Central blood pressure and pulse wave velocity with spot measurement and ABPM

Abstract

Very early in the history of blood pressure measurement the focus was on the determination of central aortic blood pressure. In particular later research shows that the central blood pressure is a decisive indicator in assessing the cardiovascular risk. In addition, this indicator is important for assessing with all certainty whether
there is hypertension in a patient or if an anti-hypertensive treatment is efficient. The blood pressure software custo screen which integrates the analysing algorithm Antares (Redwave Medical GmbH) now enables to
determine pulse wave velocity (PWV) by using the blood pressure recorder custo screen 310, both in a single blood pressure measurement (spot measurement) and in ambulatory blood pressure monitoring (ABPM).
Antares was clinically validated within a multi-centric study. Thus, the blood pressure analysis at custo med is complemented in medically adequate form, enabling the physician to assess the cardiovascular risk of a patient optimally and to comply with the recommendations of the current guideline of arterial hypertension. 

Thus, the central blood pressure can be exactly determined in the established and familiar brachial cuff measurement at the upper arm, in an approach that is familiar to clinicians, accepted by patients and accessible as a wide-spread method. In other words: this modern blood pressure technology can meet the
original purpose of the measurement of central aortic blood pressure, as it was intended more than 100 years ago.
The PWV has an additional prognostic significance for cardiovascular events going beyond the classical cardiovascular risk factors. Although it is not possible to directly conclude from the diagnosis of increased
arterial stiffness that there is atherosclerosis or a coronary heart disease, a PWV exceeding 10 m/s should nevertheless be considered as pathological. When choosing devices, it is important that a manufacturerindependent,
standardized validation as well as an additive valence proved in epidemiologic and prognostic studies exist – which is the case for the blood pressure recorder custo screen 310 and the software module custo screen with Antares.

Introduction

The original purpose of determining brachial blood pressure more than 100 years ago was the evaluation of central (aortic) blood pressure. In the original reports of Riva-Rocci from 1896 about the use of a cuff device for measuring blood pressure, the technology was described as measurement of pressure "[...] either in the aorta itself [...]" or "[...] at a point quite close to the aorta [...]" [1].
It is therefore logical that today the central blood pressure gains in importance in relation to the established brachial blood pressure measured at the arm [2]. Although the brachial measurement over 24h at the upper arm is still the gold standard for blood pressure measurement, it is clear in the meantime that health professionals should keep an eye on "[...] the whole pressure curve and not only on the two extreme values [...]" [3]. Today, the blood pressure curve is experiencing a renaissance thanks to modern pulse wave analysis.
A high blood pressure is an important cardiovascular risk factor. However, it is also known that in humans with a comparable brachial blood pressure, big differences may occur in the central systolic blood pressure - partly more than 30 mmHg [3]. Experience made in anti-hypertensive therapy has made clear that blood pressure
lowering drugs may affect the central blood pressure differently than the brachial BP [4].
If the central blood pressure of a patient is known, the following statements can be made:

• a validated cardiovascular risk biomarker exists [5]
• a significantly improved prediction of future cardiovascular events is possible, going beyond the validity of brachial blood pressure and other cardiovascular risk factors [6]
• there is a higher diagnostic accuracy compared to brachial blood pressure
• an improved patient management is possible, compared to the care that is exclusively oriented towards brachial blood pressure.

With the option "central blood pressure" it is possible to complement the classical blood pressure measurement by this important parameter. Based on the current ESH recommendations [7], the module
complements the software platform custo diagnostic in the field of blood pressure analysis and provides - in addition to highest measurement accuracy - a validated method without requiring additional examinations. There are no changes in the classical measurement process of ABPM because the determination of central blood pressure goes hand in hand with the determination of classical blood pressure. In the following sections, more details about the individual parameters such as pulse wave, pulse wave velocity and vascular age are discussed.

Pulse wave and augmentation

The most important task of the aorta is to distribute blood from the heart to the body. To make sure that the blood does not only flow in the ejection phase but also in the relaxation phase of the heart, a large part of the
energy produced by the heart muscle is saved in the elastic fibres of the aorta. Therefore, the aorta acts like a "second heart" passing the blood to the organs. This function of the aorta, the energy uptake in the ejection phase and energy transfer in the relaxation phase, is called Windkessel effect. As the arterial diameter decreases from the centre of the body to the peripheral part of the body, the pressure increases due to physical reasons. This is why the peripheral (brachial) systolic blood pressure is normally higher than the central blood pressure. The pressure progression in the large arteries
strongly depend on age (s. Fig. 1). In young humans an amplification (increase of blood pressure due to the different arterial diameter) in the periphery and therefore a big difference between central and brachial blood pressure can be normal. At
higher ages, the increase of blood pressure amplitude is usually due to augmentation, which means the over-increase of the systolic pressure wave caused by the reflected part still during the ejection phase of the heart, while the diastolic aortic pressure decreases.
With increasing arterial stiffness, the time until the reflected pulse wave arrives at the heart shortens and thus the systolic, aortic pressure increases. The conventional measurement at the arm artery targeting the brachial blood pressure exclusively, overestimates the central blood pressure in young humans with elastic vessels and underestimates it in elderly patients with arterial stiffness and atherosclerosis [8]. The only method for a non-invasive differentiation is the pulse wave analysis. Consequently, it is not possible to draw conclusions about the central blood pressure merely on the basis of
the peripheral, brachial blood pressure. The determination of pulse wave velocity in m/s (meter per second) is an important parameter of arterial elasticity and a predictor of cardiovascular events. The Munich-based
physiologist Otto Frank described pulse wave velocity in dogs with 7 m/s for the first time in 1904. He kept an eye on the whole pressure curve as well. [3].

Figure 1: Blood pressure and pulse wave in dependence of age [3]

Pulse wave velocity and central blood pressure

The PWV specifies at which speed the pressure wave of blood moves in the arteries after a cardiac action. Arterial stiffness can be quantified with the PWV. With increasing stiffness of the aorta, the PWV becomes
higher. The prognostic importance of PWV is widely proven. The central aortic pressure (central systolic pressure) is a more exact measure for the actual hemodynamic stress of the heart than the peripheral blood pressure. Rising arterial stiffness inevitably leads to an increase of both PWV and central blood pressure values. With stiffer vessels, the PWV is higher and there is more stress on the end organs, for the central aortic pressure affects them directly. The blood flow changes with increasing arterial stiffness, with the originally laminar, consistent vascular blood circulation changing to a pulsatile flow. This means stress for the susceptible organs
which highly depend on a laminar microcirculation. These are in particular the heart, the brain, the kidneys and the eyes. This is why hypertensive organ damages correlate better with the central than with the brachial blood pressure [9]. Beside other cardiovascular risk factors, the PWV provides additional significant information about cardiovascular events. An increase of PWV by 1 m/s is associated with an increase of the cardiovascular risk by up to 15 %. It is a direct measure for arterial stiffness and reflects clinically significant, pathophysiologic changes. It correlates better with cardiovascular events and mortality than the peripheral blood pressure [10]. The standard value for PWV depends on a person’s age. The PWV in healthy humans with normal blood pressure ranges between 4 and 9 m/s, depending on age. However, a PWV exceeding 10 m/s can be considered as pathologic [11].

Vascular age

Due to the constant loss of elastic fibres, the aorta belongs to the human organs that are subject to a very early aging process. Increasing calcification is significant for the loss of elasticity due to which the Windkessel function deteriorates as well. If the elasticity loss becomes effective, the aorta cannot extend enough in the ejection phase and as a consequence the systolic blood pressure rises. The diastolic blood pressure in contrast decreases further as blood cannot flow sufficiently anymore due to missing elasticity in the relaxation phase. This process of vascular aging is called stiffening, accompanied by high systolic and low diastolic blood
pressure values. The isolated systolic hypertension, by far the most frequent form of hypertension in higher age, is based on the pathophysiologic process of vascular aging. A stiffening aorta develops as a result of conversion processes in the aortic vessel wall. This leads to fragmentations of elastin, incorporation of collagen and calcification. The vessel becomes stiffer and the reflected pulse wave relocates more and more towards the systole. 
The most important measure for aortic elasticity or stiffness is the PWV: the stiffer the artery wall, the higher the PWV. The PWV enables to regard a patient’s stiffness of vessels and compare it to that of healthy people of the
same age. This is a way to determine by how many years the vessels diverge from the chronological age. A slightly higher vascular age corresponds to a normal aging process up to a certain degree. It will become critical if the aorta is significantly older and thus deviates considerably from the chronological age. This phenomenon of premature aging of arteries is called "Early Vascular Aging" (EVA) [11]. Thus, the examination of vascular age by means of PWV has the advantage that the vascular age of a person can be determined - independently of the chronological age.

Correlation between brachial and central blood pressure

If both the brachial and the central blood pressure are in the normotensive range, a physiological arterial elasticity can be assumed. If isolated systolic hypertension is existent in elderly people or in young people, the knowledge of the central blood pressure is indispensable to differentiate between a harmless juvenile systolic hypertension with increased vessel elasticity and a pathologic systolic hypertension with increased arterial stiffness. In the first case, it is a (harmless) amplification, in the second case it is a (pathologic) augmentation in which the systolic pressure wave results in an extensive increase of systolic blood pressure (brachial and central) due to the reflected pulse wave. This is caused by increased arterial resistance. A masked aortic hypertension is defined as hypertension form with normal blood pressure values in practice or hospital and increased values in daily routine which normally come to light with ambulatory blood pressure monitoring (ABDM) or self-measurement. Then, an increased cardiovascular risk and typical hypertensive organ damages are already existent. The reversible elasticity is of crucial importance for the functional coupling between the heart and the vascular system [3].

The validated analysing algorithm Antares

For identifying aortic stiffness, the measurement of PWV between the carotid and femoral arteries is considered as gold standard. PWV and central systolic pressure can be determined indirectly in the course of a tonometric or oscillometric blood pressure measurement. Ideally, the measurement of blood pressure and
PWV should be possible all in one. The measurement accuracy of these indirect methods must be checked and validated against an invasive catheterization. Beside the parameters of arterial stiffness, additional information as to peripheral resistance and stroke volume may be helpful as they might support therapeutic decision making [9].
The ideal solution would be to obtain the central blood pressure by means of a suitable analysing algorithm within the common brachial cuff measurement because it still complies with the gold standard. It is applied on a wide scale, is known in clinical practice and acceptable for patients [10]. Here, the central blood pressure is calculated via a transfer function and an (existing) augmentation is directly derived. The analysing algorithm Antares is a software module from Redwave Medical GmbH, with which a pulse wave analysis (PWA) can be carried out. Within the framework of this PWA, the parameters central (aortic) blood
pressure and pulse wave velocity are determined. The algorithm was validated in a multi-centric study in which the central blood pressure measured invasively via a cardiac catheter was compared with the results of the cuff-based blood pressure measurement with subsequent calculation of the central blood pressure [12]. In total, 191 patients were admitted who had to undergo a cardiac catheter examination. From these, 145 patients could be further analysed. The invasive recordings of the central blood pressure were compared with the central blood pressure values determined simultaneously and in non-invasive manner. Those lastmentioned
ones were calculated by using the Antares algorithm and a custo screen recorder. The mean difference between the invasive and non-invasive systolic central blood pressure was 0.71 mmHg, with a standard deviation of 5.95 mmHg. Thus, the requirements of the validation protocols of the ARTERY Society, ESH, BHS and AAMI are fully met. On the basis of this knowledge, the validated Antares algorithm has been integrated into the blood pressure analysing software custo screen. In combination with the blood pressure recorder custo screen 310 it is now possible to conduct a pulse wave analysis easily and everywhere.

Diagnostic importance of central blood pressure

Regarding the benefit of central blood pressure, the recommendations of the European Societies for Hypertension and Cardiology report as follows: "Not to treat young patients with systolic hypertension found in conventional measurement per arm artery and measure the pulse wave velocity as biomarker of the vascular function" [3]. Due to the pulse wave analysis it is possible to determine the physiologic parameters central blood pressure and pulse wave velocity [13]. The natural aging process of humans makes the blood pressure rise and it may reach a similar level as the peripheral blood pressure [14]. A number of studies showed that the central blood pressure in hypertension patients correlates stronger with end organ damages than the peripheral blood pressure. This means that especially young patients with low/normal central blood pressure do not need treatment despite showing increased peripheral blood pressure. Thus, over-treatment can be avoided [15]. While analysing data of the Framingham study, the correlation between blood pressure and arterial stiffness was examined over a period of 7 years in approx. 1,800 subjects. It was concluded that increased arterial stiffness correlates significantly with the occurrence of hypertensive blood pressure values. Conversely however, the increased peripheral blood pressure values alone do not prove to be very helpful for predicting a rising arterial stiffness in later stages [11].  Also, with regard to the drug therapy, the central blood pressure proves to be a diagnostically relevant indicator. The CAFE study compared how different drugs (Amlodipin vs. Atenolol) which cause a comparable, peripheral blood pressure lowering, affect the central blood pressure and subsequently mortality and morbidity. It showed that the Amlodipin treatment could reduce the central blood pressure more efficiently than Atenolol and has therefore a better cardiovascular outcome regarding morbidity and mortality [16]. The shape of the pulse wave ("shape") and the PWV, depending decisively on arterial stiffness, are relevant parameters for the assessment of central blood pressure. Pulse wave velocity and central blood pressure are predictive parameters for myocardial infarction and stroke, as they enable to view the state of the vessels indirectly. Consequently, they are superior to a mere risk identification based on the known factors such as peripheral blood pressure, age or cholesterol. An increased central blood pressure means an increase in cardiac afterload which reduces the diastolic coronary flow and thus the myocardial microcirculation. As a consequence, other organs such as kidneys and brain may be damaged as well. [9]. Due to the independent prognostic value of arterial stiffness for cardiovascular events such as ischemic heart disease, stroke and renal insufficiency, arterial stiffness is a risk marker for atherosclerotic vessel diseases of a patient [11]. The prognostic value of arterial PWV surpasses classical risk scores such as for example the Framingham risk score and can be used for risk stratification with other underlying risk factors (hyperlipidemia, diabetes etc.) as well. The PWV-based risk evaluation is superior to a risk assessment performed according to "known" risk factors, as it is done in the Framingham risk score with gender, age, blood pressure, cholesterol, diabetes and smoking status. The combination of both however, arterial stiffness and conventional risk factors, has brought a very realistic prediction as to the occurrence of cardiovascular events, and that is exactly what modern cardiovascular diagnostics requires [17]. However, it is doubtful whether for elderly patients (>80 years) the prognostic significance of the PWV will not reach its limit due to the probably high calcification and associated vessel damages. For practical, clinical considerations the correlations between arterial stiffness (PWV), blood pressure and age are highly interesting, not least because a PWV exceeding 10 m/s has been adopted as additional end organ damage in the guidelines of the European hypertension league [7].
A recently published study (Project ASINPHAR@2action) carried out in pharmacies of 11 Portuguese communities, aims at raising awareness of arterial stiffening and early vascular aging (EVA) by means of blood pressure determination. The central and peripheral blood pressure was measured oscillometrically. The proportion of study participants with increased arterial stiffening was around 20%. The model that best fitted for arterial stiffening included age, gender, central aortic blood pressure, visceral fat, HDL cholesterol, augmentation index, total arterial resistance, hypertension and diabetes. The measurements of the arterial
function in community pharmacies is to provide a basis for the operationalisation of the sub-clinical screening of target organ damages and thus serve as a strategy for improving the supervision of the cardiovascular risk and for promoting treatment adherence [18].

Implementation in custo diagnostic
Screen 310 - the recorder for determining central blood pressure

For determining the central blood pressure and pulse wave velocity, it is required to process the entire scope of all oscillations occurring in a blood pressure measurement. This required extensions for the blood pressure recorders regarding data saving and processing, which have been implemented in the new blood pressure
recorder custo screen 310. custo screen 310 differs from its predecessor custo screen 300 in various hardware extensions (memory, processor) and a special firmware. The determination of central blood pressure in custo diagnostic is only possible with a custo screen 310. However, the examination procedure does not differ from the so-far handling regarding recorder start and recorder readout. When downloading a blood pressure examination carried out with custo screen 310, the central blood pressure is determined, the PWV is calculated and the results are displayed in the software.

The software module central blood pressure
The spot measurement (single measurement)

The spot measurement is a singular blood pressure measurement which delivers the central and brachial blood pressure, the pulse wave, pulse wave velocity and the vascular age. By means of the spot measurement the cardiovascular risk can be assessed on the basis of pulse wave velocity. If the result of a spot measurement
is unclear or borderline, it can be repeated as often as required. All measurements are shown in chronological order (see also Fig. 3a).

They can be confirmed, printed or deleted. If there is a reasonable suspicion of hypertension, for example due to suspicious PWV, a 24h-recording can be arranged to clarify it. The pulse waves can be displayed individually, according to the currently selected measurement (s. Fig.3a), or for all performed measurements of a patient (s. Fig.3b). When carrying out a spot measurement, it is recommended to let the patient calm down before the measurement starts because notably psychological stress situations may lead to untypically high blood pressure values [19]. If high blood pressure values are obtained in the initial measurement, a further measurement is recommended after a short waiting period. Fig. 3a shows that after the waiting period, the patient achieves lower blood pressure values than at the beginning. The variability of pulse wave velocity and vascular age is visible as well. A further repeated measurement confirms the second measurement and shows that the
patient’s blood pressure values are in the standard range. However, an ABPM could give information about how often and how long the patient is exposed to stressful situations, to clarify for example a masked hypertension.

ABPM

Beside the brachial, systolic and diastolic blood pressure values, in ABPM with custo screen 310 the central blood pressure values are also determined for each point in time of the measurement. Furthermore, the analysis provides information about pulse wave velocity and vascular age. In addition, the corresponding pulse wave is displayed for each measurement. The respective day and night threshold values can be fixed and faded in both for the brachial and the central blood pressure.Beside the brachial, systolic and diastolic blood pressure values, in ABPM with custo screen 310 the central
blood pressure values are also determined for each point in time of the measurement. Furthermore, the analysis provides information about pulse wave velocity and vascular age. In addition, the corresponding pulse wave is displayed for each measurement. The respective day and night threshold values can be fixed and faded
in both for the brachial and the central blood pressure.

In the summary table, the average values of the determined parameters are listed for the whole measurement period and are subdivided in day and night. The line description of the individual parameters on the left border of the table at the same
time serves as a button in order to show or hide the graphic view of values - simply per mouse click on the desired parameter. On the lower right border of the table, the calculated vascular age of the patient is specified, essentially
calculated on the basis of pulse wave analyses of the single measurements (Fig. 4a).
In the initial analysis of an examination, two pulse waves are automatically marked for the printout which are representative for the day and night average. The advantage is that the user gets at least
two representative pulse waves as printouts, even without having to make a print selection. With a mouse click on the button "Print", further pulse waves can be marked for the printout or once selected markings can be de-selected again.

Conclusion

A high brachial blood pressure is an important cardiovascular risk factor. However, it is also common that patients having a comparable brachial blood pressure may differ considerably in their central systolic blood pressure values.
There is evidence that anti-hypertensive treatment can affect the central blood pressure in another way than the brachial blood pressure. The actual and desired treatment effect of a comprehensive blood pressure reduction cannot be exclusively assessed on the basis of brachial blood pressure. [16].
Knowledge about the central blood pressure provides the following benefits:

• enables improved predictability of future cardiovascular events, going beyond the brachial blood
  pressure and other cardiovascular risk factors [6].
• represents superior diagnostic precision compared to brachial blood pressure and
• enables an improved patient management instead of the usual care focusing on brachial blood
  pressure.

In sum, the above statements demonstrate that the central blood pressure represents a better cardiovascular risk biomarker than the brachial blood pressure [5]. The central blood pressure can be exactly assessed with a suitable analysing algorithm and by using the brachial cuff, in an approach that is familiar to clinicians, acceptable for patients and accessible due to its wide-spread use. In other words: this modern blood pressure technology can meet the original purpose of the measurement of central aortic blood pressure, as it was intended more than 100 years ago. Although the turning point for routine application has not been reached yet, the available studies indicate that the central blood pressure should be used in clinical practice [10]. On the basis of the analysing software "custo screen" by custo med, it is possible to complement the classical blood pressure measurement by this important parameter. Based on the current ESH recommendations, the module complements custo diagnostic in the field of blood pressure analysis and provides highest measurement accuracy, a validated procedure and all that in one device without needing additional examinations. The exclusively brachial blood pressure measurement is not sufficient anymore today to characterize exactly
enough all forms of hypertension in every age group and to create an adequate risk stratification.

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