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Resistive Cerebral Blood Flow as a Potential Marker of Subclinical Brain Damage in Essential Hypertension

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Introduction: Subclinical brain damage in essential hypertension is more prevalent than cardiovascular or renal impairment; nevertheless, screening for nervous system involvement is difficult due to the low accessibility and high costs of these techniques. Objective: To assess the frequency of silent target organ damage in a cohort of asymptomatic hypertensive patients and to evaluate the potential usefulness of carotid ultrasonographic (US) variables as predictors of subclinical brain damage. Patients and Methods: Thirty four neurologically asymptomatic subjects (mean age 59 years) with essential hypertension were included. Target organ damage was evaluated: degree of hypertensive retinopathy, heart, kidney and brain. Structural and hemodynamical carotid Doppler US parameters were also investigated. Results: The brain was the most frequently affected target organ (70.6%), followed by the heart (67.9%) and kidney (58.6%). Carotid US parameters showed no association of intima media thickness with brain MRI results; nevertheless, decreased diastolic flow velocity and increased resistive index pointed to a resistive carotid flow pattern in patients with classical brain MRI lesions and predicted subclinical lesions with a sensitivity of 70% and 74% and a specificity of 72% and 80% respectively. Conclusions: This study supports previous findings that place the brain as the most frequently affected target organ in essential hypertensive patients and sheds more light on the potential usefulness of carotid structure and hemodynamics as imaging biomarkers of subclinical brain lesions.
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World Journal of Cardiovascular Diseases, 2014, 4, 169-178
Published Online April 2014 in SciRes. http://www.scirp.org/journal/wjcd
http://dx.doi.org/10.4236/wjcd.2014.44025
How to cite this paper: González-García, S., Hernández-Díaz, Z., Quevedo-Sotolongo, L., et al. (2014) Resistive Cerebral
Blood Flow as a Potential Marker of Subclinical Brain Damage in Essential Hypertension. World Journal of Cardiovascular
Diseases, 4, 169-178. http://dx.doi.org/10.4236/wjcd.2014.44025
Resistive Cerebral Blood Flow as a
Potential Marker of Subclinical
Brain Damage in Essential
Hypertension
Sergio González-García1, Zenaida Hernández-Díaz1, Luis Quevedo-Sotolongo2,
Marisol Peña-Sánchez1, Yaima Pino-Peña1, Rebeca Fernández-Carriera1,
Caridad Menéndez-Saínz1, Alina González-Quevedo1,
Janis Eells3
1Institute of Neurology and Neurosurgery, La Habana, Cuba
2Cira García Central Clinic, La Habana, Cuba
3College of Health Sciences, University of Wisconsin-Milwaukee, Milwaukee, USA
Email: sergiogg@infomed.sld.cu
Received 3 March 2014; revised 6 April 2014; accepted 15 April 2014
Copyright © 2014 by authors and Scientific Research Publishing Inc.
This work is licensed under the Creative Commons Attribution International License (CC BY).
http://creativecommons.org/licenses/by/4.0/
Abstract
Introduction: Subclinical brain damage in essential hypertension is more prevalent than cardi-
ovascular or renal impairment; nevertheless, screening for nervous system involvement is diffi-
cult due to the low accessibility and high costs of these techniques. Objective: To assess the fre-
quency of silent target organ damage in a cohort of asymptomatic hypertensive patients and to
evaluate the potential usefulness of carotid ultrasonographic (US) variables as predictors of sub-
clinical brain damage. Patients and Methods: Thirty four neurologically asymptomatic subjects
(mean age 59 years) with essential hypertension were included. Target organ damage was eva-
luated: degree of hypertensive retinopathy, heart, kidney and brain. Structural and hemodynami-
cal carotid Doppler US parameters were also investigated. Results: The brain was the most fre-
quently affected target organ (70.6%), followed by the heart (67.9%) and kidney (58.6%). Carotid
US parameters showed no association of intima media thickness with brain MRI results; never-
theless, decreased diastolic flow velocity and increased resistive index pointed to a resistive caro-
tid flow pattern in patients with classical brain MRI lesions and predicted subclinical lesions with
a sensitivity of 70% and 74% and a specificity of 72% and 80% respectively. Conclusions: This
study supports previous findings that place the brain as the most frequently affected target organ
in essential hypertensive patients and sheds more light on the potential usefulness of carotid
structure and hemodynamics as imaging biomarkers of subclinical brain lesions.
S. González-García et al.
170
Keywords
Subclinical Brain Damage, Essential Hypertension, Carotid Doppler
1. Introduction
Hypertension (HT) is the most common health condition affecting adult individuals in populations throughout
the world. Currently a billion persons have hypertension [1]-[3]. It represents in itself a disease, as well as a risk
factor for other diseases. Chronic hypertension affects vascular systems of various organs, especially the heart,
brain, kidney and retina [2] [3]. The brain is one of the target organs which is frequently affected by high blood
pressure (HBP), and constitutes the major modifiable risk factor for ischemic and hemorrhagic stroke, as well as
small-vessel disease. It has been reported to predispose the development of white matter hyperintensities
(WMH), lacunar infarction and microbleedings which are mostly silent, and has been linked to the occurrence of
vascular dementia and other malfunctions of the central nervous system [1] [2] [4] [5]. Currently, HT guidelines
recognize the heart and kidneys as the main target organs affected by high blood pressure [3]. However, Hens-
kens et al. showed that silent cerebrovascular damage is more common in hypertensive subjects than cardiorren-
al impairment [6]. Likewise, the European Guidelines for the Management of Hypertension reported that silent
brain lesions were more frequent than subclinical cardiac and renal damage [2]. The evaluation of the conse-
quences of HT on the heart and kidneys has become a routine clinical practice for years. However, methods for
demonstrating asymptomatic neurological damage by HT are still sought, as there are no accessible and cost ef-
fective evaluation techniques to assess the damage.
The suggested underlying mechanism linking elevated blood pressure levels with WMH includes hyperten-
sion-induced structural vessel changes in microcirculation such as lipohyalinosis and fibrinoid degeneration [7].
Also high blood flow affecting macrocirculation causes arterial remodeling and atheromatosis [8]. Changes in
macrocirculation can be assessed by high-resolution B-mode ultrasonography. Limited studies have evaluated
the relation between WMHs on brain MRI and ultrasound assessments of structural macrocirculation-vessel
changes with partly conflicting findings [9]-[12]. Due to the high cost and low availability of MRI studies, the
use of carotid Doppler as a potential marker of asymptomatic cerebral damage remains a very attractive option.
The aim of this investigation was to assess the frequency of silent target organ damage in a cohort of asympto-
matic hypertensive patients and to evaluate the potential usefulness of carotid ultrasonographic variables as pre-
dictors of target organ damage.
2. Patients and Methods
Hypertensive patients were referred by physicians to the Neurology and Neurosurgery Institute from January
2012 to June 2013 for evaluation of the degree of retinopathy. Confirmation of the status of each patient was
performed by a neurologist and an ophthalmologist, considering the Seventh Report on Prevention, Detection,
Evaluation, and Treatment of HTA [13]. Systolic and diastolic blood pressure (SBP and DBP respectively) were
measured in all subjects in the right arm with an aneroid sphygmomanometer, in a sitting position and after a
resting period of 5 minutes. They underwent an ophthalmological examination to establish signs of hypertensive
retinopathy, classified according to Scheie [14]. Inclusion criteria were: men and women aged 40 to 75 years
with a history of essential hypertension, and without neurological brain disease. Exclusion criteria were: sec-
ondary causes of HT, carotid stenosis > 70%, previous cerebrovascular disease or other neurological diseases.
All hypertensive patients collected a urine sample for semiquantitative determination of microalbuminuria
(μalb), employing the Microalb-Látex (HELFA Diagnostics) method. The presence of μalb was established
when concentrations > 0.02 g/L were detected. The Cockroft-Gault formula was employed to estimate creatinine
clearance [15] and glomerular filtration rates (DGFR) were considered decreased when values < 70 mL/min
were encountered.
Brain MRI study was performed with a Siemens (MAGNETOM Concerto) 0.2 Tesla open permanent magnet
scanner. All scans were controlled and stored in the image analysis center of the Central Clinic “Cira Garcia” in
Havana. Brain MRI changeswhite matter hyperintensities (WMH), lacunar infarcts (LI) and dilated Virchow-
Robin spaces (>2 mm) were classified in increasing severity as detailed in a previous work [16]. Cerebral atro-
S. González-García et al.
171
phy (Yes or No) was also evaluated. The lesions found on MRI were also classified as classical or non-classical.
Lesions were considered classical when lacunar infarcts and/or white matter hyperintensities were present; and
non-classical when there were only dilated Virchow-Robin spaces (DVRS) and/or brain atrophy (A). All MRI
scans were evaluated by the same investigator (LQS) who was blinded to the ultrasound parameters and clinical
variables of the study population.
The echocardiographic study was performed with a conventional M-mode echocardiograph (PROSOUND
ALOKA Alpha model 10). Thickness of the interventricular septum (IVS) and the rear wall (RW) were meas-
ured. Reference values were: IVS < 11 mm and RW < 7 mm - 11 mm. Diastolic dysfunction was recorded as
Yes or No.
The presence of target organ damage (Yes or No) was evaluated as follows: Brain: Presence of classic lesions
(LI and/or WMH) on brain MRI. Heart: Presence of diastolic dysfunction and/or IVS and/or RW hypertrophy by
echocardiography. Kidney: Presence of µalb and/or decreased glomerular filtration rate.
Neurosonology Protocol. An experienced neurosonology investigator (ZHD), blinded to clinical and MRI
data, performed the ultrasound investigations within one month after MRI. Carotid ultrasound scanning was
performed using an ALOKA brand PROSOUND alpha model 10 scanner equipped with a 7.5 - 13 MHz linear
transducer, placed on each side of the patients neck, after application of gel transmitter. The scan was per-
formed in a room with the necessary hygienic conditions and dim light for adequate appreciation of details. The
patient was placed supine on a stretcher; his neck slightly extended and rotated with both arms close to the body,
in order to obtain maximum descent of the shoulders. The same scanning sequence of the carotid axis was al-
ways followed to avoid confusion and mistakes. The following indicators were measured:
Intima-Media thickness (IMT): Measurements were made bilaterally at the level of the common carotid ar-
tery (CCA), 1 cm from the bulb at the end of diastole.
Peak systolic and diastolic velocities and mean velocity of flow at the internal carotid artery (PSV, PDV and
MVF respectively).
Resistance and pulsatility indexes (RI and PI respectively).
2.1. Statistical Analyses
Frequencies of demographic and clinical variables were calculated and continuous variables were tested for
normal distribution using Kolmogorov-Smirnov test. Associations between categories of variables were meas-
ured by the χ2 test. Differences between groups for continuous variables were assayed employing the Mann-
Whitney U test or Kruskall-Wallis tests. Statistical calculations were performed with Statistica 8.0 for Windows
(StatsoftInc, 2010). Statistical significance was achieved if p < 0.05 (two-sided p values).
2.2. Ethical Procedures
The research was approved by the Ethics Committee of the Neurology and Neurosurgery Institute, and con-
ducted according to the provisions of the latest version of the Declaration of Helsinki. The purposes of the re-
search were explained to all patients who agreed to participate in the study and signed informed consent.
3. Results
3.1. Characteristics of Hypertensive Patients and Target Organ Damage by Hypertension
The mean age of the 34 patients was 59 years (40 - 70 years); 22 were female (64.7%), 22 (64.7%) were of
white ethnic origin and 12 (35.8%) were black ethnic or mixed. Means (± SD) for SBP and DBP were 141.8 ±
17.9 mmHg and 93.5 ± 11.7 mmHg respectively. The duration of hypertension (mean ± SD) was 15.4 ± 10.4
years (2 - 50 years); 33% suffered from hypertension for less than 10 years and 94.1% were subjected to some
scheme of antihypertensive medication. The classification of patients according to BP and grade of retinopathy
are shown in Table 1. An association between BP group and grade of retinopathy was observed (χ2 = 21.8; p =
0.0092).
The results of brain MRI studies are summarized in Table 2. Hyperintensities were found in 23 patients
(67.6%), whereas 11 subjects showed no hyperintense lesions. Grade I hyperintensities were observed in 8 pa-
tients, grade II in 10 and only 5 were classified as grade III. The presence of lacunar infarctions, dilated Vir-
chow-Robin spaces and atrophy were detected in 6 (17.6%), 17 (50.0%) and 16 (47.1%) patients respectively.
S. González-García et al.
172
Table 1. Classification of patients according to blood pressure and grade of
retinopathy.
Blood pressure (mmHg) n %
<120/80 4 11.8
120 - 139/80 - 89 15 44.1
140 - 159/90 - 99 7 20.6
≥160/100 8 23.5
Grade of retinopathy n %
0 2 6.1
I 14 42.4
II 14 42.4
III 3 9.1
Table 2. MRI variables in hypertensive subjects.
Brain MRI (n = 34) n % Total
White matter
hyperintensities
No 11 32.4
Grade I 8 23.5
23 (67.6%) Grade II 10 29.4
Grade III 5 14.7
Lacunar Infarctions
No 28 82.4
≤3 6 17.6 6 (17.6%)
>3 0 -
Dilated Virchow Robin
spaces
No 17 50.0
≤3 4 11.8 17 (50.0%)
>3 13 38.2
Atrophy No 16 47.1
Yes 16 47.1 16 (47.1%)
The final classification of patients according to brain MRI findings showed that only 4 patients (11.8%) were
free of lesions, 6 (17.6%) classified as non-classical and 24 patients (70.6%) had classical lesions.
Patients with no lesions and with non-classical lesions were grouped and compared to patients with classical
lesions according to duration of hypertension in years and SBP respectively (Figure 1). It can be observed that
the presence of classical lesions on MRI was associated with a longer duration of hypertension and higher values
of SBP.
Table 3 shows the effect of essential HT on the different vascular beds in patients enrolled in the study. Heart
and kidney were assessed in 28 and 29 hypertensive patients respectively, of whom 67.9% had some type of
damage to the heart and 58.6% had some type of renal damage. Classical brain lesions were the most frequent
(70.6%), thus establishing that brain was the most frequently damaged organ in the group of hypertensive pa-
tients studied.
The complete assessment of the 3 systems (heart, kidney and brain) was achieved in 27 hypertensive subjects.
Figure 2 shows the percentage of patients according to the affected target organs as a consequence of hyperten-
sion. Damage to the 3 vascular beds was found in 31% of all hypertensive subjects; the combinations brain-heart
and brain-kidney followed in frequency (23.1% each), and 11.5% of the subjects had brain damage without car-
diorrenal impairment. Of the 22 subjects with cardiorrenal damage, 91% showed some brain impairment, while
4 patients without cardiorrenal impairment already had brain lesions.
3.2. Carotid Doppler Findings and Target Organ Damage
Classical lesions (LI and/or WMH) on brain MRI were associated with a more resistive carotid flow pattern, ie
increased vascular resistance index (RI) and decreased peak diastolic velocity (PDV) (Figure 3). Pulsatility in-
S. González-García et al.
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dex, peak systolic velocity and intimal thickening were not related to brain injuries (data not shown).
Heart and kidney damage were not associated with any of the Doppler ultrasound parameters explored.
As resistance index and peak diastolic velocity were associated with the presence of classical lesions, ROC
curves were calculated (Figure 4). ROC analysis showed that a cutoff value of 0.61 in RI predicted the appear-
ance of classical lesions (WMH and/or LI) with a sensitivity of 74% and a specificity of 80%. On the other hand,
PDV values below 20.6 predicted classical lesions with a sensitivity and specificity of 70% and 72% respectively.
Table 3. Target organ damage in hypertensive subjects.
Variables of target organ damage n %
Echocardiogram (n = 28)
No alterations 9 36.0
Diastolic dysfunction (DD) 7 25.0
IVS and/or RW hypertrophy 0 0
DD + IVS and/or RW hypertrophy 12 42.9
Kidney function (n = 29)
No alterations 12 41.4
µalb 7 24.1
DGFR 5 17.2
µalb + DGFR 5 17.2
MRI (n = 34)
No alterations 4 11.8
Non classical lesions 6 17.6
Classical lesions 24 70.6
IVSInterventricular Septum; RWRear Wall; DGFRGlomerular Filtration Rates; µalb
Microal-Buminuria.
Figure 1. MRI findings according to years of hypertension and SBP values.
S. González-García et al.
174
Figure 2. The complete evaluation of the systems affected by HT.
Figure 3. RI and PDV according to the brain lesions in MRI.
4. Discussion
The present cross-sectional study in a cohort of 34 hypertensive patients (mean age 59 years) showed that the
most frequently affected target organ was the brain, as 70.6% had classical brain MRI lesions (associated with
the years of hypertension and SBP); while cardiac and renal involvement was seen in 67.9% and 58.6% respec-
tively. Damage to the three target organs was found in 31% of patients and of the 22 subjects with cardio-renal
involvement, 91% had classical brain MRI lesions. Carotid ultrasound parameters and cardiorrenal variables ex-
plored were not associated; nevertheless, decreased peak diastolic velocity and increased resistive index pre-
dicted classic brain MRI lesions with a sensitivity of 70% and 74% and a specificity of 72% and 80% respec-
tively.
S. González-García et al.
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Ultrasound variable Cut off Sensitivity Specificity Area and 95% Confidence Interval
RI 0.61 0.74 0.80 0.800 (0.619 - 0.981)
DVF 20.6 0.70 0.72 0.743 (0.538 - 0.947)
Figure 4. ROC for RI and PDV.
Other authors have reported the brain as the most frequently affected organ, when compared with the heart
and kidney [17]-[19]. While the entire vasculature is exposed to the action of HT, the particular effects on small
vessels is crucial in the severity of damage to cerebral structures [20] [21]. In the ARIC study (Atherosclerosis
Risk in Communities Study), conducted in 940 hypertensive subjects aged 55 - 72 years, the prevalence of
WMH was 85.0% [21], while in the Cardiovascular Health Study, conducted in 1452 hypertensive subjects
WMH prevalence was 87.0% [22]. Van Boxtel et al. reported WMH in 65% of hypertensive patients with a
mean age of 57.4 years [23]; while Henskens et al., observed that 44% of hypertensive patients, with a lower
mean age (51.6 years) had brain injuries [6].
Interestingly, in the two cohorts studied in Cuba there was a low percentage of hypertensive patients totally
free of lesions in the brain MRI: 26% in the study of Hernández et al. [18] and 11.8% in ours. The most striking
difference was seen in the distribution of patients according to the presence of classical or non-classical lesions.
Hernández [18] detected 38% and 36% of patients with classical and non-classical lesions respectively, whereas
in the present study a predominance of classical lesions (70.6%) with respect to non classical (17.6%) was found.
This could be explained by the considerably lower average age of their cohort (44 years) regarding ours.
Considering our results and the aforementioned reports, it can be concluded that the frequency of WMH is
high among hypertensive patients, and that it may vary depending on the average age of the study group. The
frequency of WMH increases with aging and years of hypertension [24] but it must be taken into account that
the way lesions are classified can also influence the results. For example, Henskens et al. [25] classified grade I
WMH (according to Fazekas scale) as non-classical lesions.
From the moment that an individual is exposed to a risk factor to the onset of its clinical consequences there is
a period of asymptomatic structural damage. In the case of HT those tests considered early markers of injury
are actually delayed, as major structural alterations in different organs have been reported as we have previously
documented. HT Clinical Guidelines routinely recommend on identifying early damage of the heart or kidney;
nevertheless, the routine examination for asymptomatic lesions of the CNS is seldom suggested due to the high
cost it implies.
In our study two carotid ultrasound parameters of macrocirculation (PDV and RI) were associated with the
extent of structural changes in microcirculation as reflected by WMH burden in a sample of hypertensive indi-
S. González-García et al.
176
viduals without prior history of neurological impairment. Both parameters denote early changes in blood flow:
increased resistive index and decreased diastolic velocity, indicating a resistive carotid flow pattern in hyperten-
sive patients with classical brain MRI lesions.
There are very few studies correlating structural and hemodynamic carotid US parameters with the extent of
brain MRI lesions in otherwise asymptomatic hypertensive patients, and the results are controversial. The most
frequently tested variable has been IMT, which was found increased in association to brain MRI lesions [9] [18]
[26]. Nevertheless, this association was not encountered very recently by Heliopoulos et al. in a sample of 52
hypertensive patients (mean age 71.4 years), nor in the present study. The lack of association of carotid IMT has
been argued as it being a marker of large-vessel rather than small-vessel disease damage [27].
On the other hand, hemodynamic parameters were reported in two studies as not being associated with the
severity of brain lesions [26] [27]; although while in the present cohort we found that pulsatility index and dias-
tolic flow velocity measures pointed to a resistive carotid flow pattern in this group of hypertensive patients.
Nevertheless, the discrepant results across different studies could be related to sample size. Although the French
study was conducted in 198 individuals [9], the rest varied from 34 (in this study) to 52 [18] [26] [27], thus a
type II error cannot be ruled out. Other issues to consider are differences in demographic characteristics, specif-
ically considering mean age (44 - 69.3 years) and ethnic origin: Caucasians and Asians [9] [26] [27] and Afro-
Caucasians in this study and in Hernández et al. [18]. An important concern is related to the criteria employed
for patient inclusion, which also varied: all patients with subjective memory complaints [9], all patients were
hospitalized and antihypertensive medication was discontinued [26], all patients had WMH in brain MRI,
hypertensive patients included from a community study [18]. Finally, different equipment and methodology for
structural and hemodynamic measurements also have to be considered.
Our study has two main limitations: First, its cross-sectional design does not allow inferring a cause-effect re-
lationship between brain MRI findings and carotid US variables, and furthermore, the sample size was relatively
small, although strict inclusion criteria were applied to avoid including subjects with known underlying diseases
which could bias results.
In the present study the carotid US parameters pulsatility index and peak diastolic velocity exhibited relatively
good sensitivities and specificities (above 70%) for the prediction of silent brain lesions in this group of patients.
These results establish more grounds in the search of relatively simple, low cost techniques for the prediction of
subclinical brain damage in essential hypertension.
5. Conclusion
In conclusion, this study supports previous findings that place the brain as the most frequently affected target
organ in essential hypertensive patients and sheds more light on the potential usefulness of carotid structure and
hemodynamics as imaging biomarkers of subclinical brain lesions. Further observational studies with larger and
more homogenous cohorts are needed to determine specifically which extracranial carotid US parameters could
be the most adequate ones.
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List of Abbreviations
WMHwhite matter hyperintensities
DVRSDilated Virchow-Robin spaces
LILacunar infarcts
IMTIntima-Media thickness
PSVPeak systolic velocity
PDVPeak diastolic velocities
MVFmean velocity of flow
RIResistance index
PIPulsatility index
DDDiastolic dysfunction
RWRear wall
IVSInterventricular septum
... Since the brain is one of the most affected target organs in hypertension [15][16][17], early damage in the cerebral microcirculation leading to a microangiopathy-Called cerebral small vessel disease (CSVD)-is present [18,19]. These vascular lesions can be symptomatic or subclinical ("silent") and have been related to essential HT in neurologically asymptomatic individuals [16,[20][21][22][23]. In neuroimaging, these lesions can be observed as lacunar infarcts, microbleeds, white matter hyperintensities (WMH) and enlarged Virchow-Robin spaces (EVRPS) [18,19]. ...
... CSVD is five times more frequent than symptomatic CVD in the general population [24], and increase significantly with advancing age and HT [25,26]. These lesions are considered potential causes of disability [27,28], with unfavorable prognosis, and their presence predicts CVD and cognitive deterioration more frequently [20,21,23,25,[29][30][31]. In fact, the annual cost, due to disability and rehabilitation for cardiovascular disease and stroke in the United States, has been estimated at 329.7 billion dollars [26]. ...
... Brain magnetic resonance imaging (MRI) has provided evidence of subclinical brain damage in asymptomatic subjects with comorbidities. Other more inexpensive and accessible biomarkers (clinical, imaging, molecular, and neurophysiological) have been explored with this objective, but studies are still inconclusive [20,21]. For this reason, the present investigation characterized CSVD in asymptomatic hypertensive patients and explored the relationship between CSVD and some indicators of subclinical vascular damage, as these indicators might be useful for screening hypertensive individuals, which are exposed to a higher risk of CVD, cognitive deterioration, and dementia. ...
Article
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Background: Cerebral small vessel disease (CSVD) is frequent in patients with cardiovascular risk factors including arterial hypertension, and it is associated with vascular damage in other organs and the risk of stroke, cognitive impairment, and dementia. Early diagnosis of CSVD could prevent deleterious consequences. Objective: To characterize CSVD associated with indicators of subclinical vascular damage in asymptomatic hypertensive patients. Materials and Methods: Participants were hypertensive (HT) and non-hypertensive (non-HT) individuals; without signs of cerebrovascular disease, dementia, and chronic renal failure. For CSVD, white matter hyperintensities (WMH), enlarged Virchow–Robin perivascular spaces (EVRPS), lacunar infarcts, and microbleeds were investigated. Subclinical vascular damage was evaluated (hypertensive retinopathy, microalbuminuria, and extracranial carotid morphology: intima media thickness (IMT) and atheroma plaque). Results: CSVD MRI findings were more frequent in HT; as well as greater intimal thickening. The IMT + plaque was significantly associated with all MRI variables; but retinopathy was correlated with EVRPS and lacunar infarcts. Only microalbuminuria was related to the greater severity of WMH in HT. Multivariate analysis evidenced that CSVD was independently associated with the combination of indicators of vascular damage and systolic blood pressure. Conclusions: Combining indicators of subclinical vascular damage, such as carotid morphological variables, microalbuminuria, and hypertensive retinopathy for early detection of CSVD in asymptomatic hypertensive patients could prove to be useful to take actions for the prevention of irreversible brain damage, which could lead to cognitive impairment, dementia and stroke.
... Small vessel disease, such as silent lacunar infarcts, advanced deep white matter lesions and microbleeding, may lead to ischaemic and haemorrhagic stroke and vascular dementia in patients with hypertension. 33 In hypertensive patients, magnetic resonance imaging revealed the presence of silent cerebrovascular lesions in 44% of the patients, much more than cardiac (21%) and renal (26%) subclinical damage. 3 It has been suggested that microcirculation disorders and endothelial dysfunction may be a reason for impaired cognitive function in hypertensive patients. ...
... 35 Hypertension-induced lipohyalinosis and fibrinoid degeneration has also been found in white matter hyperintensities. 33 Role of nebivolol in reducing oxidative damage to brain Arterial hypertension may lead to brain damage. 35 Oxidative stress, inflammation and abnormalities in blood-brain barrier have been found to be underlying mechanisms for brain damage. ...
... 3,26 Active antihypertensive treatment significantly reduces vascular dementia in older patients with isolated systolic hypertension. 33,34 As nebivolol possesses significant antioxidant activity, its role in preventing cerebrovascular damage owing to ROS and inflammation may be postulated. In addition, nebivolol has also been shown to reduce arterial stiffness, which is a leading cause of vascular damage in the brain. ...
Article
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Hypertension is one of the leading risk factors for morbidity and mortality in patients with cardiovascular and cerebrovascular diseases and renal impairment. It also leads to target organ damage (TOD), which worsens organ function and the patient’s clinical status. Reactive oxygen species (ROS)-mediated oxidative stress may contribute significantly to TOD in patients with hypertension. NO (nitric oxide) is a paracrine factor derived from endothelial cells that has been shown to alleviate ROS-mediated oxidative damage. Nebivolol is a third-generation β-blocker with vasodilator activity, both actions contributing to decreased blood pressure in hypertensive patients. Its vasodilatory function is mediated by the endothelial l-arginine NO pathway. Nebivolol increases the bioavailability of NO in the vasculature. Its efficacy and safety profile is comparable to other commonly used antihypertensive agents. In this article, we review the current literature to understand TOD secondary to oxidative stress in patients with hypertension and the role of nebivolol in its prevention. A better understanding of the underlying mechanisms by which nebivolol reduces ROS-mediated TOD will not only help in the development of targeted therapies but may also improve health outcomes in hypertensive patients.
... [7] In one Cuban study of HT patients with a mean age of 44.2 years, classical silent brain lesions were detected in 40%; [17] while our group reported silent WML in 73.9% of an older cohort (mean age 59 years) of essential HT patients, [18] and more recently, classical silent MRI-detected brain lesions in 70.6% of essential HT patients. [19] In sum, WML frequency increases with age. ...
... Silent brain damage without cardiorenal impairment was observed in 11.5% (Figure 1). [19] Van Dijk demonstrated that systolic and diastolic blood pressure were positively associated with WML progression, in patients aged 60-90 years, new lesions occurring in up to 40% of patients. [20] This effect on brain lesion progression was stronger in younger patients and remained after adjusting for use of antihypertensive medications. ...
... Source: González-García, [19] ...
Article
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Arterial hypertension is the most prevalent non-communicable disease worldwide, and has long been recognized as a major risk factor for cardiovascular and cerebrovascular diseases. High blood pressure has deleterious consequences on the main target organs (heart, kidney, brain), and several studies have shown that brain damage is more frequent than heart and kidney involvement. Silent lesions can subsequently lead to cognitive decline, dementia or stroke. Nevertheless, screening for subclinical brain deterioration is rarely performed because it requires imaging techniques whose scarcity and high cost rule out routine use by primary care physicians. The challenge is thus early detection of asymptomatic brain lesions with cost-effective techniques to test thousands of patients in the community. In this review we present an update on the status of biomarkers explored as alternatives for early detection of brain damage in arterial hypertension, potentially useful to identify patients needing referrals for brain MRI: Ambulatory blood pressure monitoring, quantitative retinal microvascular assessment, quantitative electroencephalography, carotid ultrasonography, neurocognitive studies and blood-based biomarkers. We place special emphasis on blood-based biomarkers, for which our group reported the fi rst preliminary evidence of an association between serum neuron-specifi c enolase and severity of white matter lesions in patients with essential hypertension. This review consequently explores the potential for blood-based biomarkers to provide a faster, cheaper and more accessible early-detection solution, particularly benefi cial in resource-limited settings such as Cuba's.
... [31,32] Other less expensive and more available techniques have been explored, but to date none has been able to be put in practice for different reasons. Among these the most evaluated have been ambulatory blood pressure monitoring (ABPM) [12,21,[33][34][35], quantitative retinal microvascular assessment, [24,[36][37][38] quantitative electroencephalography, [20,39,40] carotid ultrasonography [41][42][43][44] and neurocognitive studies. [21,26,[45][46][47] ...
... [56] Our group reported no association of IMT with brain MRI findings in hypertensive patients; but, increased resistive index and decreased diastolic velocity were associated with classical brain MRI lesions, possibly indicating a resistive carotid flow pattern in these patients. [41] Likewise, Heliopoulos et al, in a sample of 52 hypertensive patients (mean age 71.4 years), did not find association between IMT and WMH. [42] Notwithstanding, when we calculated later the MRI total CSVD score in a larger sample of asymptomatic hypertensive patients (n=120), an association between increased intimal thickness and more severe CSVD score was recognized. ...
Chapter
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Cerebral small vessel disease (CSVD) refers to a syndrome of clinical and imaging findings associated with pathologies in perforating cerebral arterioles, capillaries and venules, which include mainly white matter hyperintensities (WMHs), lacunes, recent small subcortical infarcts, enlarged perivascular spaces, cerebral microbleeds and atrophy. It is closely related to aging and vascular risk factors, tripling the risk of stroke, and majorly contributing to cognitive impairment and dementia. After aging, arterial hypertension is the major risk factor for developing CSVD, which very frequently goes unrecognized for many years (silent or asymptomatic CSVD). Brain MRI is the gold standard for diagnosis of CSVD, but it is very costly and has restricted availability at the primary care level; thus, less expensive and more available methods are necessary to screen the population at higher risks. In the present chapter we describe asymptomatic CSVD, its estimated prevalence, and main clinical and neuroimaging findings. We also review some of the most frequent methods that have been evaluated to identify silent CSVD in neurologically asymptomatic individuals. In this context, measuring brain specific proteins in the blood has been an option which has begun to be explored during the last decade with promising expectations. We review the results in this line of thought in the scientific literature and discuss our experience with neuron specific enolase, S100B protein and autoantibodies against the NR2 peptide of the NMDA receptor in hypertensive patients.
... It has been reported to predispose the development of white matter hyperintensities (WMH), lacunar infarction and microbleeds which mostly occur silently [4]. Subclinical cerebrovascular damage has been reported to be more frequent in hypertensive subjects than cardiorrenal impairment [4][5][6][7][8]; nevertheless, evaluation of the consequences of HT on the heart and kidneys constitutes a routine procedure in clinical practice, while screening for nervous system involvement is difficult due to the low accessibility and high costs of brain magnetic resonance imaging (MRI), which is the gold standard for detecting silent brain damage [4,9]. Other alternative biomarkers which could be used for the early detection of asymptomatic lesions of the brain in essential hypertension have been explored [8,[10][11][12][13][14][15][16], but the ideal biomarker for screening at a community level still remains unavailable. ...
... Subclinical cerebrovascular damage has been reported to be more frequent in hypertensive subjects than cardiorrenal impairment [4][5][6][7][8]; nevertheless, evaluation of the consequences of HT on the heart and kidneys constitutes a routine procedure in clinical practice, while screening for nervous system involvement is difficult due to the low accessibility and high costs of brain magnetic resonance imaging (MRI), which is the gold standard for detecting silent brain damage [4,9]. Other alternative biomarkers which could be used for the early detection of asymptomatic lesions of the brain in essential hypertension have been explored [8,[10][11][12][13][14][15][16], but the ideal biomarker for screening at a community level still remains unavailable. ...
Article
The object of this work was to explore if blood based biomarkers of brain damage could predict subclinical brain lesions and clinical outcome during follow-up in asymptomatic hypertensive patients. This was a cross-sectional study including 101 patients with essential hypertension and no clinical evidence of neurological disease and 53 healthy controls, followed by a longitudinal study of 62 hypertensive patients for an average of 33 months. Serum concentrations of two brain specific proteins (S100B and neuron specific enolase - NSE) were determined at inclusion. Fundoscopic exploration, brain MRI and echocardiographic studies were also performed. Clinical outcome at follow-up was registered: transient ischemic attack (TIA), stroke, vascular headache or migraine, cardiovascular events and death. Higher serum NSE and S100B concentrations were observed in hypertensive patients; and multiple regression analysis revealed independent associations of clinical variables and more severe white matter lesions only with NSE concentration. A panel combining two clinical variables (blood pressure > 140/90 and years of hypertension > 10) and serum NSE > 13 μg/L predicted more severe white matter lesions with 80% sensitivity and 94.4% specificity. Higher NSE levels at inclusion were associated not only with the occurrence of vascular events related with the CNS (stroke, TIA and vascular headache), but also with an earlier presentation of these events during the follow-up period. Serum NSE concentration could be a useful biomarker to predict subclinical brain damage and future vascular events related with the CNS in hypertension. Blood based biomarkers could aid in filtering hypertensive patients with a higher risk of cerebrovascular disease for brain MRI scanning.
... Five published papers regarding to the identification of subclinical brain lesions in neurologically asymptomatic subjects with vascular risk factors have been published by our group [112][113][114][115][116]. ...
Chapter
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Cerebral small vessel disease (CSVD) is one of the most prevalent pathological processes affecting the structure and function of the smallest cerebral blood vessels. Depending on the location and dispersion of the lesions, it would be responsible for a quarter of all ischemic strokes, mood disturbance, cognitive impairment, motor gait disorders and is the most important contribuitor to vascular dementia. The burden of the disease is not focalized at an initial-single lesion. Lesion spreading and further disruption in structural and functional network connectivity, leads to an important clinical variability. The evolution of CSVD lesions is highly dynamic, and is not only the result of a chronic process; in addition, acute repetitive events over years contribute to the evolution of brain lesions. These can have a similar appearance on MRI studies, can progress, regress and even disappear, causing local and distal effects on brain structure and function. Advanced MRI techniques could have the potential to explore CSVD in a global conceptualization, considering its diffuse nature and the complexity of microvascular pathologies involved. The use of stronger magnetic field MRI has also assisted in the visualization and characterization of tiny and previously underappreciated lesions associated with CSVD. Additionally, the basis of the clinical-imaging dissociation observed could be influenced by brain resilience, a process which is incompletely understood. A global vision of CSVD could give a more detailed knowledge of the disease, emphasizing not only its high prevalence, but also the dynamic evolution and progression of the initial lesions.
... Эндотелиальная дисфункция является ключевым звеном в патогенезе многих заболеваний, таких как артериальная гипертензия, инсульт, сахарный диабет, метаболический синдром, эректильная дисфункция и почечная недостаточность [7][8][9]. Дисфункция эндотелия является начальной стадией морфологических изменений при этих заболеваниях [10]. Она особенно часто наблюдается у пациентов с традиционными факторами риска, включающими ожирение, гиперхолестеринемию, сахар ный диабет и артериальную гипертензию, часто еще задолго до того, как сами заболевания начинают клинически проявляться [11]. ...
Article
В работе подводятся некоторые итоги почти 40-летней работы авторов в области липосомологии, начатые в 80-х годах прошлого века под руководством академика НАМН Украины Александра Викторовича Стефанова.Создание нужной концентрации лекарственных веществ в органе-мишени, не затрагивая при этом не вовлеченные в патологический процесс органы и ткани, – задача непростая. За последние несколько лет предпринято множество попыток решить эту проблему, и оказалось, что лучшимипереносчиками лекарств являются именно липосомы.Преимущества липосом перед другими носителями обусловлены такими их свойствами:– сродство с природными мембранами клеток по химическому составу;– универсальность. Липосомы способны переносить разнообразные фармакологически активныевещества, а также дополнительные источники энергии для клетки и генетический материал; - липосомы сравнительно легко биодеградируют, высвобождая доставленные вещества. В пути следования липосомы надежно укрывают свое содержимое от контакта с иммунной системой и не вызывают защитных и аллергических реакций организма;– способ взаимодействия липосом с клетками, который происходит в разных формах. При этом могут изменяться свойства клеточных мембран, например: вязкость и проницаемость; величина электрического заряда; фосфолипидное окружение ферментов и ионных каналов и, соответственно, их активность (вот почему даже так называемая пустая липосома может быть биологически активным агентом).Благодаря липосомам появляется новый способ направленного воздействия на клетку, который можно назвать «мембранной инженерией», то есть, появляется возможность модифицировать клеточную мембрану в заданном направлении.Оказалось, что липосомы могут быть не только переносчиками лекарств, но и обладают самостоятельной биологической активностью. Продемонстрирована способность так называемых пустых фосфатидилхолиновых липосом (ФХЛ) оказывать влияние на электрическую и сократительную активность сосудистых гладких мышц. При гипоксии ФХЛ восстанавливают измененную для ионов проницаемость плазматических мембран гладких мышц сосудов, а у крыс со спонтанной артериальной гипертензией улучшают эндотелий-зависимые дилататорные реакции сосудов.Кроме того, было показано, что «пустые» ФХЛ эффективно восстанавливают вызванное ацетилхолином эндотелий-зависимое расслабление изолированных колец грудной аорты, нарушенное воздействием гамма-облучения. Липосомы также восстанавливают пониженную после облучения чувствительность сосудистой ткани к ацетилхолину и оксиду азота.С целью усиления антигипоксического и антиоксидантного действия липосом в их структуру был внедрен антиоксидант кверцетин. Использование липосомальной формы кверцетина приводит к полноценному восстановлению коронарного кровотока в послеокклюзионном периоде приострой субтотальной ишемии миокарда, в значительной степени уменьшает проявления характерного для репеперфузионного периода окислительного стресса и предупреждает повышение содержания лейкотриенов С4 и Е4. Синтез простациклина при этом не уменьшается. Применение липосомальной формы кверцетина приводит к уменьшению зоны некроза миокарда в два раза.Липосомальная форма кверцетина практически полностью предотвращает или в значительной степени корригирует нарушения ритма сердечных сокращений и восстанавливает сократительную активность миокарда.Липосомальная форма кверцетина эффективно восстанавливает функцию калиевых каналов большой проводимости у облученных крыс.Перспективным может оказаться включение в состав липосом цитохрома С. Липосомальная форма цитохрома С приводит к коррекции нарушений гемостаза и предотвращает развитие синдрома ДВС при острой массивной кровопотере.Многочисленные патологические процессы, такие как гипертония, атеросклероз, нарушение кровотока в центральной нервной системе, вызваны недостаточностью эндогенного синтеза/высвобождения NO. В таких случаях дополнительное введение NO может быть очень эффективнойстратегией в лечении заболеваний, связанных с указанными патологическими процессами.Разработка современных доноров оксида азота, обладающих способностью контролируемого и дозированного высвобождения действующего вещества, представляет собой чрезвычайно сложную задачу. Создание липидной системы доставки NO, способной обеспечить естественную скорость высвобождения, и разработка ее стабильной лекарственной формы стало следующей целью наших исследований.Проведенные исследования специфического действия сконструированной липосомальной формы оксида азота (ЛФ NO) свидетельствуют о его ее чрезвычайно высокой дилататорной, антиишемической активности. Это подтверждается выраженным дозозависимым расслаблением сегментов интактной аорты крыс и продолжительной гипотензивной реакцией системного кровообращения. ЛФ NO предотвращает развитие критических нарушений насосной функции сердца и способствует сохранению его сократительной активности при субтотальной ишемии. Действие ЛФ NOпроявляется значительным также дозозависимым расслаблением полосок пещеристых тел полового члена и миометрия.Новый NO-содержащий липосомальный конструкт эффективно открывает одиночные кальцийзависимые калиевые каналы большой проводимости в сосудистых гладких мышцах и значительно увеличивает вероятность их нахождения в открытом состоянии.Таким образом, ЛФ NO обещает быть эффективной при лечении ангиопатий различного генеза (включая диабетическую), эректильной дисфункции, гиперактивного мочевого пузыря, артериальной гипертензии, геморрагического и ишемического инсульта. Учитывая возможность применения в ингаляционной форме, она может быть использована для лечения легочной гипертензии.Высказывается мнение, что потенциальные возможности липосом существенно выше пока известных нам. Мы только начали понимать, как липосомы работают с клеткой.
Chapter
Arterial hypertension is the most prevalent noncommunicable disease worldwide and has long been recognized as a major risk factor for stroke, cognitive decline, and dementia. The main goal for prevention is to identify high-risk patients, targeting the modifiable risk factors, and among these, hypertension is the most powerful one. Screening for subclinical brain deterioration is rarely performed because it requires very expensive and not widely available neuroimaging techniques. The main challenge is to detect asymptomatic brain lesions with noninvasive and cost-effective techniques that can be easily performed and interpreted for widespread screening in the community. In this chapter we present an update on the status of blood-based biomarkers explored as alternatives for early detection of brain damage in neurologically asymptomatic subjects (community studies, arterial hypertension, diabetes mellitus, and elderly individuals) and longitudinal studies to explore their value as long-term predictors of incident acute cerebrovascular events. This would undoubtedly have a very positive effect for primary stroke prevention. Numerous blood biomarkers have been investigated with very controversial results. Nevertheless, blood-based brain-specific biomarkers are beginning to stand out in this field and will probably be able to offer much more in the future for the detection of asymptomatic CSVD and in the long-term prediction of acute cerebrovascular events, due to the fact that they can more directly represent what is occurring in the brain.
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