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Elevated central aortic pressure indices (e.g., systolic pressure and pulse pressure) predict cardiovascular (CV ) events and mortality in addition to structural changes (e.g., left ventricular hypertrophy, carotid intima-media thickness and reduced glomerular filtration rate). These elevated risks have been shown in multiple studies to be superior to, and in others, at least as high as that associated with brachial pressures. Threshold values for the diagnosis of elevated central arterial pressures have been defined and can be considered target goals of treatment. Measurements of central arte- rial pressures can be incorporated into the current approaches to hypertension management utilizing currently avail- able non-invasive devices that measure central pressures during the measurement of brachial BP. The objective of this review is to outline the rationale and evidence supporting incorporation of central aortic pressure monitoring into the care of patients with hypertension. Keywords: Blood pressure, Hypertension, Central aortic blood pressure, Management, Pulse wave analysis 1 Background whom had hypertension . Average annual medical Hypertension remains a common disorder responsible expenditure attributable to hypertension was $9,089 for substantial vascular morbidity and mortality. In 2018, per diagnosed patient. Patients with hypertension had hypertension as a primary or contributing cause was $1,920 higher annual adjusted incremental expenditure, responsible for approximately 500,000 deaths in the USA 2.5 times the inpatient cost, 2 times the outpatient cost, . According to the current definition for hypertension and 3 times the prescription medication expenditure. (≥ 130/80 mmHg), approximately 45% of adults in the Specifically, for prescription medications, the annual United States have hypertension or have been prescribed expenditure was $2,371 for individuals with hypertension medication for hypertension . The Centers for Disease compared with $814 for those without hypertension. Control and Prevention reports that hypertension is Overall, the estimated adjusted annual incremental under control in only 22% of patients . cost was $131 billion per year higher for adults with The Medical Expenditure Panel Survey, a United hypertension relative to adults without hypertension . States nationally representative database, was analyzed Management of hypertension through to estimate annual healthcare expenditure for patients sphygomanometric cuff measurement of peripheral with hypertension using data from 2003–2014 . (brachial artery) pressures has dramatically but The database included a total of 224,920 adults, 37% of incompletely improved the ability of health care providers and their patients to control hypertension and reduce associated end-organ damage. Multiple issues *Correspondence: email@example.com likely contribute to the ongoing socioeconomic burden SKC Life Sciences, 7476 Capstan Dr, Carlsbad, CA 92011, USA of hypertension despite the availability of multiple Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Kest en et al. Artery Research (2022) 28:128–139 129 effective medications and widespread educational efforts. to approximately 20 mmHg with almost no change in Such issues include, but are not limited to, case finding brachial systolic pressure . (early diagnosis), continuity and continued follow-up of The relationship between central aortic and periph - care, affordability of care, medication adverse effects, eral pressure waveforms had been described in a math- medication compliance and challenges in modifying ematical transfer function, which can be generalized and lifestyle behavior. applied to an adult population . Non-invasive pulse An underappreciated but clinically relevant area wave analysis (PWA) is a technique that applies the trans- to consider is the precision and reliability of current fer function on the peripheral arterial pressure wave- monitoring which is based on brachial blood pressure forms to obtain central aortic pressure waveform with measurements, including patient and health care provider cardiovascular related features. Central pressure wave- factors. Cheng and colleagues placed the issue in context form features calculated include central aortic systolic and noted that cuff brachial blood pressure measurement and diastolic pressures, augmentation index (the ratio of “is not so much a surrogate, but a compromised measure the extra pressure load due to wave reflection relative to that is recorded because of technical limitations” . The the pulse pressure), central aortic pulse pressure (systolic reference is to cuff pressures being a surrogate for central minus diastolic pressure), end-systolic pressure, mean (i.e. aortic) blood pressures, which represent the actual pressures in systole and diastole, and subendocardial via- pressures that are transmitted to organs effected by bility ratio (the ratio of the area under the curve during hypertension (e.g. heart, brain, kidney) due to the closer diastole to systole) (Fig. 1). Even though peripheral (bra- proximity of the ascending aorta to vital organs. chial) blood pressures correlate with central pressures The central aortic pressure pulse reflects more in large cohorts, significant variability exists in systolic accurately the cardiac load, which will have an impact pressure  such that central pressures cannot be reli- on the left ventricular myocardium, coronary artery, ably inferred from brachial pressures in individual cases and cerebral vasculature [5, 6]. In addition, there are . Additionally, brachial systolic pressures are gener- significant difference in the pressure pulse between the ally higher than central (aortic) pressures due to wave central aorta and the peripheral arteries like the brachial reflection resulting from the difference in arterial proper - artery. Early studies showed when injecting a fast- ties between the two arteries. The ratio of the peripheral acting vasodilator drug (glyceryl trinitrate), the central to central pulse pressure is referred to as pulse pressure systolic pressure decreases significantly in some cases Fig. 1 Central aortic pressure waveform with cardiovascular related features Kesten et al. Artery Research (2022) 28:128–139 130 amplification, which studies have shown to be associated However, given the significant difference between with cardiovascular disease and events [11–13]. cSBP and pSBP and the high variability of cSBP within The technology for non-invasive assessment of central hypertension pSBP class , measuring cSBP can aortic pressures through PWA had been validated differentiate patients with risk even if they have the same in invasive studies [14, 15] and is currently available pSBP [17, 18]. and approved by the United States Food and Drug Central pulse waveform shape that results from PWA is Administration (FDA). Systems that incorporate PWA determined by ventricular ejection pattern and the elastic is considered as complementary to brachial pressure and geometric properties of the arterial tree . The measurements and can help guide treatment decisions features can provide a significant insight into the status of designed to prevent or reduce long-term target organ the arteries and its effect on cardiac function, which may damage and cardiovascular events resulting from assist in identifying risk and contribute to hypertension increased aortic pressure. management decisions. 2 The Need for Evaluation of Central Aortic 3 Central Aortic Pressure as a Predictive Measure Pressures of Cardiovascular Risk Despite dramatic success in the diagnosis and Peripheral (brachial) blood pressure elevation has management of hypertension, the disease continues to be been proven to be a prominent risk factor for vascular- associated with a high socioeconomic burden globally as related end-organ damage, morbidity, and mortality noted in the previous section. Related issues that provide [20–25]. Blood pressure reduction has been definitively compelling examples of the need include the problem demonstrated to reduce vascular end-organ damage, of white-coat hypertension (in-office blood pressure morbidity, and mortality [26–28]. A comprehensive measurements elevated relative to home-based readings), meta-analysis encompassing 306,273 participants from direct and indirect medication adverse effects in the case 74 trials demonstrated that antihypertensive drugs of over-treatment (i.e., symptoms that lead to medication reduce mortality and cardiovascular disease based on a discontinuation, morbidity such as hypotension, threshold (baseline) systolic blood pressure ≥ 140 mmHg metabolic effects, and organ adverse effects). PWA is . They further noted that no benefit was documented an additional tool that can be seamlessly adapted to for pharmacotherapy in primary prevention of CV the current cuff brachial blood pressure monitoring disease at systolic blood pressures below 140 mmHg paradigm, which has the following potential utility: a) although benefit may be present in those with coronary reduce over-treatment, b) improve under-treatment, artery disease. A recent study (SPRINT)  suggests c) reduce costs of management (e.g., medication that the thresholds for initiation of pharmacotherapy costs, monitoring such as ambulatory blood pressure should be lower and is referred to in hypertension monitoring (ABPM)). PWA has also shown significant management guidelines [28, 29]. With reference to benefits in treatment and management of chronic heart systolic blood pressure, the 2017 Guidelines for the failure . Prevention, Detection, Evaluation and Management of Incorporation of PWA into routine clinical care High Blood Pressure in Adults recommend follow-up requires an evidence-based guidance for how to use PWA monitoring and lifestyle modifications at lower pressures in patient management. The guidance should fit into (i.e. systolic blood pressures 120 to 139 mmHg) and existing algorithms for the management of hypertension recommend pharmacotherapy at lower thresholds where and be supported by sufficient evidence to justify the a patient has known risk factors for cardiovascular clinical utility of PWA. The following sections focuses disease (i.e., 130 to 139 mmHg) . on using central aortic blood pressure in hypertension Threshold values have been defined that represent the management. However, the other central pressure targets for initiation of treatment (lifestyle treatments waveform features from PWA, such as augmentation such as diet and exercise, and pharmacotherapy) and pressure and subendocardial viability ratio can certainly values have been defined for the goals of treatment. contribute to further understanding of the physiology However, sparse data has been published on how and and potential impacts of elevated pressures. what target values should be used for recommending Central aortic systolic blood pressure (cSBP) fits within reductions in pharmacotherapy. the current paradigm for utilizing peripheral (brachial) End-organ damage associated with hypertension systolic blood pressure (pSBP) in that management is related to central pressures and is physiologically decisions are currently guided by predefined pSBP intuitive, as such pressures are directly transmitted to thresholds as well as diastolic BP thresholds in all vital organs. Central systolic pressures are correlated national and international hypertension guidelines. to peripheral systolic pressures with the correlations Kest en et al. Artery Research (2022) 28:128–139 131 relative to brachial pulse pressure was numerically varying from 0.6 to 0.9 [30–32]. Despite the correlation, associated with a higher relative risk of clinical events prediction of aortic systolic pressures based on (p = 0.057) . brachial systolic pressures cannot be reliably inferred A more recent meta-analysis assessed 24 prospective as demonstrated by McEniery et al. using data from studies with 146,986 individuals . Adjusted pooled over 10,000 subjects participating in the Anglo-Cardiff hazard ratio (95% confidence interval [CI]) were Collaborative trial . The study by McEniery reinforces determined total cardiovascular events based on the variation in central systolic pressure that may occur changes for the following variables: cSBP (per 10 mmHg within the same category of peripheral systolic pressure increase) = 1.10 (1.04–1.16), central pulse pressure (per and that central and peripheral pressures are related but 10 mmHg increase) = 1.12 (1.05–1.19), and central not interchangeable. augmentation index (per 10% increase) = 1.18 (1.09– Multiple studies, including meta-analyses, have 1.27). For all-cause mortality, the hazard ratio (95% evaluated central blood pressure (cBP) variables and CI) based on (a) central pulse pressure (per 10 mmHg suggested that cBP has a higher predictive value for increase) was 1.22 (1.14–1.31) and (b) based on AIx (per cardiovascular events relative to peripheral blood 10% increase) was 1.19 (95% CI 1.05–1.34). The authors pressure, with others uniformly demonstrating that concluded that central hemodynamic variables are non-invasive cBP is at least as predictive as peripheral independent predictors of cardiovascular disease and all- blood pressure [5, 6, 33–35]. A meta-analysis conducted cause mortality . by Wang et al. indicated that central blood pressure A prospective study by Lamarche et al. published appears to have a higher predictive value for end-organ in 2021 evaluated the predictive value of cSBP for damage . In a study of 1,169 participants, the group cardiovascular events in 13,461 patients using available of patients with a normal/high-normal peripheral BP central blood pressure measurements and follow-up with cSBP values that were less than the 95% confidence data from administrative databases . A total of 1327 interval (CI) of healthy participants with optimal BP major adverse cardiovascular events occurred during values (45% of those with a normal/high normal BP), follow-up (median approximately 9 years). The hazard had no evidence of target organ changes . In patients ratio for risk of major adverse cardiovascular events with a normal/high-normal BP with cSBP values that was 1.16 (95% CI 1.09–1.22) for cSBP and 1.15 (95%CI exceeded optimal threshold values, left ventricular mass 1.09–1.22) for brachial sBP for a one standard deviation index was increased and estimated glomerular filtration increase. Modeling data evaluating area under the curve rate was decreased. The report demonstrated that central for risk indicated a slightly higher risk using cSBP vs. pressure may have higher predictive value for end-organ pSBP that was statistically but not clinically significant. damage related to hypertension . Nevertheless, the study provided further data based on Wang and colleagues evaluated the relationship of “real-world” data verifying the predictive value of central central and peripheral pressures to end-organ damage BP for adverse cardiovascular outcomes. in 1272 subjects . Carotid intima-media thickness Another variable that can provide additional data and glomerular filtration rate were more strongly related regarding cardiovascular risk is Augmentation Index, to central pressures than peripheral pressures. A total of (AIx), which is the ratio of the central systolic pressure to 130 participants died with 37 dying from a cardiovascular cause. Peripheral and central blood pressure predicted the pressure at the first inflection during cardiac ejection all-cause and cardiovascular mortality. After adjustment (Fig. 1). AIx (adjusted to heart rate of 75 beat per minute) for demographic, as well as biochemical and physiologic has been demonstrated to be associated with coronary disease related variables (heart, kidney, arterial, etc.), artery disease severity in patient with high Framingham cSBP was the only BP variable that consistently and score, and an increased incidence of death, myocardial independently predicted death from cardiovascular infarction, and stent restenosis in patient undergoing disease (hazard ratio = 1.30 per 10 mmHg increase) . coronary angiography [42, 43]. Vlachopoulos et al. reported a meta-analysis of 11 Several limitations should be acknowledged regarding studies that incorporated central hemodynamics and the aforementioned studies. Published investigations had followed 5,648 subjects for a mean of 45 months often examine associations to surrogate endpoints (e.g., . cSBP was associated with a pooled relative risk of carotid intima-medial thickness, left ventricular mass total CV events of 1.088 (95% CI 1.040–1.139) for a index and glomerular filtration rate) rather than long- 10 mmHg increase of cSBP, 1.137 (95% CI 1.063–1.215) term outcome studies, or do not have sufficient power for a 10 mmHg increase of central pulse pressure, and and duration of follow-up for definitive conclusions 1.318 (95% CI 1.093–1.588) for a 10% absolute increase of regarding clinical endpoints of most interest such as central augmentation index (AIx). Central pulse pressure major cardiovascular events and mortality. Regarding the Kesten et al. Artery Research (2022) 28:128–139 132 clinical endpoint publications especially meta-analyses, Table 1 Current staging of hypertension by ESH/ESC and ACC/ AHA. Adapted from NICE, ESH/ESC and ACC/AHA guidelines only summary data is without the ability to assess individual patient responses (i.e., patient level data). Systolic BP Diastolic BP The data in multiple peer-reviewed publications ESH/ESC (2018) demonstrate an increased risk for cardiovascular events Optimal < 120 < 80 with elevated central pressures, particularly cSBP and Normal 120–129 80–84 it is therefore reasonable to conclude that reductions High Normal 130–139 85–89 in hypertension based on cSBP will be associated with Grade 1 Hypertension 140–159 and/or 90–99 reduced CV events, as has been proven with brachial Grade 2 Hypertension 160–179 and/or 100–109 blood pressure. Furthermore, the predictive value of cSBP Grade 3 hypertension ⩾180 and/or ⩾110 is higher than pSBP in multiple studies, and uniformly ACC/AHA (2017) at least as high as pSBP in others. While the supportive Normotension < 120 and < 80 data should not be considered definitive, an objective of Elevated BP 120–129 and < 80 treatment should be to lower central systolic pressures Stage 1 Hypertension 130–139 or 80–89 to values (or thresholds) that correspond to the targets Stage 2 Hypertension ≥140 or ≥90 set for peripheral systolic pressures for the purpose of reducing vascular risk. ACC, American College of Cardiology; AHA, American Heart Association; BP, blood pressure; ESC, European Society of Cardiology; ESH, European Society of Hypertension 4 Threshold Values for Central Systolic Blood Pressure and then validated the results against a second inde- Management decisions for the treatment of hypertension pendent cohort (validation cohort). In the derivation are based on specific values for systolic and diastolic cohort (1,272 individuals and a median follow-up of brachial pressures regardless of age and gender. 15 years), diagnostic thresholds for central blood pres- The 2017 ACC/AHA Guidelines for the Prevention, sure were determined using guideline-endorsed cut- Detection, Evaluation, and Management of High offs for brachial blood pressure with a bootstrapping Blood Pressure in Adults specify the following: normal method (resampling by drawing randomly with replace- BP: < 120/80 mmHg, elevated BP > 120–129/ < 80 mmHg, ment) and an approximation method. The thresholds Stage 1 hypertension: 130–139/80–89 mmHg, and Stage from the derivation cohort were tested in 2,501 indi- 2 hypertension ≥ 140/90 mmHg . The 2018 ESH/ASC viduals with median follow-up of 10 years (validation Guidelines provide additional levels of hypertension and cohort) for prediction of cardiovascular outcomes has some differences in nomenclature (Table 1). . The analyses (derivation and validation cohort) Expert recommendations based on agreed-upon yielded similar threshold values for central aortic pres- thresholds are provided for brachial BP goals for sures. Relative to optimal (central BP < 110/80 mmHg), adults with confirmed hypertension as follows : the risk of cardiovascular mortality in subjects with (a) with known CV disease or 10-year atherosclerotic hypertension (central BP ≥ 130/90 mmHg) was clini- CV disease (ASCVD) event risk of 10% or higher, a BP cally and statistically elevated (hazard ratio: 3.08, 95% target of < 130/80 mmHg is recommended, (b) without CI 1.05 to 9.05). Modeling demonstrated that central additional markers of increase CV disease risk, a BP BP ≥ 130/90 mmHg was associated with the largest target of < 130/80 may be reasonable. Given the high contribution to the prediction of cardiovascular events. correlation to brachial pressures and the predictive value The authors discussed the clinical relevance of central for CV events, thresholds for management decisions pressures and noted “…in current international guide- based on central systolic pressures can be determined. lines, the classification of cuff BP values disregards Guidelines do not exist for central BP thresholds; age, sex, and other cardiovascular risk factors. In our however, published research indicates a degree of multivariate model, the results were consistent after consistency that can be used for establishing central BP accounting for these factors. In line with current clini- management targets. cal practice and considering the higher clinical events Cheng and colleagues published an analysis demon- in the aged population, we now propose diagnostic strating central aortic BP < 110/80 mmHg as optimal, thresholds of CBP without age and sex specification” 110–129/80–89 mmHg as prehypertension (corre- . In reference to spurious systolic hypertension and sponding to “elevated” and Stage 1 hypertension in the white coat hypertension, the authors recognized the 2017 Guidelines) and ≥ 130/90 mmHg as hypertension clinical utility of measuring central aortic BP in that (corresponding to Stage 2 hypertension in the 2017 Guidelines) . The analysis utilized a derivation cohort Kest en et al. Artery Research (2022) 28:128–139 133 Booysen et al. reported an upper threshold for cSBP the diagnosis can be inferred based on a high cuff (bra - of 112 mmHg in a study of 1169 participants . In chial) BP and low/normal central BP . patients with a normal/high-normal BP with cSBP values Takase and colleagues evaluated the distribution of that were less than 95% CI of healthy participants with central blood pressure values in a population study optimal BP values (45% of those with a normal/high of Japanese subjects . This cross-sectional study normal BP), no target organ changes were noted. In involved 10,756 subjects without overt cardiovascular patients with a normal/high-normal BP with cSBP values disease. The analysis used data from 7,348 subjects that exceeded optimal threshold values, left ventricular who were not receiving antihypertensive, antidiabetic mass index was increased and estimated glomerular or lipid-lowering drug treatment. Optimal brachial BP filtration rate was decreased. The report demonstrated was defined as systolic < 120 and diastolic < 80 mmHg. that central pressure may have higher predictive value Normal BP was defined as systolic < 130 and for end-organ damage related to hypertension . The diastolic < 85 mmHg. The cSBP values in those without previously discussed report by Lamarche and colleagues cardiovascular risk factors (other than hypertension) recently identified central and brachial systolic pressures was 125.8 ± 37.2 (mean ± 2 SD, n = 3,760) mmHg . of 112 mmHg (95% CI 111.2–114.1) and 121 mmHg For subjects with no cardiovascular risk factors the (95% CI 120.2–121.9) as optimal BP thresholds based numbers were 112.6 ± 19.2 (n = 1,975) mmHg for on cardiovascular risk . Data indicate a consistency optimal and 129.2 ± 14.9 mmHg for normal brachial around a target goal for central systolic pressure of blood pressure categories (n = 697). Therefore, the 112 mmHg. inference is that reference values of optimal and normal Yu et al. investigated the prevalence of central cSBP categories can be considered as approximately hypertension and its association with end-organ damage 113 mmHg and 129 mmHg respectively . The study in 1983 elderly people . Brachial hypertension was provides further support for cSBP reference values and defined as ≥ 140/90 mmHg or using antihypertensive threshold values based on risk and is corroborative medications. Central hypertension was defined by data for the threshold of ≥ 130 mmHg as published by central BP ≥ 130/90 mmHg or using antihypertensive Cheng et al. . medications. Both normal brachial and central pressures North American Artery is a professional society whose occurred in 28.4% of subjects, concordant brachial purpose is to “encourage, support, and understanding and central hypertension occurred in 67.9%, isolated of vascular structure and function and its application brachial hypertension (normal central pressures) in to clinical medicine, research, and pharmaceutical 2.3% (consistent with white coat hypertension group), and medical device development”. The organization and isolated central hypertension in 1.4% of subjects includes national and international experts in the field of (consistent with masked hypertension group). Measures hypertension. The organization sponsored a symposium of end-organ damage were significantly associated with on the clinical use of PWA in which a central aortic the concordant hypertensive group (left ventricular systolic value of 124 mmHg was recommended as a hypertrophy: adjusted odds ratios [95% confidence reasonable upper limit of normal based on data that interval] = 2.03 [1.55, 2.68], left ventricular diastolic demonstrated a corresponding brachial systolic pressure dysfunction: 2.29 [1.53, 3.43], urinary albumin-creatinine of 140 mmHg . While slightly more stringent than the ratio > 30 mg/g: 1.97 [1.58, 2.44]), compared to isolated value noted above, it is still similar to what was proposed by the other investigators. brachial hypertension or isolated central hypertension. Based on the totality of the data, a threshold for The study results demonstrated that groups can be the diagnosis of hypertension (corresponding to distinguished based on concordance and discordance of Stage 2 Hypertension in the 2017 guidelines) can be hypertension using threshold values of 140/90 mmHg considered as ≥ 130/90 mmHg; however, justification (brachial pressure) and 130/90 mmHg (central aortic is available to consider a threshold of ≥ 125 mmHg. pressure) for risk evaluation and treatment decisions Target goals are desirable for the widespread utility . While the discordant groups were a minority of the of central pressures as a complementary approach to population, the data indicate that both measurements blood pressure management. Incorporating cSBP into of central and peripheral pressures should be reviewed brachial BP treatment goals should lead to more precise given that treatment decisions often constitute a life- and reliable patient management. The previous studies commitment to pharmacotherapy. have documented what is considered optimal central In summary, threshold values that represent a decision pressures, which can be considered the target goal. point for medication prescription for hypertension can Several other reports exist that corroborate the values be determined based on published data from multiple noted [38, 40]. studies involving an overall large population. A central Kesten et al. Artery Research (2022) 28:128–139 134 pressures must be evaluated for risk evaluation and treat- systolic pressure of ≥ 130 mmHg (possibly ≥ 125 mg) ment decisions. Discordant hypertension was not asso- should be considered clinically equivalent to the brachial ciated with left ventricular hypertrophy, left ventricular systolic pressure threshold of ≥ 140 mmHg (Stage II diastolic dysfunction and renal dysfunction. While the hypertension as per the 2017 AHA guidelines) (Table 2). discordant groups were a minority of the population, Furthermore, a normal central systolic pressure of both measurements must be considered given that treat- 112 mmHg can be considered as clinically equivalent ment decisions often constitute a life-commitment to to a brachial pressure of 120 mmHg for the purpose of pharmacotherapy. establishing treatment goals. Saladini and colleagues studied a cohort of 354 young to middle-aged participants (18 to 45 years) who had 5 Central Aortic Pressure for Evaluation of White isolated systolic hypertension (ISH), had never received Coat Hypertension (WCH) treatment for hypertension and fell into the category of An elevated blood pressure in an office setting with Stage 1 hypertension . The control group consisted normal values for home assessed blood pressure values of 34 participants with normal blood pressure. The ISH (ABPM) or home blood pressure monitoring) is referred population was divided into low (ISH-low) and high to as white-coat hypertension (WCH). A meta-analysis of (ISH-high) central aortic systolic blood pressure based 7 studies with 11,502 participants indicated a prevalence on the group median (120.5 mmHg). The duration of 13% . A report of national and international of follow-up has 9.5 years. Hypertension requiring registries reported a prevalence between 10 and 50%. pharmacotherapy occurred in 54.0% of the ISH group  The incidence is increased in the elderly, men, and 14.7% of the control group. The odds ratio for elevated lipids, and obesity . Data suggests that developing sustained hypertension in the ISH-high vs. patients with WCH may be at increased risk of adverse control was 6.0 (95% CI 1.5 – 24.0, p = 0.01). For the cardiovascular consequences that may be somewhere in ISH-low vs. control group, the odds ratio was 1.1 (95% between those meeting standard hypertension criteria CI 0.2 – 5.3, p = 0.90). Importantly, the associations were [49–51]. However, the data is somewhat inconclusive. still statistically significant when a threshold central For example, a meta-analysis of over 11,000 participants systolic pressure of 125 mmHg was used and when the found that the incidence of cardiovascular events was model included ambulatory blood pressure . The not significantly different between people with WCH study reinforces the clinical relevance of including central and those with normal blood pressure . The diagnosis pressure measurement in the consideration of white coat currently requires confirmation with repeated office and hypertension in addition to hypertension in general. out-of-office BP measurements, including ambulatory Office-based measurements may provide over- blood pressure monitoring. Nevertheless, it appears estimations of blood pressure (i.e., white coat that the use of ambulatory blood pressure monitoring hypertension) in patients who are and are not receiving is exceedingly low given the documented prevalence of treatment including pharmacotherapy for hypertension. white coat hypertension.  Use of ABPM requires an additional expense (medical The study by Yu et al  was discussed in the previ - device, transmission and review of data, time to train ous section but is highly applicable with regard to the patients and transfer of the device to and from a clinic, issue of white coat hypertension. Central hypertension and the need to have a fully cooperative patient for the was defined by central BP ≥ 130/90 mmHg or using anti- 24-h measurements. The use of PWA in the office setting hypertensive medications. Measures of end-organ dam- can provide both confirmation of hypertension (elevated age were significantly associated with the concordant peripheral and central pressures) and the diagnosis of hypertensive group compared to isolated brachial hyper- white coat hypertension (elevated peripheral systolic tension or isolated central hypertension . The study pressure and normal central systolic pressure) and may results demonstrate that both brachial and central blood represent a cost-effective and practical approach to improving hypertension management. Table 2 Proposed central systolic blood pressure threshold values corresponding to the American Heart Association brachial systolic blood pressure threshold values6 Optimization of Pharmacotherapy for Hypertension Hypertension stage Central systolic BP Other than lifestyle modification, pharmacotherapy Normal < 112 mmHg is the primary treatment modality for hypertension. Stage I > 112 to < 130* mmHg Treatment with combined (i.e., fixed dose combination) Stage II > 130 *mmHg medications are often the mainstay of treatment. Nevertheless, despite the availability of multiple *125 mmHg can be considered as the threshold Kest en et al. Artery Research (2022) 28:128–139 135 Changes thereafter consist of exchanging medication medications and multiple classes of medications, classes, increased dosing of a medication or the suboptimal treatment and the consequences thereof are addition of another class of medications. However, readily recognized as ongoing societal problems in terms given medication costs and potential adverse events, of morbidity and socioeconomic costs. Specific issues such lifelong decisions should be carefully considered related to prescription hypertension medications include with assurance of the appropriateness of the lifetime undertreatment, overtreatment, compliance, drug cost, recommendation. Confirmation of hypertension adverse events, and interactions with concomitant with central blood pressure measurement should medications, all of which impact a patient’s adherence be considered for inclusion as part of care for this behavior to prescribed treatment and the burden of reason and for guidance as to the option of decreasing hypertension. Optimizing prescription medication and pharmacotherapy. the self-administration of therapy is critical to controlling A thoughtful and practical example of how to hypertension. incorporate central pressure monitoring in clinical Incorporation of PWA into the treatment paradigm for practice can be found in the BP GUIDE study . The hypertension has the following advantages: study was a prospective randomized trial evaluating 1. Confirmation of hypertension so that initiation of the use of central aortic blood pressure (n = 142) medication is more likely to be the correct decision for compared with best-practice care without central a patient. pressure measurements (n = 144) to guide hypertension • Scenario: Concurrent elevation in brachial and central management. Best-practice usual care included office, pressures home, and 24-h ambulatory blood pressure. The group 2. Avoiding initiation of medication when white coat that had the addition of central aortic blood pressure hypertension is suspected. guided management had a significant reduction in the • Scenario: Elevated brachial pressure and normal amount of medication they required. In addition, 16% central pressures, provided that an elevated heart rate of patients in the central pressure guided group had all does not confound the results. hypertension medications discontinued and maintained 3. Confirmation that increased treatment may not be brachial blood pressure control. In the best-practice care needed. only group, only 2% had all hypertension medications • Scenario: Borderline high peripheral pressures and discontinued . While the study size was relatively normal central pressures small, the data demonstrate that incorporating central 4. Targeting when to consider reduction of medication. pressure data into office practice can be clinically • Scenario: Normal peripheral and low central important to patient care. pressures, or extended period of normal peripheral and Although not the focus of this discussion, it is normal central pressures (particularly in the setting of relevant to note that incorporation of central pressure medication tolerance issues). measurements may assist in the selection of anti- Although the above scenarios are based on physiologic hypertensive medication classes. The CAFÉ Study principals, additional prospective data is needed for was a sub-study of the Anglo-Scandinavian Cardiac definitive proof of long-term clinical outcomes when Outcomes Trial . The objective was to evaluate using central pressure variables as proposed. In some cases, clinical data exists that is supportive; however, two hypertension lowering-regimens (atenolol/ prospective randomized clinical trials of sufficient thiazide, amlodipine/perindopril) on central aortic duration have not been performed examining each pressures and hemodynamics. The study included clinical situation as a primary outcome. 2,199 patients who had central aortic pressures and Previous sections in this document highlight the issues hemodynamic indexes on visits for up to 4 years. of confirmation of hypertension using both peripheral Brachial systolic pressures were similar between and central pressures for treatment decisions and when treatment groups (difference = 0.7 mmHg; 95% CI 0.4 to delay or avoid medication prescriptions when white to 1.7; p = 0.2); however, central pressures were reduced coat hypertension is suspected (e.g., emphasize scheduled in the amlodipine regimen (difference in systolic monitoring, lifestyle counselling along with delaying or pressure = 4.3 mmHg; 95% CI 3.3 to 5.4, p < 0.0001; avoiding medications). Regarding medications, national difference in central aortic pulse pressure = 3.0 mmHg; and international guidelines focus on initiation and 95% CI 2.1 to 3.9, p < 0.0001). A post-hoc analysis up-titration with almost no references or instruction revealed an association between central pulse pressure on lowering medications. In the absence of intolerable and a composite of total cardiovascular events/ adverse effects, hypertensive patients who start on drug procedures and development of renal impairment treatment are essentially committed to life-long therapy. (p < 0.05). The authors concluded that anti-hypertensive Kesten et al. Artery Research (2022) 28:128–139 136 medications appear to have different effects on central vs. cost-effective approach to confirmation of normotension, peripheral blood pressure and such effects may explain hypertension, and white coat hypertension and has posi- differences in the clinical outcomes observed between tive economic implications (Table 3). treatment groups (i.e., superior effects of amlodipine/ The issues related to pharmacoeconomic implications perindopril vs. atenolol/thiazide) . This effect could, would benefit from additional prospective studies where in part, explain the lower degree of regression of left the addition of information from central pressures is the ventricular hypertrophy with atenolol compared to primary intervention. losartan for similar reduction in brachial pressures in the LIFE study. 8 Additional Considerations The publications and data described above indicate that It is also acknowledged that the proposals in this review the adjunctive measurement of central pressures may would benefit from additional long-term data where the provide clinically important patient care information. The primary endpoints are specific clinical outcomes that provision of both peripheral and central pressures can have meaningful impact on health-related quality of life occur during the same office visit through commercially and the economics of health delivery. There are several available devices that measure both central and brachial approaches to the collection of prospective data other pressures, appears to have clinical utility and is likely than the classical randomized clinical trial with sufficient a cost-effective approach to managing hypertension, power to test a specific hypothesis or address specific particular with regard to medication treatment decisions. questions. Real-world evidence is increasingly recognized as a viable alternative to randomized controlled trials. Given that noninvasive central pressure measurement 7 Clinical and Economic Implications equipment is currently available and used, albeit not Brachial blood pressure monitoring and management widely, real-world evidence can be generated, which can decisions based on brachial pressures have had an enor- include matched cohort designs. mous positive impact on the consequences of hyperten- From a technology assessment view, the calibration sion (predominantly cardiac, cerebral, and renal related of non-invasive central aortic pressure to brachial cuff diseases). Despite the success of using cuff brachial values has the inherent feature of discordance between pressures to guide management decisions, hyperten- invasive and noninvasive values, which is predominantly sion-related vascular disease continues to be a promi- due to the known general underestimation of cuff nent socioeconomic burden [1–3]. Furthermore, over systolic pressure compared to brachial invasive pressure. and undertreatment represent additional costs that are Nevertheless, it is the central pressure in relation to not often considered [3, 56]. Cuff brachial blood pres - the conventional brachial cuff pressure that is relevant sure may overestimate the true cardiovascular risk of in associated risk predictions as invasive pressure are hypertension in the subset of patients with white coat generally obtained only in acute or life-threatening hypertension, which is a common phenomenon [46– situations. Another consideration is that non-invasive 51]. Non-invasive central aortic pressure measurement determinations of central BP can be device dependent. represents the true pressures that are transmitted to We have focused our review on non-invasive central organs at risk. A discrepancy such as a low central aor- pressures based on the approach of using the generalized tic systolic pressure is indicative of white coat hyperten- transfer function as we consider it the most accurate sion, while the matching of elevated pressures serves as approach. There are other approaches and devices a confirmation of hypertension and reassurance that the besides the transfer function . As different devices treatment algorithm is applicable. The two non-invasive may have different precision ; users of such systems arterial blood pressure measurements (brachial and cen- should be cautious regarding direct comparability and tral aortic pressures) provided by the same device is a applicability. Table 3 Positive potential economic effects for the use of non-invasive monitoring of central pressures Reduced additional costs for confirmation of white coat hypertension Avoidance of medication costs for treatment of hypertension when white coat hypertension is present. Reduced costs due to avoidance of medication side effects Earlier aggressive treatment when there is confirmation of hypertension with associated reduction in socioeconomic costs due to subsequent reduced morbidity Guidance to attempting trials of medication reduction in treated patients who may have low or low-normal central pressures and normal brachial pressures Kest en et al. Artery Research (2022) 28:128–139 137 measurement systems, the clinical rationale and the As previously stated, this paper is not a comprehensive clinical published research, incorporation of central review, and we wish to acknowledge that there are publi- aortic pressure monitoring should be considered for the cations with data indicating central pressure associations care of patients with hypertension. with cardiovascular risk similar to but not statistically superior to peripheral pressure associations to cardiovas- cular risk [58,59]. Overall, the aim of this review and the Abbreviations pragmatic proposals is to encourage additional investiga- ABPM: Ambulatory blood pressure monitoring; ACC : American College of tions that continue building the evidence for evaluation Cardiology;; AHA: American Heart Association; AIx: Augmentation index; ASCVD: Atherosclerotic CV disease; BP: Blood pressure; cBP: Central blood of central blood pressure monitoring for hypertension. pressure; cSBP: Central aortic systolic blood pressure; CI: Confidence interval; CV: Cardiovascular; ESC: European Society of Cardiology; ESH: European Society of Hypertension; FDA: Food and Drug Administration; ISH: Isolated 9 Summary and Conclusions systolic hypertension; mmHg: Millimeters mercury; pSBP: Peripheral systolic Hypertension is common and responsible for continued blood pressure; PWA: Pulse wave analysis; WCH: White-coat hypertension. morbidity, mortality and high socioeconomic costs Acknowledgements despite the widespread availability and use of cuff brachial Not applicable. artery measurements for diagnosis and monitoring. Authors’ contributions Elevated brachial arterial pressures predict CV events SK, AQ and AA contributed to the content, writing, and review of the and mortality in addition to structural changes (e.g., left manuscript. SK, AQ and AA read and approved the final manuscript. ventricular hypertrophy, carotid intima-media thickness Funding and reduced glomerular filtration rate). Lowering The review article was supported by CardieX Limited. elevated brachial arterial pressures through lifestyle modification and pharmacotherapy reduces the risk of Availability of data and material Not applicable. cardiovascular events and improves survival. Central aortic systolic pressure is correlated to brachial systolic Declarations pressures; however, central systolic pressures cannot be reliably inferred from brachial pressures in individual Conflict of interest measurements. Elevated central aortic pressure predicts Dr. S. Kesten receives payment from CardieX Limited for consulting services including writing of the manuscript. Dr. A Qasem is an employee of CardieX cardiovascular events and mortality in addition to Limited. Dr. A. Avolio receives payment from CardieX Limited for consulting structural changes (e.g., left ventricular hypertrophy, services including writing of the manuscript. carotid intima-media thickness and reduced glomerular Ethics approval and consent to participate filtration rate). The risk of adverse CV outcomes is Not applicable. associated with elevated central pressures and these risks have been shown in multiple studies to be superior, and in Consent for publication Not applicable. others, at least as high than that associated with brachial pressures. A recent meta-analysis, which incorporated Author details 1 2 multiple baseline factors including brachial systolic SKC Life Sciences, 7476 Capstan Dr, Carlsbad, CA 92011, USA. CardieX Limited, Sydney, Australia. Macquarie Medical School, Faculty of Medicine, pressure, demonstrated that central systolic pressure is Health and Human Sciences, Macquarie University, Sydney, Australia. independently predictive of cardiovascular events and therefore provides additional risk information. Received: 29 May 2022 Accepted: 26 September 2022 Published online: 20 October 2022 Based on the published data on prediction of risk, it is clinically appropriate to consider that lowering of elevated central systolic pressures may reduce the risk of cardiovascular events and mortality. Threshold values References 1. Centers for Disease Control and Prevention. Underlying Cause of Death, for the diagnosis of elevated central arterial pressures 1999–2020. CDC WONDER Online Database. Atlanta, GA: Centers for have been defined and have been referenced to the Disease Control and Prevention. https:// wonder. cdc. gov/ ucd- icd10. html. threshold values for the diagnosis of hypertension based Accessed March 12, 2020. 2. 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Artery Research – Springer Journals
Published: Dec 1, 2022
Keywords: Blood pressure; Hypertension; Central aortic blood pressure; Management; Pulse wave analysis
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