ORIGINAL
PAPER
Cerebral Blood Flow and Cognitive Function in Patients With Metabolic Syndrome: Effect of Antihypertensive Therapy Irina Efimova, MD, PhD, DSc;1 Natalya Efimova, MD, PhD, DSc;1 Yuri Lishmanov, MD, PhD, DSc1,2 Federal State Budgetary Scientific Institution Research Institute for Cardiology, Tomsk, Russia;1 and National Research Tomsk Polytechnic University, Tomsk, Russia2
The aim of the study was to estimate regional cerebral blood flow (rCBF) and cognitive function in patients with metabolic syndrome (MetS) before and after antihypertensive combination therapy. The study included 24 patients with MetS (average age 52.41.6 years). All patients underwent brain single-photon emission computed tomography with technetium-99m hexamethylpropyleneamine oxime and comprehensive neuropsychological testing before and after 6-month antihypertensive combination
therapy. All patients with MetS showed lower rCBF values in all regions of the brain compared with the control group. Their parameters of attention, immediate visual memory, and mentation were lower by 25%, 22%, and 13% compared with the control group, respectively. Sixmonth antihypertensive combination therapy increased cerebral perfusion and improved attention, mentation, and visual memory in MetS patients. J Clin Hypertens (Greenwich). 2014:1–7. ª2014 Wiley Periodicals, Inc.
For the past 20 years, the prevalence of the metabolic syndrome (MetS) has been increasing worldwide, ranging from 10% to 50% in the general population.1,2 Arterial hypertension (AH) is one of the most important elements of MetS pathogenesis and is present in more than half of all patients with MetS. AH, dyslipidemia, and hyperglycemia are considered major risk factors for stroke.3–5 Indeed, the risk of stroke is seven times higher in patients with MetS than in the general population because of the presence of additional cerebrovascular factors other than AH.2,6,7 Patients with MetS often have no signs of hemodynamically significant stenosis of the major cerebral arteries, suggesting a more important role of microvascular damage. AH contributes to onset and progression of vascular dementia,8 seen as clinically significant deterioration of cognitive function (CF) (eg, memory, thinking, attention, and orientation) and decline in social skills negatively affecting quality of life.9 Implementation of state-of-the-art computer visualization such as magnetic resonance imaging and single-photon emission computed tomography (SPECT) provides the way for noninvasive examination of structural and functional states of the brain. Asymptomatic structural changes in the brain are present in the early stages of AH. However, there is a lack of studies presenting data on functional evaluation of cerebral circulation in hypertensive patients with MetS.10,11 Adequate treatment of high blood pressure (BP) in patients with MetS before irreversible organ damage is an important challenge of medicine. Both BP reduction
and immediate effects of therapy on the target organs including the brain should be examined to assess clinical efficacy of new therapies. However, only a small number of publications have evaluated cerebral perfusion in patients with MetS who receive antihypertensive treatment.10–12 It is known that in 35% to 70% of hypertensive patients, high BP is resistant to monotherapy even with a powerful antihypertensive drug.13 At the same time, guidelines of the European Society of Hypertension recommend administration of the combination of antihypertensive drugs in high-risk patients.14 However, the effects of treatments with different combinations of antihypertensive drugs on the cerebral blood flow and CF in hypertensive patients with MetS remain understudied. The aim of the present study was to assess regional cerebral blood flow (rCBF) and CF in patients with MetS before and after antihypertensive combination therapy.
Address for correspondence: Irina Efimova, MD, PhD, DSc, Department of Nuclear Medicine, RI Cardiology, Kievskaya, 111a, Tomsk 634012, Russia E-mail: [email protected] Manuscript received: July 2, 2014; revised: September 8, 2014; accepted: September 14, 2014 DOI: 10.1111/jch.12435
PATIENTS AND METHODS Patient population The study comprised 24 patients (10 men and 14 women aged 52.41.6 years) diagnosed with MetS according to the criteria established by the International Diabetes Federation. Mandatory criterion of inclusion in the study was the presence of AH. All patients underwent comprehensive clinical and instrumental examination including history taking, clinical observation, electrocardiography, biochemical blood tests, blood cell morphology tests, x-ray, echocardiography, ambulatory BP monitoring, neuropsychological testing, and brain perfusion SPECT. Main clinical and biochemical characteristics of the patients are shown in Table I. Exclusion criteria were symptomatic hypertension, white-coat hypertension, severe kidney and liver failure, The Journal of Clinical Hypertension
1
CBF and Cognitive Function in Patients With MetS | Efimova et al.
TABLE I. Main Clinical and Biochemical Characteristics of MetS Patients Variables
Values (MeanStandard Deviation)
Age, y
52.41.6
Men/women BMI, kg/m2
10/14 33.22.8
WC, cm
104.67.9
Smoker/nonsmoker Systolic BP, mm Hg
3/24 156.311.9
Diastolic BP, mm Hg AH I, No. (%)
99.47.9 7 (29)
AH II, No. (%) AH III, No. (%) Duration of AH, y Total cholesterol, mmol/L
15 (63) 2 (8) 11.52.5 6.31.2
Triglycerides, mmol/L LDL-C, mmol/L
2.10.3 4.10.8
HDL-C, mmol/L Fasting glucose, mmol/L
1.00.3 4.81.2
HOMA-IR
3.41.1
Abbreviations: AH, arterial hypertension; BMI, body mass index; BP, blood pressure; HDL-C, high-density lipoprotein cholesterol; HOMAIR, homeostasis model of insulin resistance; LDL-C, low-density lipoprotein cholesterol; WC, waist circumference.
chronic diseases in the acute stage, myocardial infarction, stroke, atherosclerotic carotid artery stenosis, pulmonary embolism, angina pectoris of functional class II through IV, cardiac arrhythmia and conduction disorders, chronic heart failure of New York Heart Association functional class II through IV, diabetes and other endocrine pathology, mental health problems, oncological diseases, pregnancy and lactation, hormonal therapy, alcohol abuse, and patient’s refusal to participate in the study. After a washout period of 10 to 14 days, patients were randomized using random numbers into two groups comparable in the main clinical parameters. Every patient with an even number received oral combination therapy with the angiotensin-converting enzyme (ACE) inhibitor enalapril at a starting dose of 5 mg twice a day and the calcium channel blocker nifedipine retard at a starting dose of 40 mg/d (group 1). Each patient with an odd number was administered the ACE inhibitor enalapril at the same dose and the I1imidazoline receptor agonist moxonidine at a starting dose of 0.2 mg/d (group II). Drug doses were adjusted once every 1 or 2 weeks depending on the office BP measurements and clinical status of patients. The average therapeutic doses were 20 mg/d for enalapril, 40 mg/d to 80 mg/d for nifedipine retard, and 0.2 mg/d to 0.6 mg/d for moxonidine. The control group comprised 10 healthy normotensive patients of similar age with normal body mass index and without angiographic signs of carotid atherosclerosis, coronary artery disease, AH, neurological disorders, mental illnesses, or history of general anesthesia. 2
The Journal of Clinical Hypertension
Study Protocol All patients underwent brain SPECT with technetium99m hexamethylpropyleneamine oxime (99mTcHMPAO, Ceretec; GE Healthcare, Arlington Heights, IL) and comprehensive neuropsychological testing before and after 24-week hypotensive therapy. The study was approved by the ethics committee of the author’s institution and was conducted according to international ethical standards. Written informed consent was obtained from each patient before the study. Brain SPECT Tc-HMPAO was prepared according to the manufacturer’s instructions and was used within 5 minutes after labeling. Brain perfusion SPECT examinations were conducted 10 to 12 minutes after the injection of 99m Tc-HMPAO at a dose of 740 MBq. Brain SPECT was performed using a rotating dual head gamma camera (Forte Gamma Camera; Philips, Amsterdam, The Netherlands) equipped with a high-resolution lowenergy collimator and interfaced with a dedicated computer system for scintigraphic data processing (JETStream Workspace; Philips Medical Systems, Milpitas, CA). A 20% window centered at 140 keV was used. Data were recorded in 128 projections using a 128928 matrix with an exposure time of 30 seconds per frame. Rotation of detectors occurred in the auto stepwise mode with a displacement angle of 2.8° along noncircular orbit with maximal approximation of detectors to the patient’s body surface. 99m
SPECT Data Analysis Brain SPECT images were divided into 14 symmetrical (right and left) regions of interest in every patient: the inferior and superior frontal lobes; the temporal lobes; the anterior and posterior parietal lobes; the occipital lobes; and the cerebellar hemispheres. To calculate regional cerebral blood flow (rCBF, mL/100 g/min), we used a three-component 99mTc-HMPAO kinetics model that was developed by Lassen and colleagues15 and was modified by Yonekura and colleagues.16 Neuropsychological Testing We assessed the cognitive status of the patients by using seven neuropsychological tests (Table II).17,18 The Rey Auditory Verbal Learning Test (AVLT) was used to assess verbal memory. Patients were asked to recall as many words as possible after an oral presentation of a list containing 15 words. The immediate verbal recall was measured using the Digit Span Test, which required patients to reproduce orally presented series of numbers of increasing length: first forward and then in reversed order. Recall after a delay of 30 minutes without additional presentation of the word list was used to assess delayed memory. The recall score after the fifth trial was used to assess learning. The Token Test was used to assess verbal comprehension. The number of correct responses was measured.
CBF and Cognitive Function in Patients With MetS | Efimova et al.
TABLE II. Neuropsychological Tests Used to Assess Cognitive Deficits Cognitive Test
Purpose
The Rey Auditory Verbal Learning Test (AVLT) (score)
Immediate verbal memory, delayed memory, learning, attention (trial 1)
Digit Span Forward Backward (score) Token Test (score)
Immediate verbal memory, attention Verbal comprehension
Digit Symbol Test (score) The Bourdon-Wiersma Dot Cancellation Test (DCT) (s)
Psychomotor speed, attention, immediate nonverbal memory Psychomotor speed, sustained and activity visual attention, concentration
The Trail Making Test (TMT) Part A (s) The Trail Making Test (TMT) Part B (s)
Volume and sustained attention, psychomotor speed Volume and shift attention, psychomotor speed, mental flexibility
The Complex Figure Test (CFT) (score)
Visuoconstruction (copy), immediate visual memory, delayed memory
The Digit Symbol Test was used to characterize sustained attention, immediate nonverbal memory, and visuomotor speed. In this test, patients were asked to label geometric symbols with numbers according to the key pairing symbols with the numbers. The score corresponded to the number of correctly transcribed symbols. The Bourdon-Wiersma Dot Cancellation Test (DCT) was used to assess sustained visual attention. The concentration score was derived based on both speed and accuracy of the responses. The test included a cancellation task that required patients to cross out all groups of a certain number of dots in the rows of groups with varying numbers of dots. The Trail Making Test (TMT Parts A and B) was used to assess visual searching speed, attention, and mental flexibility. Part A required patients to draw lines to connect consecutively numbered circles randomly distributed on a test sheet. Part B required patients to consecutively number the lettered circles and connect them by alternating between the numbers and letters. For both parts, the time to completion represented the measure taken. In TMT Part A, the quantity of searches for symbols longer than 30 seconds was measured.
The Complex Figure Test (CFT) was used to assess nonverbal memory. This test required patients to reproduce the points of geometric pattern in the order in which they were presented. The taken measures included the immediate and delayed recall scores. To reduce the “test-retest” effects, different versions of neuropsychological tests were used. Statistical Analysis The values are presented as meanstandard deviation. The nonparametric Mann-Whitney U test was used to compare quantitative data between the MetS and control groups. Wilcoxon rank-sum test was used to compare the parameters obtained before and after antihypertensive therapy. Differences were considered statistically significant at P
PAPER
Cerebral Blood Flow and Cognitive Function in Patients With Metabolic Syndrome: Effect of Antihypertensive Therapy Irina Efimova, MD, PhD, DSc;1 Natalya Efimova, MD, PhD, DSc;1 Yuri Lishmanov, MD, PhD, DSc1,2 Federal State Budgetary Scientific Institution Research Institute for Cardiology, Tomsk, Russia;1 and National Research Tomsk Polytechnic University, Tomsk, Russia2
The aim of the study was to estimate regional cerebral blood flow (rCBF) and cognitive function in patients with metabolic syndrome (MetS) before and after antihypertensive combination therapy. The study included 24 patients with MetS (average age 52.41.6 years). All patients underwent brain single-photon emission computed tomography with technetium-99m hexamethylpropyleneamine oxime and comprehensive neuropsychological testing before and after 6-month antihypertensive combination
therapy. All patients with MetS showed lower rCBF values in all regions of the brain compared with the control group. Their parameters of attention, immediate visual memory, and mentation were lower by 25%, 22%, and 13% compared with the control group, respectively. Sixmonth antihypertensive combination therapy increased cerebral perfusion and improved attention, mentation, and visual memory in MetS patients. J Clin Hypertens (Greenwich). 2014:1–7. ª2014 Wiley Periodicals, Inc.
For the past 20 years, the prevalence of the metabolic syndrome (MetS) has been increasing worldwide, ranging from 10% to 50% in the general population.1,2 Arterial hypertension (AH) is one of the most important elements of MetS pathogenesis and is present in more than half of all patients with MetS. AH, dyslipidemia, and hyperglycemia are considered major risk factors for stroke.3–5 Indeed, the risk of stroke is seven times higher in patients with MetS than in the general population because of the presence of additional cerebrovascular factors other than AH.2,6,7 Patients with MetS often have no signs of hemodynamically significant stenosis of the major cerebral arteries, suggesting a more important role of microvascular damage. AH contributes to onset and progression of vascular dementia,8 seen as clinically significant deterioration of cognitive function (CF) (eg, memory, thinking, attention, and orientation) and decline in social skills negatively affecting quality of life.9 Implementation of state-of-the-art computer visualization such as magnetic resonance imaging and single-photon emission computed tomography (SPECT) provides the way for noninvasive examination of structural and functional states of the brain. Asymptomatic structural changes in the brain are present in the early stages of AH. However, there is a lack of studies presenting data on functional evaluation of cerebral circulation in hypertensive patients with MetS.10,11 Adequate treatment of high blood pressure (BP) in patients with MetS before irreversible organ damage is an important challenge of medicine. Both BP reduction
and immediate effects of therapy on the target organs including the brain should be examined to assess clinical efficacy of new therapies. However, only a small number of publications have evaluated cerebral perfusion in patients with MetS who receive antihypertensive treatment.10–12 It is known that in 35% to 70% of hypertensive patients, high BP is resistant to monotherapy even with a powerful antihypertensive drug.13 At the same time, guidelines of the European Society of Hypertension recommend administration of the combination of antihypertensive drugs in high-risk patients.14 However, the effects of treatments with different combinations of antihypertensive drugs on the cerebral blood flow and CF in hypertensive patients with MetS remain understudied. The aim of the present study was to assess regional cerebral blood flow (rCBF) and CF in patients with MetS before and after antihypertensive combination therapy.
Address for correspondence: Irina Efimova, MD, PhD, DSc, Department of Nuclear Medicine, RI Cardiology, Kievskaya, 111a, Tomsk 634012, Russia E-mail: [email protected] Manuscript received: July 2, 2014; revised: September 8, 2014; accepted: September 14, 2014 DOI: 10.1111/jch.12435
PATIENTS AND METHODS Patient population The study comprised 24 patients (10 men and 14 women aged 52.41.6 years) diagnosed with MetS according to the criteria established by the International Diabetes Federation. Mandatory criterion of inclusion in the study was the presence of AH. All patients underwent comprehensive clinical and instrumental examination including history taking, clinical observation, electrocardiography, biochemical blood tests, blood cell morphology tests, x-ray, echocardiography, ambulatory BP monitoring, neuropsychological testing, and brain perfusion SPECT. Main clinical and biochemical characteristics of the patients are shown in Table I. Exclusion criteria were symptomatic hypertension, white-coat hypertension, severe kidney and liver failure, The Journal of Clinical Hypertension
1
CBF and Cognitive Function in Patients With MetS | Efimova et al.
TABLE I. Main Clinical and Biochemical Characteristics of MetS Patients Variables
Values (MeanStandard Deviation)
Age, y
52.41.6
Men/women BMI, kg/m2
10/14 33.22.8
WC, cm
104.67.9
Smoker/nonsmoker Systolic BP, mm Hg
3/24 156.311.9
Diastolic BP, mm Hg AH I, No. (%)
99.47.9 7 (29)
AH II, No. (%) AH III, No. (%) Duration of AH, y Total cholesterol, mmol/L
15 (63) 2 (8) 11.52.5 6.31.2
Triglycerides, mmol/L LDL-C, mmol/L
2.10.3 4.10.8
HDL-C, mmol/L Fasting glucose, mmol/L
1.00.3 4.81.2
HOMA-IR
3.41.1
Abbreviations: AH, arterial hypertension; BMI, body mass index; BP, blood pressure; HDL-C, high-density lipoprotein cholesterol; HOMAIR, homeostasis model of insulin resistance; LDL-C, low-density lipoprotein cholesterol; WC, waist circumference.
chronic diseases in the acute stage, myocardial infarction, stroke, atherosclerotic carotid artery stenosis, pulmonary embolism, angina pectoris of functional class II through IV, cardiac arrhythmia and conduction disorders, chronic heart failure of New York Heart Association functional class II through IV, diabetes and other endocrine pathology, mental health problems, oncological diseases, pregnancy and lactation, hormonal therapy, alcohol abuse, and patient’s refusal to participate in the study. After a washout period of 10 to 14 days, patients were randomized using random numbers into two groups comparable in the main clinical parameters. Every patient with an even number received oral combination therapy with the angiotensin-converting enzyme (ACE) inhibitor enalapril at a starting dose of 5 mg twice a day and the calcium channel blocker nifedipine retard at a starting dose of 40 mg/d (group 1). Each patient with an odd number was administered the ACE inhibitor enalapril at the same dose and the I1imidazoline receptor agonist moxonidine at a starting dose of 0.2 mg/d (group II). Drug doses were adjusted once every 1 or 2 weeks depending on the office BP measurements and clinical status of patients. The average therapeutic doses were 20 mg/d for enalapril, 40 mg/d to 80 mg/d for nifedipine retard, and 0.2 mg/d to 0.6 mg/d for moxonidine. The control group comprised 10 healthy normotensive patients of similar age with normal body mass index and without angiographic signs of carotid atherosclerosis, coronary artery disease, AH, neurological disorders, mental illnesses, or history of general anesthesia. 2
The Journal of Clinical Hypertension
Study Protocol All patients underwent brain SPECT with technetium99m hexamethylpropyleneamine oxime (99mTcHMPAO, Ceretec; GE Healthcare, Arlington Heights, IL) and comprehensive neuropsychological testing before and after 24-week hypotensive therapy. The study was approved by the ethics committee of the author’s institution and was conducted according to international ethical standards. Written informed consent was obtained from each patient before the study. Brain SPECT Tc-HMPAO was prepared according to the manufacturer’s instructions and was used within 5 minutes after labeling. Brain perfusion SPECT examinations were conducted 10 to 12 minutes after the injection of 99m Tc-HMPAO at a dose of 740 MBq. Brain SPECT was performed using a rotating dual head gamma camera (Forte Gamma Camera; Philips, Amsterdam, The Netherlands) equipped with a high-resolution lowenergy collimator and interfaced with a dedicated computer system for scintigraphic data processing (JETStream Workspace; Philips Medical Systems, Milpitas, CA). A 20% window centered at 140 keV was used. Data were recorded in 128 projections using a 128928 matrix with an exposure time of 30 seconds per frame. Rotation of detectors occurred in the auto stepwise mode with a displacement angle of 2.8° along noncircular orbit with maximal approximation of detectors to the patient’s body surface. 99m
SPECT Data Analysis Brain SPECT images were divided into 14 symmetrical (right and left) regions of interest in every patient: the inferior and superior frontal lobes; the temporal lobes; the anterior and posterior parietal lobes; the occipital lobes; and the cerebellar hemispheres. To calculate regional cerebral blood flow (rCBF, mL/100 g/min), we used a three-component 99mTc-HMPAO kinetics model that was developed by Lassen and colleagues15 and was modified by Yonekura and colleagues.16 Neuropsychological Testing We assessed the cognitive status of the patients by using seven neuropsychological tests (Table II).17,18 The Rey Auditory Verbal Learning Test (AVLT) was used to assess verbal memory. Patients were asked to recall as many words as possible after an oral presentation of a list containing 15 words. The immediate verbal recall was measured using the Digit Span Test, which required patients to reproduce orally presented series of numbers of increasing length: first forward and then in reversed order. Recall after a delay of 30 minutes without additional presentation of the word list was used to assess delayed memory. The recall score after the fifth trial was used to assess learning. The Token Test was used to assess verbal comprehension. The number of correct responses was measured.
CBF and Cognitive Function in Patients With MetS | Efimova et al.
TABLE II. Neuropsychological Tests Used to Assess Cognitive Deficits Cognitive Test
Purpose
The Rey Auditory Verbal Learning Test (AVLT) (score)
Immediate verbal memory, delayed memory, learning, attention (trial 1)
Digit Span Forward Backward (score) Token Test (score)
Immediate verbal memory, attention Verbal comprehension
Digit Symbol Test (score) The Bourdon-Wiersma Dot Cancellation Test (DCT) (s)
Psychomotor speed, attention, immediate nonverbal memory Psychomotor speed, sustained and activity visual attention, concentration
The Trail Making Test (TMT) Part A (s) The Trail Making Test (TMT) Part B (s)
Volume and sustained attention, psychomotor speed Volume and shift attention, psychomotor speed, mental flexibility
The Complex Figure Test (CFT) (score)
Visuoconstruction (copy), immediate visual memory, delayed memory
The Digit Symbol Test was used to characterize sustained attention, immediate nonverbal memory, and visuomotor speed. In this test, patients were asked to label geometric symbols with numbers according to the key pairing symbols with the numbers. The score corresponded to the number of correctly transcribed symbols. The Bourdon-Wiersma Dot Cancellation Test (DCT) was used to assess sustained visual attention. The concentration score was derived based on both speed and accuracy of the responses. The test included a cancellation task that required patients to cross out all groups of a certain number of dots in the rows of groups with varying numbers of dots. The Trail Making Test (TMT Parts A and B) was used to assess visual searching speed, attention, and mental flexibility. Part A required patients to draw lines to connect consecutively numbered circles randomly distributed on a test sheet. Part B required patients to consecutively number the lettered circles and connect them by alternating between the numbers and letters. For both parts, the time to completion represented the measure taken. In TMT Part A, the quantity of searches for symbols longer than 30 seconds was measured.
The Complex Figure Test (CFT) was used to assess nonverbal memory. This test required patients to reproduce the points of geometric pattern in the order in which they were presented. The taken measures included the immediate and delayed recall scores. To reduce the “test-retest” effects, different versions of neuropsychological tests were used. Statistical Analysis The values are presented as meanstandard deviation. The nonparametric Mann-Whitney U test was used to compare quantitative data between the MetS and control groups. Wilcoxon rank-sum test was used to compare the parameters obtained before and after antihypertensive therapy. Differences were considered statistically significant at P
