, which mainly occurs in the subendothelial space of medium-sized to large arteries at regions of disturbed blood flow or bifurcations and is linked to pre-hypertension.