**5. Ultrasound of carotid arteries**

**4. Doppler ultrasound of renal arteries**

104 Advancements and Breakthroughs in Ultrasound Imaging

Clinical signs for a renovascular hypertension include the following:

**•** A unilateral small kidney or a difference in renal size more than 1.5cm

**•** Resistant hypertension, defined as hypertension refractory to treatment with at least three

**•** An elevation of the serum creatinine level > 30% under the treatment with an ACE inhibitor

It should be mentioned, that a difference of more than 1.5 cm in length between the two kidneys, which is usually considered as being diagnostic for renal artery stenosis is only found

The examination itself can be limited by factors such as bowel gas, obesity, cooperation of the patient and from the fact that it is a highly operator dependent examination. The atherosclerotic induced renal artery stenosis is easily detectable, because it usually involves the ostium and the proximal 1/3 of the renal artery. On the other hand fibromuscular dysplasia involves the distal 2/3 of renal artery and their segmental branches and is thus difficult to depict. With

**•** Hypertension in individuals younger than 30 years of age

antihypertensive drugs (including a diuretic agent)

in 60 – 70% of the patients with renovascular hypertension [34].

predictive value.

**•** Generalized atherosclerosis

**•** Abdominal bruit with lateralization,

or an AT1-receptor antagonist

Renovascular hypertension is the second most common cause of secondary hypertension in approximately 2% of adult patients who present with blood pressure elevation when assessed in specialized centres [31]. This is caused by one or more stenoses of the extrarenal arteries, which in the elderly population have frequently an atherosclerotic nature. Fibromuscular dysplasia accounts for up to 25% of total cases and is the most common variety in young adults. Unfortunately there is not any optimal screening test available for the time. A screening test should have a high sensitivity in order to keep the false negative results in the lowest possible level. The Doppler ultrasound of renal arteries allows an analysis of the renal perfusion. According to various studies the sensitivity and specificity of Doppler ultrasound in the diagnosis of renal artery stenosis lies approximately at 90% [32, 33]. Due to the fact that renovascular hypertension in individuals with mild and medium hypertension has a preva‐ lence below 1%, an unselective examination of all individuals with hypertension would lead to a high rate of false positive results. That would result to a high rate of unnecessary angiog‐ raphies. On the other hand in a preselected population of hypertensives with clinical impli‐ cations of increased probability of renal artery stenosis the Doppler ultrasound of the renal arteries is a very appropriate screening examination, due to the fact that the prevalence of renovascular hypertension in acute, severe and resistant hypertension is significantly higher (10-45%). In other words, the use of Doppler ultrasound as a diagnostic tool in a selected population, has a significantly higher positive predictive value with a still acceptable negative

> The carotid wall thickening is an early marker of atherosclerosis and subclinical organ damage. It precedes the evolution of arteriosclerotic plaques. Ultrasound of the carotid arteries constitutes a very good opportunity to evaluate hypertension-induced vascular end organ damage. Several cardiovascular risk factors including male sex, ageing, elevated blood pressure, diabetes, smoking and obesity are positively associated with increased carotid intima-media thickness (IMT) in observational and epidemiological studies. Above these factors, high systolic blood pressures have the greatest effect on IMT [40]. An IMT > 0.9 mm in the common carotid artery is generally seen as abnormal; however there is a continuous relationship between IMT and cardiovascular events. An intima-media thickness (IMT) > 0.9 mm or the presence of a carotid plaque predict the occurrence of stroke and myocardial infarction [2, 41]. Particularly, in a meta-analysis of data from 8 studies in general populations, including about 37,000 subjects who were followed up for a mean of 5.5 years, the risk for a myocardial infarction increases by 10-15% and the stroke risk by 13-18% for every 0.1 mm increase of the IMT [42]. For the assessment of CVD risk, the carotid artery wall, rather than the degree of luminal narrowing, is examined to identify areas of increased thickness and nonocclusive atherosclerotic plaque, which represent early stages of arterial injury and athero‐ sclerosis. Furthermore, the detection of early signs of vascular damage has to include ultrasound not only of the common carotid arteries, but of bifurcations and/or internal carotids

where atherosclerosis progresses more rapidly and plaques are more frequent [43]. Ultrasound imaging of the far wall of the carotid artery produces two echogenic lines, which correspond to the lumen-intima interface and the media-adventitia interface. The current ultrasound technology enables in the clinical practice the combined measurement of the thickness of the intimal and medial layers of the arterial wall which constitute the IMT. Carotid plaque is defined as the presence of focal wall thickening that is at least 50% greater than that of the surrounding vessel wall or as a focal region with IMT greater than 1.5 mm that protrudes into the lumen. Both near and far walls can be used for assessment of the IMT. However, IMT of the near wall is less accurate because the ultrasound beam is traveling from more to less echogenic layers at the adventitia-media and intima-lumen interfaces of the near wall [44]. Histological data suggest an underestimation of the IMT around 20% when the near wall is used [45]. A linear-array transducer operating at a frequency of at least 7 MHz [44]. Three methods most frequently used to measure the IMT by using B –Mode are the following: 1. Averaging the maximum IMT of the four far walls of the carotid bifurcations and of the distal common carotid arteries. 2. Assessing the mean maximum thickness (M max) of up to 12 different sites (right and left, near and far walls, distal common, bifurcation, and proximal internal carotid). 3. The maximum measured IMT of a single measurement is taken into account. The last method provides more reproducible results when IMT measurement is restricted to the far wall of the distal segment of the common carotid artery, providing only a 3% of relative difference between two successive measurements [46]. Analysis may be performed by manual cursor placement or by automated computerized edge detection. As we mentioned above, B-mode imaging is preferred over M-mode imaging. M-mode, in spite of a superior temporal resolution, provides measurement of one single point of thickness, rather than a segmental value as it is enabled by B-mode. However, carotid wall thickening is not uniform and a singe point measurement may not represent accurately the arterial status and is less reproducible for follow-up measurements. A novel noninvasive echo-tracking system measuring the IMT and other mechanical properties of the carotid wall has been proposed [47]. This method enables an additional evaluation of the carotid plaque stability and composition.

significantly higher prevalence of atherosclerotic lesions compared to control subjects [51]. Assessment of IMT plays an important role in the risk stratification. Interestingly, about 30% of hypertensive subjects classified as at low or moderate added risk without ultrasound for carotid artery thickening or plaque were placed in the high added risk group after detecting

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The predictive value of the carotid ultrasound and its role in risk stratification has been demonstrated in a lot of trials as aforementioned. Whether a decrease of IMT progression is associated with a reduction of cardiovascular events and an improvement in prognosis remains at the time elusive. Therapeutic double blind trials have shown that antihypertensive drugs may have a more or less marked effect on carotid IMT progression. A recent metaanalysis of 22 randomized controlled trials has evaluated the effects of an antihypertensive drug versus placebo or another antihypertensive agent of a different class on carotid intimamedia thickness. The results have shown that compared with no treatment, diuretics/± betablockers, ACE inhibitors and calcium antagonists attenuate the rate of progression of carotid intima-media thickening, in some trials even in the absence of any significant reduction of the blood pressure [52]. In patients with hypertension and hypercholesterolemia the administra‐ tion of pravastatin prevents the progression of carotid intima-media thickness [53]. In the ELSA trial the treatment-induced changes of the IMT did not predict cardiovascular events as was the case by the baseline values. However, these results are not conclusive due to the smallness

of the IMT changes and the large individual differences in baseline IMT [49].

and more strict control of risk factors to prevent stroke [58].

Beyond the identification of subclinical organ damage of the carotid arteries, ultrasound is a useful tool for identification of carotid stenoses in progressive atherosclerosis. High blood pressure is a major risk factor for stroke with a correlation between elevated BP and occurrence of stroke. This correlation holds over a wide BP range, from systolic levels as low as 115 mm/ Hg and diastolic levels as low as 70 mm/Hg [54], with systolic BP having a stronger association with higher stroke risk. Elevated BP is positively associated with both ischemic and hemor‐ rhagic stroke, with a higher association appearing in hemorrhagic stroke and secondary prevention [56]. Large vessel disease of the extracranial arteries accounts for half of the

Doppler sonography is the most common imaging study performed for the diagnosis of carotid disease. It is part of the imaging tests taking place early after a transient ischemic attack (TIA) or stroke in order to identify patients with tight symptomatic arterial stenosis who could benefit from endarterectomy or angioplasty. Carotid Doppler-studies are fast, non-invasive and easily applicable however provide limited information, require skilled operators and are investigator-dependent. Doppler ultrasound has a similar specificity and sensitivity for carotid artery stenosis with computed tomography angiography (CTA) but both are inferior to contrast-magnetic resonance angiography (MRA) [57]. For asymptomatic patients with hypertension, assessment for carotid artery stenosis is also useful as part of risk stratification and is recommended for patients with two or more risk factors for atherosclerosis. Evidence of an internal carotid artery stenosis (ICA) supports recommendation of antiplatelet therapy

of vascular damages [29].

ischemic strokes.

The normal IMT values are influenced by age and sex and IMT normal values may be defined in terms of statistical distribution within a healthy population. IMT values greater than the 75th percentile are considered high and indicate an increased cardiovascular risk. Values in the 25th to 75th percentile are considered average and indicative of unchanged CVD risk. Values less than or equal to 25th percentile are associated with a low CVD risk [44]. However, available data indicate that IMT > 0.9 mm represents a risk of myocardial infarction and/or cerebrovascular disease and in the clinical practice this cut-off value may better defined in terms of increased risk [48]. Recent data have further strengthened the relationship of carotid IMT and plaques with cardiovascular events. A new report from the European Lacidipine Study on Atherosclerosis (ELSA) trial suggests that baseline carotid IMT predicts cardiovas‐ cular events independent of blood pressure and this occurs both for the IMT value at the carotid bifurcations and for the IMT value at the level of the common carotid artery [49]. The adverse prognostic significance of carotid plaques has also been reported in patients with high normal blood pressure prospectively followed for about 13 years [50]. In the Risk Intervention Study (RIS) study patients with severe essential hypertension and high cardiovascular risk had a significantly higher prevalence of atherosclerotic lesions compared to control subjects [51]. Assessment of IMT plays an important role in the risk stratification. Interestingly, about 30% of hypertensive subjects classified as at low or moderate added risk without ultrasound for carotid artery thickening or plaque were placed in the high added risk group after detecting of vascular damages [29].

where atherosclerosis progresses more rapidly and plaques are more frequent [43]. Ultrasound imaging of the far wall of the carotid artery produces two echogenic lines, which correspond to the lumen-intima interface and the media-adventitia interface. The current ultrasound technology enables in the clinical practice the combined measurement of the thickness of the intimal and medial layers of the arterial wall which constitute the IMT. Carotid plaque is defined as the presence of focal wall thickening that is at least 50% greater than that of the surrounding vessel wall or as a focal region with IMT greater than 1.5 mm that protrudes into the lumen. Both near and far walls can be used for assessment of the IMT. However, IMT of the near wall is less accurate because the ultrasound beam is traveling from more to less echogenic layers at the adventitia-media and intima-lumen interfaces of the near wall [44]. Histological data suggest an underestimation of the IMT around 20% when the near wall is used [45]. A linear-array transducer operating at a frequency of at least 7 MHz [44]. Three methods most frequently used to measure the IMT by using B –Mode are the following: 1. Averaging the maximum IMT of the four far walls of the carotid bifurcations and of the distal common carotid arteries. 2. Assessing the mean maximum thickness (M max) of up to 12 different sites (right and left, near and far walls, distal common, bifurcation, and proximal internal carotid). 3. The maximum measured IMT of a single measurement is taken into account. The last method provides more reproducible results when IMT measurement is restricted to the far wall of the distal segment of the common carotid artery, providing only a 3% of relative difference between two successive measurements [46]. Analysis may be performed by manual cursor placement or by automated computerized edge detection. As we mentioned above, B-mode imaging is preferred over M-mode imaging. M-mode, in spite of a superior temporal resolution, provides measurement of one single point of thickness, rather than a segmental value as it is enabled by B-mode. However, carotid wall thickening is not uniform and a singe point measurement may not represent accurately the arterial status and is less reproducible for follow-up measurements. A novel noninvasive echo-tracking system measuring the IMT and other mechanical properties of the carotid wall has been proposed [47]. This method enables an additional evaluation of the carotid plaque stability and composition.

106 Advancements and Breakthroughs in Ultrasound Imaging

The normal IMT values are influenced by age and sex and IMT normal values may be defined in terms of statistical distribution within a healthy population. IMT values greater than the 75th percentile are considered high and indicate an increased cardiovascular risk. Values in the 25th to 75th percentile are considered average and indicative of unchanged CVD risk. Values less than or equal to 25th percentile are associated with a low CVD risk [44]. However, available data indicate that IMT > 0.9 mm represents a risk of myocardial infarction and/or cerebrovascular disease and in the clinical practice this cut-off value may better defined in terms of increased risk [48]. Recent data have further strengthened the relationship of carotid IMT and plaques with cardiovascular events. A new report from the European Lacidipine Study on Atherosclerosis (ELSA) trial suggests that baseline carotid IMT predicts cardiovas‐ cular events independent of blood pressure and this occurs both for the IMT value at the carotid bifurcations and for the IMT value at the level of the common carotid artery [49]. The adverse prognostic significance of carotid plaques has also been reported in patients with high normal blood pressure prospectively followed for about 13 years [50]. In the Risk Intervention Study (RIS) study patients with severe essential hypertension and high cardiovascular risk had a The predictive value of the carotid ultrasound and its role in risk stratification has been demonstrated in a lot of trials as aforementioned. Whether a decrease of IMT progression is associated with a reduction of cardiovascular events and an improvement in prognosis remains at the time elusive. Therapeutic double blind trials have shown that antihypertensive drugs may have a more or less marked effect on carotid IMT progression. A recent metaanalysis of 22 randomized controlled trials has evaluated the effects of an antihypertensive drug versus placebo or another antihypertensive agent of a different class on carotid intimamedia thickness. The results have shown that compared with no treatment, diuretics/± betablockers, ACE inhibitors and calcium antagonists attenuate the rate of progression of carotid intima-media thickening, in some trials even in the absence of any significant reduction of the blood pressure [52]. In patients with hypertension and hypercholesterolemia the administra‐ tion of pravastatin prevents the progression of carotid intima-media thickness [53]. In the ELSA trial the treatment-induced changes of the IMT did not predict cardiovascular events as was the case by the baseline values. However, these results are not conclusive due to the smallness of the IMT changes and the large individual differences in baseline IMT [49].

Beyond the identification of subclinical organ damage of the carotid arteries, ultrasound is a useful tool for identification of carotid stenoses in progressive atherosclerosis. High blood pressure is a major risk factor for stroke with a correlation between elevated BP and occurrence of stroke. This correlation holds over a wide BP range, from systolic levels as low as 115 mm/ Hg and diastolic levels as low as 70 mm/Hg [54], with systolic BP having a stronger association with higher stroke risk. Elevated BP is positively associated with both ischemic and hemor‐ rhagic stroke, with a higher association appearing in hemorrhagic stroke and secondary prevention [56]. Large vessel disease of the extracranial arteries accounts for half of the ischemic strokes.

Doppler sonography is the most common imaging study performed for the diagnosis of carotid disease. It is part of the imaging tests taking place early after a transient ischemic attack (TIA) or stroke in order to identify patients with tight symptomatic arterial stenosis who could benefit from endarterectomy or angioplasty. Carotid Doppler-studies are fast, non-invasive and easily applicable however provide limited information, require skilled operators and are investigator-dependent. Doppler ultrasound has a similar specificity and sensitivity for carotid artery stenosis with computed tomography angiography (CTA) but both are inferior to contrast-magnetic resonance angiography (MRA) [57]. For asymptomatic patients with hypertension, assessment for carotid artery stenosis is also useful as part of risk stratification and is recommended for patients with two or more risk factors for atherosclerosis. Evidence of an internal carotid artery stenosis (ICA) supports recommendation of antiplatelet therapy and more strict control of risk factors to prevent stroke [58].

The first step of a carotid ultrasound test is to identify plaques via B-mode as referred above. Addition of color Doppler enables identification of origin and course of the internal carotid artery and a differentiation between severe stenosis and occlusion. Stenotic areas are identified in the presence of the "aliasing" phenomenon occurring due to high velocities in the center of the stenotic lumen and post-stenotic flow disturbances. Flow velocities in the spectral analysis are the main parameters used for evaluating the severity of carotid stenosis. Flow velocity must be sampled through the whole area of presumed stenosis until the distal end of the plaque is seen to ensure that the site of the highest velocity has been detected. Compared to angiographic data, a wide range of flow velocities was recorded for any given degree of angiographic stenosis so that the sensitivity and specificity of the method may vary [59]. A better correlation to angiographic determined stenoses is achieved by assessing the peak systolic velocity in the internal carotid artery and the ratio of the peak systolic velocity in the internal carotid artery to that in the ipsilateral common carotid artery as proposed by the current guidelines [60]. Based on Doppler sonography, carotid stenoses are classified into two grades: Grade 1- with the rate of stenosis measuring between 50% to 69% and Grade 2 measuring 70-99%, which also represents a severe non-occlusive disease. In equivocal cases, further imaging methods may be additionally used. In Table 1 the sonographic criteria for grading of carotid artery stenosis are summarized.

damage. It can be assessed using several methods, with flow-mediated dilation (FMD) being currently the gold-standard in non-invasive evaluation of endothelial dysfunction. In this ultrasound-based method brachial artery diameter is measured before and after an increase in shear stress that is induced by reactive hyperemia. When a sphygmomanometer cuff placed on the forearm or upper-arm and is inflated at 50 mm/Hg above systolic pressure, arterial inflow is occluded causing a local ischemia and dilation of downstream arteries. Cuff deflation induces a high-flow state through the brachial artery (reactive hyperemia) to accommodate the dilated resistance vessels. The increased shear stress leads to endothelium dependent dilation of the brachial artery. FMD occurs predominantly as a result of local endothelial release of nitric oxide. Figure 1 shows the B-mode and Doppler flow images of the brachial artery of a patient with hypertension at baseline and after deflation of the cuff (hyperemia). The FMD was calculated by the equation: FMD = (diameter hyperemia – diameter baseline) \* 100 / diameter baseline. A value of 8.1% suggesting a near normal value (>8%) was found.

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By using invasive and non-invasive methods impaired endothelial function has been found in uncomplicated hypertensive patients [62, 63]. In one prospective trial a reduction of blood pressure in response to antihypertensive treatment leads to improvement of the FMD sug‐ gesting a beneficial effect of antihypertensive treatment on endothelial function [64]. Several other large trials have found relationships between endothelial dysfunction assessed by FMD and prognostic markers of cardiovascular disease and atherosclerosis [65, 66]. Although the FMD test has opened a new field in the clinical research of conduit artery endothelial biology, some practical challenges of this technique have prevented its broad use in daily clinical practice so far. The most important of these are the need for highly trained operators, the timeconsuming analysis of results and the care required to minimize environmental or physiolog‐

ical influences such as eating, caffeine ingestion and variations of temperature [67].

**Figure 1.** Ultrasound images during testing of the flow mediated dilation. A slightly increase of the brachial diameter from 5.44mm at baseline to 5.88mm under hyperemia was recorded. The Doppler flow shows an increase of the

blood flow after deflation of the cuff (hyperemia).

An ultrasound examination for detection of carotid stenoses and plaques and evaluation of the intima-media thickness should be performed in hypertensive patients with concomitant risk factors such as smoking, dyslipidemia, diabetes, obesity and family history of cardiovas‐ cular disease. The results can be useful for re-assessing CVD risk in some asymptomatic patients and consequently re-assessing therapeutic strategies. For accurate results, strict attention to quality control in image acquisition, measurement and interpretation are neces‐ sary.


**Table 1.** Grading of internal carotid artery stenosis upon Doppler velocities and B-mode
