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1.  Independent and combined influence of AGTR1 variants and aerobic exercise on oxidative stress in hypertensives 
Blood pressure  2009;18(4):204-212.
Angiotensin II (AngII), via the AngII type 1 receptor (AT1R), contributes to oxidative stress. Aerobic exercise training (AEXT) reduces the risk of cardiovascular (CV) disease, presumably by reducing the grade of oxidative stress. We investigated the independent and combined influence of the AGTR1 A1166C and −825 T/A polymorphisms on oxidative stress and plasma AngII responses to AEXT in pre- and stage 1 hypertensives. Urinary 8-iso-PGF2α significantly increased with AEXT (p=0.002); however, there were no significant changes in superoxide dismutase activity or AngII levels. There was a significant difference in the change in AngII levels with AEXT between A1166C genotype groups (p=0.04) resulting in a significant interactive effect of the A1166C polymorphism and AEXT on the change in AngII (p<0.05). Only the TT genotype group of the −825 T/A polymorphism had a significant reduction in plasma AngII (p=0.02). Risk allele analysis revealed a significant reduction in plasma AngII (p=0.04) and a significant increase in urinary 8-iso-PGF2α (p=0.01) with AEXT in individuals with two risk alleles only. Our findings suggest that variation in the AGTR1 gene is associated with differential changes in plasma AngII but not oxidative stress.
PMCID: PMC2922402  PMID: 19593696
AGTR1; angiotensin II; exercise; isoprostanes; oxidative stress
2.  Endothelial Activation Microparticles and Inflammation Status Improve with Exercise Training in African Americans 
African Americans have the highest prevalence of hypertension in the world which may emanate from their predisposition to heightened endothelial inflammation. The purpose of this study was to determine the effects of a 6-month aerobic exercise training (AEXT) intervention on the inflammatory biomarkers interleukin-10 (IL-10), interleukin-6 (IL-6), and endothelial microparticle (EMP) CD62E+ and endothelial function assessed by flow-mediated dilation (FMD) in African Americans. A secondary purpose was to evaluate whether changes in IL-10, IL-6, or CD62E+ EMPs predicted the change in FMD following the 6-month AEXT intervention. A pre-post design was employed with baseline evaluation including office blood pressure, FMD, fasting blood sampling, and graded exercise testing. Participants engaged in 6 months of AEXT. Following the AEXT intervention, all baseline tests were repeated. FMD significantly increased, CD62E+ EMPs and IL-6 significantly decreased, and IL-10 increased but not significantly following AEXT. Changes in inflammatory biomarkers did not significantly predict the change in FMD. The change in VO2 max significantly predicted the change in IL-10. Based on these results, AEXT may be a viable, nonpharmacological method to improve inflammation status and endothelial function and thereby contribute to risk reduction for cardiovascular disease in African Americans.
PMCID: PMC3652180  PMID: 23691280
3.  Characterization of an ADP-Ribosyltransferase Toxin (AexT) from Aeromonas salmonicida subsp. salmonicida 
Journal of Bacteriology  2002;184(7):1851-1858.
An ADP-ribosylating toxin named Aeromonas salmonicida exoenzyme T (AexT) in A. salmonicida subsp. salmonicida, the etiological agent of furunculosis in fish, was characterized. Gene aexT, encoding toxin AexT, was cloned and characterized by sequence analysis. AexT shows significant sequence similarity to the ExoS and ExoT exotoxins of Pseudomonas aeruginosa and to the YopE cytotoxin of different Yersinia species. The aexT gene was detected in all of the 12 A. salmonicida subsp. salmonicida strains tested but was absent from all other Aeromonas species. Recombinant AexT produced in Escherichia coli possesses enzymatic ADP-ribosyltransferase activity. Monospecific polyclonal antibodies directed against purified recombinant AexT detected the toxin produced by A. salmonicida subsp. salmonicida and cross-reacted with ExoS and ExoT of P. aeruginosa. AexT toxin could be detected in a wild type (wt) strain of A. salmonicida subsp. salmonicida freshly isolated from a fish with furunculosis; however, its expression required contact with RTG-2 rainbow trout gonad cells. Under these conditions, the AexT protein was found to be intracellular or tightly cell associated. No AexT was found when A. salmonicida subsp. salmonicida was incubated in cell culture medium in the absence of RTG-2 cells. Upon infection with wt A. salmonicida subsp. salmonicida, the fish gonad RTG-2 cells rapidly underwent significant morphological changes. These changes were demonstrated to constitute cell rounding, which accompanied induction of production of AexT and which led to cell lysis after extended incubation. An aexT mutant which was constructed from the wt strain with an insertionally inactivated aexT gene by allelic exchange had no toxic effect on RTG-2 cells and was devoid of AexT production. Hence AexT is directly involved in the toxicity of A. salmonicida subsp. salmonicida for RTG-2 fish cells.
PMCID: PMC134929  PMID: 11889090
4.  The Number of Endothelial Progenitor Cells is Decreased in Patients With Non-Dipper Hypertension 
Korean Circulation Journal  2012;42(5):329-334.
Background and Objectives
Circulating endothelial progenitor cells (EPCs) play a key role in the maintenance of endothelial homeostasis and promote vascular repair. A reduced number of EPCs and the functional activity have been associated with several cardiovascular risk factors. However, the relationship between the number of EPCs and circadian rhythm of the blood pressure (BP) remains unclear. The purpose of the present study was to evaluate the relationship between the circadian rhythm of the BP and EPCs in patients with essential hypertension.
Subjects and Methods
A total of 45 patients with essential hypertension who were newly identified by outpatient BP measurements, underwent 24-hour ambulatory BP monitoring. Among the 45 patients with essential hypertension, 20 were classified as dippers (12 men and 8 women; mean age 48±14 years) and 25 as non-dippers (14 men and 11 women; mean age 52±18 years). The EPC count was isolated from the peripheral bloodstream and quantified by flow cytometry.
The baseline clinical characteristics were similar between the dipper and non-dipper hypertensive patients. The circulating EPCs were statistically reduced in the non-dipper patients as compared to the dippers (104±60 vs. 66±47 EPCs per 106 mononuclear cells, p=0.027). The circulating EPC level correlated positively with the circadian changes in the systolic and diastolic BP (r=0.435, p=0.003, and r=0.310, p=0.038, respectively).
The present study demonstrated that the EPC count was reduced in the peripheral bloodstream in non-dipper hypertensive patients.
PMCID: PMC3369964  PMID: 22701498
Hypertension; Circadian rhythm; Stem cells
5.  Assessment of the Relation between Mean Platelet Volume, Non-Dipping Blood Pressure Pattern, and Left Ventricular Mass Index in Sustained Hypertension 
Elevated mean platelet volume may reflect presence of active large platelets, which lead to fatal or non-fatal cardiovascular events. In recent studies, lack of nocturnal blood pressure fall was presented as an independent predictor of poor prognosis in essential hypertension. The relation of raised MPV with left ventricular hypertrophy has also been reported in hypertension.
The aim of this study was to investigate the relation between MPV, non-dipping blood pressure pattern, and left ventricular mass index (LVMI) in sustained hypertension.
A total of 2500 patients, whose ambulatory blood pressure (ABP) records had been evaluated retrospectively between January 2010 and December 2012, were included. Patients were divided into 3 groups according to their ABP values: non-dipper hypertensive (n=289), dipper hypertensive (n=255), and normotensive (n=306). The MPV levels and biochemical analyses were recorded from patient files and, LVMI were automatically calculated using a regression equation.
The non-dipper and dipper hypertensive groups had significantly higher MPV levels than normotensives (8.4±1 fL, 8.3±1 fL, and 8.1±0.6 fL, respectively, p<0.001). However, there was no difference among the non-dipper and dipper groups in terms of MPV level (p=0.675). Although LVMI was significantly different between non-dipper, dipper, and normotensive groups (p=0.009), no correlation was found between MPV level and LVMI in dipper and non-dipper hypertensive patients (r=−0.080, p=0.142). There was a weak correlation between MPV level and ambulatory 24-h diastolic and systolic blood pressure (r=0.076, p=0.027, and r=0.073, p=0.033, respectively).
We demonstrated that there was no correlation between MPV level, non-dipping pattern of blood pressure, and LVMI in sustained hypertension.
PMCID: PMC4215576  PMID: 25338525
Hypertension; Left Ventricular Hypertrophy; Mean Platelet Volume
6.  Echocardiographic indices of left ventricular hypertrophy and diastolic function in hypertensive patients with preserved LVEF classified as dippers and non-dippers 
Long-lasting arterial hypertension causes left ventricular hypertrophy (LVH) and impairs left ventricular diastolic function. Our aim was to compare echocardiographic parameters between hypertensive patients defined as dippers and non-dippers during ambulatory blood pressure (BP) monitoring.
Material and methods
We analysed 61 consecutive subjects with treated hypertension undergoing 24-h BP monitoring and transthoracic echocardiographic examination and included in the study patients with preserved left ventricular ejection fraction (EF ≥ 50%). Echocardiographic and arterial pressure parameters were compared between the group classified as dippers (n = 26, 57 ±13 years, 16 males) and non-dippers (n = 35, 60 ±12 years, 24 males) according to present or absent decrease of BP during the night > 10%. Echocardiographic data were compared between both groups and control subjects without hypertension.
Dippers had lower average systolic, diastolic and mean arterial pressure during the night hours but did not differ according to the mean pressure calculated from a 24-hour period. All echocardiographic parameters were similar in dippers and non-dippers. All patients with arterial hypertension presented with larger dimension of both ventricles and left atrium, thicker left ventricular walls, higher LV mass and mass index and preserved EF and E/A ratio as compared with normotensive controls. Normal geometry, concentric remodelling and eccentric hypertrophy were similarly distributed in both groups. Concentric hypertrophy was more prevalent in non-dippers as compared to the dippers (71.4% vs. 38.5%, p < 0.043).
The concentric type of LVH is the prevalent pattern in non-dippers. Non-dipping blood pressure pattern may be responsible for the development of left ventricular concentric hypertrophy secondary to hypertension.
PMCID: PMC3648830  PMID: 23671437
echocardiography; ambulatory blood pressure monitoring
7.  Ocular pulse amplitude and retrobulbar blood flow change in dipper and non-dipper individuals 
Eye  2011;25(6):762-766.
To evaluate ocular pulse amplitude (OPA), IOP values, and hemodynamic changes in the ophthalmic artery, central retinal artery, and short posterior ciliary artery in dipper and non-dipper patients.
A total of 59 right eye measurements of healthy subjects with normotensive were included to the study. Ambulatory blood pressure (BP) monitoring measurement (ABPM), Doppler imaging, and OPA measurements were performed in the same day. The patients in which systolic BP decreased during the nocturnal time by 10% of the diurnal BP or more were called dippers. A patient whose nocturnal systolic BP fell by <10% or even rose was defined as non-dipper. Color Doppler imaging was used for blood flow velocity assessment of ophthalmic, central retinal, and posterior ciliary arteries. For each artery, peak systolic and end-diastolic velocities (PSV and EDV, respectively), resistive index (RI), and pulsalite index (PI) were automatically calculated by the machine. Mean IOP and OPA values were calculated after three consecutive measurements.
The mean OPA in non-dipper patients was significantly lower compared with that of dipper patients (P=0.011). There was no significant difference in IOP levels between groups. There was no significant difference in the PSV, EDV, RI, and PI in the ophthalmic, posterior ciliary, and central retinal arteries between the groups.
Our study demonstrated that OPA level in non-dippers is lower than dippers. This may give additional information about the effect of BP changes on OPA values.
PMCID: PMC3178133  PMID: 21423136
intraocular pressure; ocular pulse amplitude; retrobulbar blood flow; dipping-non-dipping blood pressure
8.  Effect of an L- and T-Type Calcium Channel Blocker on 24-Hour Systolic Blood Pressure and Heart Rate in Hypertensive Patients 
Korean Circulation Journal  2012;42(4):231-238.
Background and Objectives
The aim of this study was to evaluate the effects of an L- and T-type calcium channel blocker (CCB) on 24-hour systolic blood pressure (24-hour SBP) and heart rate (24-hour HR) profiles in essential hypertensive patients.
Subjects and Methods
Thirty-seven consecutive patients were enrolled in this study. The 24-hour SBP and HR were recorded before and after treatment with efonidipine (L- and T-type CCB, 40 mg), after waking. Changes in 24-hour SBP and HR and the diurnal to nocturnal SBP ratio were measured. The best-fit curves of changes in SBP and HR were depicted using a periodic function.
The mean 24-hour SBP and HR decreased significantly after treatment. The diurnal to nocturnal SBP ratio in dipper-type hypertension cases decreased from 16.7±6.1% to 8.3±9.8% (p<0.05), whereas in non-dipper hypertension cases, it increased from 2.3±2.9% to 7.7±5.1% (p<0.01). The antihypertensive effect was minimal at 5.0 hours after drug administration and it slowly recovered at a constant rate (2.1 mm Hg/h) over 12 hours in dipper cases. The median 24-hour changes in HR in the dipper and non-dipper cases were -2.3/min and -5.4/min, respectively. A continuous reduction in the change in HR was seen from 3.5 to 23 hours after drug administration.
The antihypertensive action of efonidipine was characterized by a slow recovery of the SBP decrease at a constant rate (2.1 mm Hg/h) and a non-administration time dependent reduction in 24-hour HR.
PMCID: PMC3341419  PMID: 22563335
Blood pressure; Calcium channel blockers; Heart rate; Hypertension
9.  Primary non-alcoholic fatty liver disease in hypertensive patients 
The Australasian Medical Journal  2013;6(6):325-330.
Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disease affecting 15–25% of the general population.
The aim of this study was to investigate the prevalence of NAFLD and the relationship between insulin sensitivity and NAFLD in grade III high and very high cardiovascular additional risk essential hypertensive patients according to the circadian blood pressure (BP) rhythm.
This four-year prospective study was conducted at the Department of Internal Medicine at Cluj-Napoca’s Diagnosis and Treatment Centre in Romania. The study included grade III essential hypertensive patients. Hypertensive patients were divided into four groups according to the diurnal index (DI) from ABPM monitoring: dipper (D), non-dipper (ND), reverse-dipper (RD), and extreme-dipper (ED). All hypertensive patients underwent 24 ABPM, blood tests and abdominal ultrasonography for the diagnosis of fatty liver disease.
Thirty-five hypertensive patients were included in the study, with 31.42% ND, 11.43% RD, 8.57% ED and 48.57% D. The prevalence of NAFLD was significantly higher in ND, RD and ED when compared to D. When compared to the dipper group of hypertensive patients a statistically significantly higher level of plasma insulin was observed: in non-dipper [86.3±17.9pmol/l vs. 62.2±203pmol/l, p<0.05], in reverse dipper [88.3±18.6pmol/l vs. 62.2±20.3pmol/l] and in extreme-dippers [86.7±16.88pmol/l vs. 62.2±20.3 pmol/l, p<0.05].
The altered dipping status (ND, RD, ED) of hypertension associated with a higher insulin resistance could be the pathogenetic link between the NAFLD and altered blood pressure status. Altered BP status could be a marker of NAFLD in hypertensive patients.
PMCID: PMC3702137  PMID: 23837080
Essential hypertension; primary non-alcoholic fatty liver disease; NAFLD; circadian blood pressure rhythm; insulin resistance
10.  Non-Dipper Status and Left Ventricular Hypertrophy as Predictors of Incident Chronic Kidney Disease 
Journal of Korean Medical Science  2011;26(9):1185-1190.
We have hypothesized that non-dipper status and left ventricular hypertrophy (LVH) are associated with the development of chronic kidney disease (CKD) in non-diabetic hypertensive patients. This study included 102 patients with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2. Ambulatory blood pressure monitoring and echocardiography were performed at the beginning of the study, and the serum creatinine levels were followed. During the average follow-up period of 51 months, CKD developed in 11 patients. There was a significant difference in the incidence of CKD between dippers and non-dippers (5.0% vs 19.0%, P < 0.05). Compared to patients without CKD, patients with incident CKD had a higher urine albumin/creatinine ratio (52.3 ± 58.6 mg/g vs 17.8 ± 29.3 mg/g, P < 0.01), non-dipper status (72.7% vs 37.4%, P < 0.05), the presence of LVH (27.3% vs 5.5%, P < 0.05), and a lower serum HDL-cholesterol level (41.7 ± 8.3 mg/dL vs 50.4 ± 12.4 mg/dL, P < 0.05). Based on multivariate Cox regression analysis, non-dipper status and the presence of LVH were independent predictors of incident CKD. These findings suggest that non-dipper status and LVH may be the therapeutic targets for preventing the development of CKD in non-diabetic hypertensive patients.
PMCID: PMC3172656  PMID: 21935274
Blood Pressure Monitoring, Ambulatory; Hypertrophy, Left Ventricular; Renal Insufficiency, Chronic
11.  Increased low-grade inflammation and plasminogen-activator inhibitor-1 level in non-dippers with sleep apnea syndrome 
Journal of hypertension  2008;26(6):1181-1187.
Patients with sleep apnea syndrome (SAS) have an increased risk of cardiovascular events and frequently show a non-dipper pattern (blunted nocturnal decline <10%) of systolic blood pressure (BP). We investigated neurohumoral activation and risk factors in relation to nocturnal BP dipping pattern and SAS.
We conducted sleep polysomnography and ambulatory BP monitoring, and measured high-sensitivity C-reactive protein (hsCRP), tissue-type plasminogen activator inhibitor-1 (PAI-1), and neurohumoral factors in 121 outpatients with suspected SAS, who were classified in 4 groups depending on the presence or absence of dipping/non-dipping and SAS.
Non-dippers with SAS had higher hsCRP (overall P<0.001), PAI-1 (overall P=0.004), and aldosterone levels (overall P=0.010) than any of the other 3 groups. After adjustment for significant covariates such as age, sex, body mass index, waist circumference, smoking, alcohol drinking, aspirin use, presence of DM, and insulin, non-dippers with SAS still had a higher hsCRP level than non-dippers without SAS (geometric mean: 1.47 vs. 0.37 mg/L, P=0.001). In multiple linear regression analysis controlling for confounding factors that related with SAS, hsCRP was significantly correlated with 3% oxygen desaturation index (P=0.047). PAI-1 was also highest in the non-dippers with SAS, but this was not independent of obesity. PAI-1 was correlated with insulin (r=0.32, P=0.002) and hsCRP levels (r=0.26, P=0.005).
Non-dipper status was associated with an increased hsCRP in patients who also had SAS, but not in those who did not, and hsCRP was closely affected by the desaturation level. PAI-1 is also increased in non-dippers with SAS, and is related to insulin and hsCRP.
PMCID: PMC3066449  PMID: 18475156
sleep apnea syndrome; non-dipper; high-sensitivity C-reactive protein; plasminogen activator inhibitor-1
12.  Evaluation of plasma chemerin levels in patients with non-dipper blood pressure patterns 
Chemerin is a novel adipokine that plays a role in inflammation and atherosclerosis. Although there are several correlations between hypertension and the inflammatory system, there is still insufficient information about the relationship between blood pressure variability and inflammatory markers. In this study, we aimed to determine whether chemerin levels are elevated in non-dipper patients compared with dippers and healthy controls.
This study was composed of a group of 90 patients: 60 hypertensive patients and 30 healthy control subjects (12 males, mean age 53.2±15.4 years). Ambulatory blood pressure monitoring devices (ABPM) were connected to all patients. Using data from the ABPM, hypertensive patients were divided into 2 groups: 30 dipper patients (12 males, mean age 52.5±15.1 years) and 30 non-dipper patients (11 males, mean age 54.6±13.0 years). Complete blood count and biochemistry were measured by standard methods and plasma chemerin concentrations were quantified by ELISA.
Non-dipper patients demonstrated higher chemerin levels compared to dippers and normotensives (219.7±16.3 vs. 182.4±21.4 ng/ml; 219.7±16.3 vs. 85.4±38.1 ng/ml, respectively, p<0.001 for both comparisons). A receiver operating characteristic curve analysis revealed that the optimal cut-off value for chemerin to predict a non-dipping pattern was 201.4, with 90% sensitivity and 90% specificity. There was a positive correlation between chemerin levels and all ambulatory blood pressure values in all hypertensive patients.
Chemerin, which plays a role in inflammation and atherosclerosis, was higher in non-dippers compared to dippers and normotensives. Additionally, chemerin shows positive correlations with blood pressure.
PMCID: PMC4010600  PMID: 24769499
Adipokines; Hypertension; Inflammation
13.  Plasma Brain-Derived Neurotrophic Factor and Reverse Dipping Pattern of Nocturnal Blood Pressure in Patients with Cardiovascular Risk Factors 
PLoS ONE  2014;9(8):e105977.
Basic studies have shown that brain-derived neurotrophic factor (BDNF) has critical roles in the survival, growth, maintenance, and death of central and peripheral neurons, while it is also involved in regulation of the autonomic nervous system. Furthermore, recent clinical studies have suggested potential role of plasma BDNF in the circulatory system.
We investigated the mutual relationships among plasma BDNF, patterns of nocturnal blood pressure changes (dippers, non-dippers, extra-dippers, and reverse-dippers), and cardiac autonomic function as determined by heart rate variability (HRV).
This was a cross-sectional study of patients registered in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) Study from October 2010 to November 2012.
Two-hundred fifty patients with 1 or more cardiovascular risk factor(s) (obesity, smoking, presence of cardiovascular event history, hypertension, dyslipidemia, diabetes mellitus, chronic kidney disease) were enrolled.
Plasma BDNF levels (natural logarithm transformed) were significantly (p = 0.001) lower in reverse-dipper patients (7.18±0.69 pg/ml, mean ± SD, n = 36) as compared to dippers (7.86±0.86 pg/ml, n = 100). Multiple logistic regression analysis showed that BDNF (odds ratios: 0.417, 95% confidence interval: 0.228–0.762, P = 0.004) was the sole factor significantly and independently associated with the reverse-dippers as compared with dippers. Furthermore, plasma BDNF level was significantly and positively correlated with the time-domain (SDNN, SDANN5, CVRR) and frequency-domain (LF) of HRV parameters. Finally, multiple logistic regression analyses showed that the relationship between plasma BDNF and the reverse-dippers was weakened, yet remained significant or borderline significant even after adjusting for HRV parameters.
Low plasma BDNF was independently associated with patients showing a reverse-dipper pattern of nocturnal blood pressure, in which an imbalance of cardiac autonomic function may be partly involved.
PMCID: PMC4143316  PMID: 25153796
14.  A Reverse Dipping Pattern Predicts Cardiovascular Mortality In a Clinical Cohort 
Journal of Korean Medical Science  2013;28(10):1468-1473.
An abnormal dipping pattern in ambulatory blood pressure monitoring (ABPM) is a cardiovascular (CV) risk factor. However, its impact on CV mortality has not been investigated sufficiently in clinical practice to be considered a standard parameter. We assessed the association between abnormal dipping patterns and increased CV mortality in a tertiary hospital in Korea. Our retrospective cohort study included 401 patients who underwent ABPM between 1994 and 1996 in Hanyang University Hospital, Seoul, Korea. The patients were classified as risers (<0% drop in systolic BP; n=107), and others included dippers and non-dippers (≥0% drop, n=294). The follow-up period was 120 months. The frequency of CV mortality was 14.0% in risers and 5.8% in others. A Cox regression analysis found a significant association between dipping pattern and CV mortality, after adjusting for age, gender, body mass index, hypertension, diabetes mellitus, smoking and hypercholesterolemia. Risers were at greater risk of CV death than others (RR, 3.02, P=0.022), but there was no difference in event rates between dippers and non-dippers. The reverse dipping pattern may be more frequent in clinical settings than in the population at large, and it is strongly associated with increased risk of CV mortality in Korea.
PMCID: PMC3792601  PMID: 24133351
Blood Pressure Monitoring, Ambulatory; Cardiovascular Mortality; Reverse Dipping Pattern
15.  Non-Dipper Pattern is a Determinant of the Inappropriateness of Left Ventricular Mass in Essential Hypertensive Patients 
Korean Circulation Journal  2011;41(4):191-197.
Background and Objectives
Inappropriately high left ventricular mass (iLVM) is known to be related to cardiovascular prognosis. A non-dipper pattern has a greater mean left ventricular (LV) mass than the dipper pattern in hypertensive patients. However, the appropriateness of LV mass in dipper or non-dipper patterns has not been adequately investigated. The aim of this study was to define the relationship between nocturnal dipping and the appropriateness of LV mass.
Subjects and Methods
Using the ambulatory blood pressure monitoring (ABPM) database, the data of 361 patients who underwent ABPM and echocardiography was analyzed retrospectively. Appropriateness of LV mass was calculated as observed/predicted ratio of LV mass (OPR) using a Korean-specified equation. Nocturnal dipping was expressed as percent fall in systolic blood pressure (BP) during the night compared to the day.
Daytime, nighttime and 24 hours BP in hypertensive patients was 140.4±14.8 mmHg, 143.7±15.2 mmHg and 129.4±20.0 mmHg, respectively. OPR was 106.3±19.9% and nocturnal dipping was 10.2±10.9 mmHg. In a multiple linear regression model, 24 hours systolic BP (β=0.097, p=0.043) and nocturnal dipping (β=-0.098, p=0.046) were independent determinants of OPR as well as age (β=0.130, p=0.025) and body mass index (BMI) (β=0.363, p<0.001). Odds ratio of the non-dipper pattern was 2.134 for iLVM (p=0.021) and 3.694 for obesity (p<0.001; BMI >25 kg/m2).
The non-dipper pattern is independently associated with iLVM in hypertensive patients as well as obesity.
PMCID: PMC3098411  PMID: 21607169
Hypertension; Hypertrophy, left ventricular; Blood pressure monitoring, ambulatory
16.  Is there a link between hyperuricemia, morning blood pressure surge, and non-dipping blood pressure pattern in metabolic syndrome patients? 
Hypertensive patients usually have a blunted nocturnal decrease, or even increase, in blood pressure during sleep. There is also a tendency for increased occurrence of cardiovascular events between 6 and 12 am due to increased morning blood pressure surge (MBPS). Co-occurrence of metabolic syndrome (MetS) and hypertension is also a common problem. Hyperuricemia might trigger the development of hypertension, chronic renal failure, and insulin resistance. In this study, we aimed to determine whether there is a relationship between hyperuricemia, MetS, nocturnal blood pressure changes, and MBPS.
A total of 81 newly diagnosed hypertensive MetS patients were included in this study. Ambulatory blood pressure monitoring of patients was done and patients’ height, weight, and waist and hip circumferences were recorded. Fasting blood glucose (FBG), lipid profile, creatinine, potassium, uric acid, hematocrit levels were studied.
Non-dipper (ie, those whose blood pressure did not drop overnight) patients had higher waist–hip ratios (WHR) (P = 0.003), uric acid (P = 0.0001), FBG (P = 0.001), total and low-density lipoprotein cholesterol levels (P = 0.0001). Risk analysis revealed that hyperuricemia was a risk factor for non-dipping pattern (P < 0.0001, odds ratio = 8.1, 95% confidence interval = 1.9–33.7). Patients in the highest quadrant for uric acid levels had higher FBG (P = 0.001), low-density lipoprotein cholesterol (P = 0.017), WHR (P = 0.01), MBPS (P = 0.003), and night diastolic blood pressure compared with lowest quadrant patients (P = 0.013). Uric acid levels were also positively correlated with night ambulatory blood pressure (ABP) (r = 0.268, P =0.05), night diastolic blood pressure (r =0.3, P =0.05), and MBPS (r =0.3, P =0.05).
Evaluation of hypertensive patients should also include an assessment of uric acid level and anthropometric measurements such as abdominal obesity. Hyperuricemia seems to be closely related to undesired blood pressure patterns and this may signal to the clinician that an appropriate therapeutic approach is required.
PMCID: PMC3647360  PMID: 23662072
hypertension; uric acid; non-dipper
17.  Non-dipper treated hypertensive patients do not have increased cardiac structural alterations 
Non-dipping pattern in hypertensive patients has been shown to be associated with an excess of target organ damage and with an adverse outcome. The aim of our study was to assess whether a reduced nocturnal fall in blood pressure (BP), established on the basis of a single 24-h BP monitoring, in treated essential hypertensives is related to more prominent cardiac alterations.
We enrrolled 229 treated hypertensive patients attending the out-patient clinic of our hypertension centre; each patient was subjected to the following procedures : 1) clinic BP measurement; 2) blood and urine sampling for routine blood chemistry and urine examination; 3) standard 12-lead electrocardiogram; 4) echocardiography; 5) ambulatory BP monitoring (ABPM). For the purpose of this study ABPM was carried-out in three subgroups with different clinic BP profile : 1) patients with satisfactory BP control (BP < 140/90 mmHg; group I, n = 58); 2) patients with uncontrolled clinic BP (clinic BP values ≥ 140 and/or 90 mmHg) but lower self-measured BP (< 20 mmHg for systolic BP and/or 10 mmHg for diastolic BP; group II, n = 72); 3) patients with refractory hypertension, selected according to WHO/ISH guidelines definition (group III, n = 99). Left ventricular hypertrophy (LVH) was defined by two gender-specific criteria (LV mass index ≥125/ m2 in men and 110 g/m2 in women, ≥51/gm2.7 in men and 47/g/m2.7 in women).
Of the 229 study participants 119 (51.9%) showed a fall in SBP/DBP < 10% during the night (non-dippers). The prevalence of non-dippers was significantly lower in group I (44.8%) and II (41.6%) than in group III (63.9%, p < 0.01 III vs II and I). The prevalence of LVH varied from 10.3 to 24.1% in group I, 31.9 to 43.1% in group II and from 60.6 to 67.7% in group III (p < 0.01, III vs II and I). No differences in cardiac structure, analysed as continuous variable as well as prevalence of LVH, were found in relationship to dipping or non-dipping status in the three groups.
In treated essential hypertensives with or without BP control the extent of nocturnal BP decrease is not associated with an increase in LV mass or LVH prevalence; therefore, the non-dipping profile, diagnosed on the basis of a single ABPM, does not identify hypertensive patients with greater cardiac damage.
PMCID: PMC153424  PMID: 12709263
hypertension; antihypertensive treatment; ambulatory blood pressure; left ventricular hypertrophy
18.  Molecular sources of residual cardiovascular risk, clinical signals, and innovative solutions: relationship with subclinical disease, undertreatment, and poor adherence: implications of new evidence upon optimizing cardiovascular patient outcomes 
Residual risk, the ongoing appreciable risk of major cardiovascular events (MCVE) in statin-treated patients who have achieved evidence-based lipid goals, remains a concern among cardiologists. Factors that contribute to this continuing risk are atherogenic non-low-density lipoprotein (LDL) particles and atherogenic processes unrelated to LDL cholesterol, including other risk factors, the inherent properties of statin drugs, and patient characteristics, ie, genetics and behaviors. In addition, providers, health care systems, the community, public policies, and the environment play a role. Major statin studies suggest an average 28% reduction in LDL cholesterol and a 31% reduction in relative risk, leaving a residual risk of about 69%. Incomplete reductions in risk, and failure to improve conditions that create risk, may result in ongoing progression of atherosclerosis, with new and recurring lesions in original and distant culprit sites, remodeling, arrhythmias, rehospitalizations, invasive procedures, and terminal disability. As a result, identification of additional agents to reduce residual risk, particularly administered together with statin drugs, has been an ongoing quest. The current model of atherosclerosis involves many steps during which disease may progress independently of guideline-defined elevations in LDL cholesterol. Differences in genetic responsiveness to statin therapy, differences in ability of the endothelium to regenerate and repair, and differences in susceptibility to nonlipid risk factors, such as tobacco smoking, hypertension, and molecular changes associated with obesity and diabetes, may all create residual risk. A large number of inflammatory and metabolic processes may also provide eventual therapeutic targets to lower residual risk. Classically, epidemiologic and other evidence suggested that raising high-density lipoprotein (HDL) cholesterol would be cardioprotective. When LDL cholesterol is aggressively lowered to targets, low HDL cholesterol levels are still inversely related to MCVE. The efflux capacity, or ability to relocate cholesterol out of macrophages, is believed to be a major antiatherogenic mechanism responsible for reduction in MCVE mediated in part by healthy HDL. HDL cholesterol is a complex molecule with antioxidative, anti-inflammatory, anti-thrombotic, antiplatelet, and vasodilatory properties, among which is protection of LDL from oxidation. HDL-associated paraoxonase-1 has a major effect on endothelial function. Further, HDL promotes endothelial repair and progenitor cell health, and supports production of nitric oxide. HDL from patients with cardiovascular disease, diabetes, and autoimmune disease may fail to protect or even become proinflammatory or pro-oxidant. Mendelian randomization and other clinical studies in which raising HDL cholesterol has not been beneficial suggest that high plasma levels do not necessarily reduce cardiovascular risk. These data, coupled with extensive preclinical information about the functional heterogeneity of HDL, challenge the “HDL hypothesis”, ie, raising HDL cholesterol per se will reduce MCVE. After the equivocal AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) study and withdrawal of two major cholesteryl ester transfer protein compounds, one for off-target adverse effects and the other for lack of efficacy, development continues for two other agents, ie, anacetrapib and evacetrapib, both of which lower LDL cholesterol substantially. The negative but controversial HPS2-THRIVE (the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) trial casts further doubt on the HDL cholesterol hypothesis. The growing impression that HDL functionality, rather than abundance, is clinically important is supported by experimental evidence highlighting the conditional pleiotropic actions of HDL. Non-HDL cholesterol reflects the cholesterol in all atherogenic particles containing apolipoprotein B, and has outperformed LDL cholesterol as a lipid marker of cardiovascular risk and future mortality. In addition to including a measure of residual risk, the advantages of using non-HDL cholesterol as a primary lipid target are now compelling. Reinterpretation of data from the Treating to New Targets study suggests that better control of smoking, body weight, hypertension, and diabetes will help lower residual risk. Although much improved, control of risk factors other than LDL cholesterol currently remains inadequate due to shortfalls in compliance with guidelines and poor patient adherence. More efficient and greater use of proven simple therapies, such as aspirin, beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, combined with statin therapy, may be more fruitful in improving outcomes than using other complex therapies. Comprehensive, intensive, multimechanistic, global, and national programs using primordial, primary, and secondary prevention to lower the total level of cardiovascular risk are necessary.
PMCID: PMC3808150  PMID: 24174878
cardiovascular prevention; low-density lipoprotein; high-density lipoprotein; statin drugs; metabolic syndrome; obesity; diabetes; niacin; AIM-HIGH study; cholesteryl ester transfer protein; endothelial progenitor cells; fibrate drugs
19.  Exercise Training, NADPH Oxidase p22phox Gene Polymorphisms, and Hypertension 
Oxidative stress that is mediated through NADPH oxidase activity plays a role in the pathology of hypertension, and aerobic exercise training reduces NADPH oxidase activity. The involvement of genetic variation in the p22phox (CYBA) subunit genes in individual oxidative stress responses to aerobic exercise training has yet to be examined in Pre and Stage 1 hypertensives.
Ninety-four sedentary Pre and Stage 1 hypertensive adults underwent 6 months of aerobic exercise training at a level of 70% V̇O2max to determine whether the CYBA polymorphisms, C242T and A640G, were associated with changes in urinary 8-iso-prostaglandin F2α (8-iso-PGF2α), urinary nitric oxide metabolites (NOx), and plasma total antioxidant capacity (TAC).
Demographic and subject characteristics were similar among genotype groups for both polymorphisms. At baseline, a significant (P = 0.03) difference among the C2424T genotype groups in 8-iso-PGF2α levels was detected, with the TT homozygotes having the lowest levels and the CC homozygotes having the highest levels. However, no differences were found at baseline between the A640G genotype groups. After 6 months of aerobic exercise training, there was a significant increase in V̇O2max (P < 0.0001) in the entire study population. In addition, there were significant increases in both urinary 8-iso-PGF2α (P = 0.002) and plasma TAC (P = 0.03) levels and a significant decrease in endogenous urinary NOx (P < 0.0001). Overall, aerobic exercise training elicited no significant differences among genotype groups in either CYBA variant for any of the oxidative stress variables.
We found that compared with CYBA polymorphisms C242T and A640G, it was aerobic exercise training that had the greatest influence on the selected biomarkers; furthermore, our results suggest that the C242T CYBA variant influences baseline levels of urinary 8-iso-PGF2α but not the aerobic exercise-induced responses.
PMCID: PMC2871250  PMID: 19516159
20.  Ambulatory Blood Pressure is a Better Marker than Clinic Blood Pressure in Predicting Cardiovascular Events in Patients With/Without Type 2 Diabetes 
American journal of hypertension  2008;21(4):10.1038/ajh.2008.4.
The prognostic significance of ambulatory blood pressure (ABP) has not been established in patients with type 2 diabetes (T2DM).
To clarify the impact of ABP on cardiovascular prognosis in patients with or without T2DM, we performed ABP monitoring (ABPM) in 1268 subjects recruited from nine sites in Japan, who were seen for the evaluation of hypertension. The mean age was 70.4±9.9 years, and 301 had diabetes; they were followed for 50±23 months. Incident cardiovascular disease (CVD) were related to different measures of ABP, including three categories of awake systolic BP (SBP <135, 135-150, and >150 mmHg), sleep SBP (<120, 120-135, and >135 mmHg), and nocturnal BP dipping (dippers, non-dippers, and risers). Cox regression models controlling for classic risk factors, were performed.
Higher awake and sleep SBP predicted higher incidence of CVD in both diabetes and non-diabetes groups. In multivariable analyses, elevated awake and sleep SBP predicted increased risk of CVD more closely than clinic BP in both groups. The relationships between ABP level and CVD were similar in both groups. In Kaplan-Meier analyses, the incidence of CVD in non-dippers was similar to dippers, but risers experienced the highest risk of CVD in both groups (ps<0.01). The riser pattern was associated with approximately a 150% increase in risk of CVD, in both groups.
These findings suggest that ABPM improves the prediction of cardiovascular risk, over and above clinic BP, as much in patients with type 2 diabetes as it does in patients without diabetes.
PMCID: PMC3881175  PMID: 18292756
type 2 diabetes; ambulatory blood pressure monitoring; non-dipper; riser; cardiovascular disease
21.  Low-Density Lipoprotein Apheresis 
Executive Summary
To assess the effectiveness and safety of low-density lipoprotein (LDL) apheresis performed with the heparin-induced extracorporeal LDL precipitation (HELP) system for the treatment of patients with refractory homozygous (HMZ) and heterozygous (HTZ) familial hypercholesterolemia (FH).
Background on Familial Hypercholesterolemia
Familial hypercholesterolemia is a genetic autosomal dominant disorder that is caused by several mutations in the LDL-receptor gene. The reduced number or absence of functional LDL receptors results in impaired hepatic clearance of circulating low-density lipoprotein cholesterol (LDL-C) particles, which results in extremely high levels of LDL-C in the bloodstream. Familial hypercholesterolemia is characterized by excess LDL-C deposits in tendons and arterial walls, early onset of atherosclerotic disease, and premature cardiac death.
Familial hypercholesterolemia occurs in both HTZ and HMZ forms.
Heterozygous FH is one of the most common monogenic metabolic disorders in the general population, occurring in approximately 1 in 500 individuals1. Nevertheless, HTZ FH is largely undiagnosed and an accurate diagnosis occurs in only about 15% of affected patients in Canada. Thus, it is estimated that there are approximately 3,800 diagnosed and 21,680 undiagnosed cases of HTZ FH in Ontario.
In HTZ FH patients, half of the LDL receptors do not work properly or are absent, resulting in plasma LDL-C levels 2- to 3-fold higher than normal (range 7-15mmol/L or 300-500mg/dL). Most HTZ FH patients are not diagnosed until middle age when either they or one of their siblings present with symptomatic coronary artery disease (CAD). Without lipid-lowering treatment, 50% of males die before the age of 50 and 25% of females die before the age of 60, from myocardial infarction or sudden death.
In contrast to the HTZ form, HMZ FH is rare (occurring in 1 case per million persons) and more severe, with a 6- to 8-fold elevation in plasma LDL-C levels (range 15-25mmol/L or 500-1000mg/dL). Homozygous FH patients are typically diagnosed in infancy, usually due to the presence of cholesterol deposits in the skin and tendons. The main complication of HMZ FH is supravalvular aortic stenosis, which is caused by cholesterol deposits on the aortic valve and in the ascending aorta. The average life expectancy of affected individuals is 23 to 25 years. In Ontario, it is estimated that there are 13 to 15 cases of HMZ FH. An Ontario clinical expert confirmed that 9 HMZ FH patients have been identified to date.
There are 2 accepted clinical diagnostic criterion for the diagnosis of FH: the Simon Broome FH Register criteria from the United Kingdom and the Dutch Lipid Network criteria from the Netherlands. The criterion supplement cholesterol levels with clinical history, physical signs and family history. DNA-based-mutation-screening methods permit a definitive diagnosis of HTZ FH to be made. However, given that there are over 1000 identified mutations in the LDL receptor gene and that the detection rates of current techniques are low, genetic testing becomes problematic in countries with high genetic heterogeneity, such as Canada.
The primary aim of treatment in both HTZ and HMZ FH is to reduce plasma LDL-C levels in order to reduce the risk of developing atherosclerosis and CAD.
The first line of treatment is dietary intervention, however it alone is rarely sufficient for the treatment of FH patients. Patients are frequently treated with lipid-lowering drugs such as resins, fibrates, niacin, statins and cholesterol absorption-inhibiting drugs (ezetimibe). Most HTZ FH patients require a combination of drugs to achieve or approach target cholesterol levels.
A small number of HTZ FH patients are refractory to treatment or intolerant to lipid-lowering medication. According to clinical experts, the prevalence of refractory HTZ FH in Ontario is between 1 to 5%. Using the mean of 3%, it is estimated that there are approximately 765 refractory HTZ FH patients in Ontario, of which 115 are diagnosed and 650 are undiagnosed.
Drug therapy is less effective in HMZ FH patients since the effects of the majority of cholesterol-lowering drugs are mediated by the upregulation of LDL receptors, which are often absent or function poorly in HMZ FH patients. Some HMZ FH patients may still benefit from drug therapy, however this rarely reduces LDL-C levels to targeted levels.
Existing Technology: Plasma Exchange
An option currently available in Ontario for FH patients who do not respond to standard diet and drug therapy is plasma exchange (PE). Patients are treated with this lifelong therapy on a weekly or biweekly basis with concomitant drug therapy.
Plasma exchange is nonspecific and eliminates virtually all plasma proteins such as albumin, immunoglobulins, coagulation factors, fibrinolytic factors and HDL-C, in addition to acutely lowering LDL-C by about 50%. Blood is removed from the patient, plasma is isolated, discarded and replaced with a substitution fluid. The substitution fluid and the remaining cellular components of the blood are then returned to the patient.
The major limitation of PE is its nonspecificity. The removal of HDL-C prevents successful vascular remodeling of the areas stenosed by atherosclerosis. In addition, there is an increased susceptibility to infections, and costs are incurred by the need for replacement fluid. Adverse events can be expected to occur in 12% of procedures.
Other Alternatives
Surgical alternatives for FH patients include portocaval shunt, ileal bypass and liver transplantation. However, these are risky procedures and are associated with a high morbidity rate. Results with gene therapy are not convincing to date.
The Technology Being Reviewed: LDL Apheresis
An alternative to PE is LDL apheresis. Unlike PE, LDL apheresis is a selective treatment that removes LDL-C and other atherogenic lipoproteins from the blood while minimally impacting other plasma components such as HDL-C, total serum protein, albumin and immunoglobulins. As with PE, FH patients require lifelong therapy with LDL apheresis on a weekly/biweekly basis with concomitant drug therapy.
Heparin-Induced Extracorporeal LDL Precipitation
Heparin-induced extracorporeal LDL precipitation (HELP) is one of the most widely used methods of LDL apheresis. It is a continuous closed-loop system that processes blood extracorporeally. It operates on the principle that at a low pH, LDL and lipoprotein (a) [Lp(a)] bind to heparin and fibrinogen to form a precipitate which is then removed by filtration. In general, the total duration of treatment is approximately 2 to 3 hours.
Results from early trials indicate that LDL-C concentration is reduced by 65% to 70% immediately following treatment in both HMZ and HTZ FH and then rapidly begins to rise. Typically patients with HTZ FH are treated every 2 weeks while patients with HMZ FH require weekly therapy. Heparin-induced extracorporeal LDL precipitation also produces small transient decreases in HDL-C, however levels generally return to baseline within 2 days. After several months of therapy, long-term reductions in LDL-C and increases in HDL-C have been reported.
In addition to having an impact on plasma cholesterol concentrations, HELP lowers plasma fibrinogen, a risk factor for atherosclerosis, and reduces concentrations of cellular adhesion molecules, which play a role in early atherogenesis.
In comparison with PE, HELP LDL apheresis does not have major effects on essential plasma proteins and does not require replacement fluid, thus decreasing susceptibility to infections. One study noted that adverse events were documented in 2.9% of LDL apheresis treatments using the HELP system compared with 12% using PE. As per the manufacturer, patients must weigh at least 30kgs to be eligible for treatment with HELP.
Regulatory Status
The H.E.L.P.® System (B.Braun Medizintechnologie GmbH, Germany) has been licensed by Health Canada since December 2000 as a Class 3 medical device (Licence # 26023) for performing LDL apheresis to acutely remove LDL from the plasma of 3 high-risk patient populations for whom diet has been ineffective and maximum drug therapy has either been ineffective or not tolerated. The 3 patient groups are as follows:
Functional hypercholesterolemic homozygotes with LDL-C >500 mg/dL (>13mmol/L);
Functional hypercholesterolemic heterozygotes with LDL-C >300 mg/dL (>7.8mmol/L);
Functional hypercholesterolemic heterozygotes with LDL-C >200 mg/dL (>5.2mmol/L) and documented CAD
No other LDL apheresis system is currently licensed in Canada.
Review Strategy
The Medical Advisory Secretariat systematically reviewed the literature to assess the effectiveness and safety of LDL apheresis performed with the HELP system for the treatment of patients with refractory HMZ and HTZ FH. A standard search methodology was used to retrieve international health technology assessments and English-language journal articles from selected databases.
The GRADE approach was used to systematically and explicitly make judgments about the quality of evidence and strength of recommendations.
Summary of Findings
The search identified 398 articles published from January 1, 1998 to May 30, 2007. Eight studies met the inclusion criteria. Five case series, 2 case series nested within comparative studies, and one retrospective review, were included in the analysis. A health technology assessment conducted by the Alberta Heritage Foundation for Medical Research, and a review by the United States Food and Drug Administration were also included.
Large heterogeneity among the studies was observed. Studies varied in inclusion criteria, baseline patient characteristics and methodology.
Overall, the mean acute1 relative decrease in LDL-C with HELP LDL apheresis ranged from 53 to 77%. The mean acute relative reductions ranged as follows: total cholesterol (TC) 47 to 64%, HDL-C +0.4 to -29%, triglycerides (TG) 33 to 62%, Lp(a) 55 to 68% and fibrinogen 56 to 65%.
The mean chronic2 relative decreases in LDL-C and TC with HELP LDL apheresis ranged from 9 to 46% and 5 to 34%, respectively. Familial hypercholesterolemia patients treated with HELP did not achieve the target LDL-C value set by international guidelines (LDL-C < 2.5mmol/L, 100mg/dL). The chronic mean relative increase in HDL-C ranged from 12 to 27%. The ratio of LDL:HDL and the ratio of TC:HDL are 2 measures that have been shown to be important risk factors for cardiac events. In high-risk patients, the recommended target LDL:HDL ratio is less than or equal to 2, and the target TC:HDL ratio is less than 4. In the studies that reported chronic lipid changes, the LDL:HDL and TC:HDL ratios exceeded targeted values.
Three studies investigated the effects of HELP on coronary outcomes and atherosclerotic changes. One noted that twice as many lesions displayed regression in comparison to those displaying progression. The second study found that there was a decrease in Agatston scores3 and in the volume of coronary calcium. The last study noted that 2 of 5 patients showed regression of coronary atherosclerosis, and 3 of the 5 patients showed no change as assessed by a global change score.
Adverse effects were typically mild and transient, and the majority of events were related to problems with vascular access. Of the 3 studies that provided quantitative information, the proportion of adverse events ranged from 2.9 to 5.1%.
GRADE Quality of Evidence
In general, studies were of low quality, i.e., case series studies (Tables 1-3). No controlled studies were identified and no studies directly compared the effectiveness of the HELP system with PE or with diet and drug therapy. Conducting trials with a sufficiently large control group would not have been feasible or acceptable given that HELP represents a last alternative in these patients who are resistant to conventional therapeutic strategies.
A major limitation is that there is limited evidence on the effectiveness and safety of HELP apheresis in HMZ FH patients. However, it is unlikely that better-quality evidence will become available, given that HMZ FH is rare and LDL apheresis is a last therapeutic option for these patients.
Lastly, there is limited data on the long-term effects of LDL apheresis in FH patients. No studies with HELP were identified that examined long-term outcomes such as survival and cardiovascular events. The absence of this data may be attributed to the rarity of the condition, and the large number of subjects and long duration of follow-up that would be needed to conduct such trials.
Homozygous Familial Hypercholesterolemia - Lipid Outcomes
Heterozygous Familial Hypercholesterolemia - Lipid Outcomes
Heterozygous Familial Hypercholesterolemia - Coronary Artery Disease Outcomes
Economic Analysis
A budget-impact analysis was conducted to forecast future costs for PE and HELP apheresis in FH patients. All costs are reported in Canadian dollars. Based on epidemiological data of 13 HMZ, 115 diagnosed HTZ and 765 cases of all HTZ patients (diagnosed + undiagnosed), the annual cost of weekly treatment was estimated to be $488,025, $4,332,227 and $24,758,556 respectively for PE. For HELP apheresis, the annual cost of weekly treatment was estimated to be $1,025,338, $9,156,209 and $60,982,579 respectively. Costs for PE and HELP apheresis were halved with a biweekly treatment schedule.
The cost per coronary artery disease death avoided over a 10-year period in HTZ FH-diagnosed patients was also calculated and estimated to be $37.5 million and $18.7 million for weekly and biweekly treatment respectively, when comparing HELP apheresis with PE and with no intervention. Although HELP apheresis costs twice as much as PE, it helped to avoid 12 deaths compared with PE and 22 deaths compared with no intervention, over a period of 10 years.
Ontario Health System Impact Analysis
Low-density lipoprotein apheresis using the HELP system is currently being funded by the provinces of Quebec and Alberta. The program in Quebec has been in operation since 2001 and is limited to the treatment of HMZ FH patients. The Alberta program is relatively new and is currently treating HMZ FH patients, but it is expanding to include refractory HTZ FH patients.
Low-density lipoprotein apheresis is a lifelong treatment and requires considerable commitment on the part of the patient, and the patient’s family and physician. In addition, the management of FH continues to evolve. With the advent of new more powerful cholesterol-lowering drugs, some HTZ patients may be able to sufficiently control their hypercholesterolemia. Nevertheless, according to clinical experts, HMZ patients will likely always require LDL apheresis.
Given the substantial costs associated with LDL apheresis, treatment has been limited to HMZ FH patients. However, LDL apheresis could be applied to a much larger population, which would include HTZ FH patients who are refractory to diet and drug therapy. HTZ FH patients are generally recruited in a more advanced state, demonstrate a longer natural survival than HMZ FH patients and are older.
For HMZ FH patients, the benefits of LDL apheresis clearly outweigh the risks and burdens. According to GRADE, the recommendation would be graded as strong, with low- to very low-quality evidence (Table 4).
In both HMZ and HTZ FH patients, there is evidence of overall clinical benefit of LDL apheresis from case series studies. Low-density lipoprotein apheresis has several advantages over the current treatment of PE, including decreased exposure to blood products, decreased risk of adverse events, conservation of nonatherogenic and athero-protective components, such as HDL-C and lowering of other atherogenic components, such as fibrinogen.
In contrast to HMZ FH patients, there remains a lot of uncertainty in the social/ethical acceptance of this technology for the treatment of refractory HTZ FH patients. In addition to the substantial costs, it is unknown whether the current health care system could cope with the additional demand. There is uncertainty in the estimates of benefits, risks and burdens. According to GRADE, the recommendation would be graded as weak with low- to very-low-quality evidence (Table 5).
GRADE Recommendation - Homozygous Patients
GRADE of recommendation: Strong recommendation, low-quality or very-low-quality evidence
Benefits clearly outweigh risk and burdens
Case series study designs
Strong, but may change when higher-quality evidence becomes available
GRADE Recommendation - Heterozygous Patients
GRADE of recommendation: Weak recommendation, low-quality or very-low-quality evidence
Uncertainty in the estimates of benefits, risks and burden, which these may be closely balanced
Case series study designs
Very weak; other alternatives may be equally reasonable
PMCID: PMC3377562  PMID: 23074505
22.  Comparison of inflammatory markers in non-dipper hypertension vs. dipper hypertension and in normotensive individuals: uric acid, C-reactive protein and red blood cell distribution width readings 
In this study, we investigated the relationship of increased inflammatory parameters (C-reactive protein – CRP), oxidative stress markers (serum uric acid – SUA) and red blood cell distribution width (RDW) with non-dipper hypertension (NDHT).
Material and methods
Among the individuals who presented to the cardiology clinic, 40 patients (32.5% male, 67.5% female; mean age: 54.4 ±7.1) who had hypertension and were diagnosed with NDHT through ambulatory blood pressure monitoring, 40 age- and sex-matched dipper hypertension (DHT) patients (25% male, 75% female, mean age: 54.2 ±7.0), and 40 normotensive individuals (42.5% male, 57.5% female, mean age: 51.9 ±9.0) were enrolled in the study. Peripheral venous blood samples were collected from all the patients in order to evaluate the hematological and biochemical parameters. All the assessed parameters were compared among the groups.
The CRP, RDW and uric acid levels were observed to be significantly higher in the non-dipper hypertension group in comparison to the dipper hypertension patients and the normotensive population (p < 0.05). These parameters were also significantly higher in the dipper HT group compared to the normotensive population (p < 0.05).
We found in our study that increased CRP, uric acid and RDW levels, which are indicators of increased inflammation and oxidative stress, are significantly higher in the non-dipper HT patients in comparison to the dipper HT patients and control group.
PMCID: PMC4108733  PMID: 25061455
non-dipper hypertension; dipper hypertension; uric acid; red blood cell distribution width; C-reactive protein
23.  The oxidation ratio of LDL: A Predictor for Coronary Artery Disease 
Disease markers  2008;24(6):341-349.
Objective: Oxidized LDL cholesterol (ox-LDL-C) is considered to be a key factor of initiating and accelerating atherosclerosis (AS). The purpose of this study is to elucidate the sensitivity and specificity of ox-LDL and oxidation ratio of LDL in the diagnosis of coronary artery disease (CAD). For the first time, we investigated the ratio of ox-LDL to ALB(ox-LDL/ALB).
Methods and results: Blood ox-LDL, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglyceride (TG) and albumin (ALB) were measured in patients with acute myocardial infarction (AMI, n = 80), unstable angina pectoris (UAP, n = 80), stable angina pectoris (SAP, n = 80), normal control (n = 60), and dyslipidemia control (n = 60). Ox-LDL was measured by competitive ELISA. The level of ox-LDL and oxidation ratio of LDL(ox-LDL/TC, ox-LDL/HDL-C, ox-LDL/ LDL-C and ox-LDL/ALB) were significantly higher in each diseased group than controls (P < 0.001). In CAD group, ox-LDL and oxidation ratio of LDL in subjects complicated with hypertension (HT) and/or diabetes mellitus (DM) increased further (P < 0.001). Ox-LDL/ALB in the AMI group was 7 times higher than normal control group (0.068 ± 0.017 vs 0.009 ± 0.007, P < 0.001). The area under the curve (AUC) of receiver operating characteristic curve (ROC curve) is a criterium to evaluate the accuracy of diagnosing a disease. The AUC of ROC curve of ox-LDL/TC, ox-LDL/HDL-C, ox-LDL, ox-LDL/ALB and ox-LDL/ LDL-C for diagnosing CAD were 0.975, 0.975, 0.966, 0.966, 0.957 respectively (P < 0.001). When ox-LDL/TC = 0.175, the sensitivity and specificity of diagnosing CAD were 0.917 and 0.925, which were almost equal to each other, indicating that the rates of missed diagnosis and misdiagnosis for CAD were the lowest.
Conclusions: The level of ox-LDL and the ratio of ox-LDL/TC, ox-LDL/LDL-C, ox-LDL/HDL-C and ox-LDL/ALB are better biomarkers than TC, TG, HDL-C and LDL-C for discriminating between patients with coronary artery disease and healthy subjects. And patients who have a high ratio of ox-LDL /TC may have a higher risk for CAD.
PMCID: PMC3850607  PMID: 18688083
Coronary artery disease; atherosclerosis; oxidized low density lipoprotein; cholesterol
24.  Evaluation of the Relationship between Circadian Blood Pressure Variation and Left Atrial Function Using Strain Imaging 
Non-dippers were reported as showing different left atrial function, compared to dippers, but no study to date investigated the changes in the left atrial function according to the diurnal blood pressure pattern, using tissue Doppler and strain imaging.
Forty never treated hypertensive patients between 30 and 80 years of age were enrolled in this study. Patients were classified as non-dippers when, during night time, they had a blood pressure decrease of less than 10%. Strain of the left atrium was measured during late systole, and peak strain rates of the left atrium were measured during systole, early and late diastolic periods.
The left atrial expansion index, left atrial active emptying volume and left atrial active emptying fraction were all significantly increased in non-dippers. They also had increased values of mean peak left atrial strain (dippers = 21.26 ± 4.23% vs. non-dippers = 24.91 ± 5.20%, p = 0.02), strain rate during reservoir (dippers = 1.29 ± 0.23 s-1 vs. non-dippers =1.52 ± 0.27 s-1, p = 0.01) and contractile period (dippers = -1.38 ± 0.24 s-1 vs. non-dippers = -1.68 ± 0.32 s-1, p < 0.01).
Strain and strain rate acquired from color Doppler tissue imaging demonstrate exaggerated reservoir and booster pump function in never-treated, non-dipper hypertensive patients. These methods are simple and sensitive for the early detection of subtle changes in the left atrial function.
PMCID: PMC3259542  PMID: 22259661
Left atrium; Echocardiography; Strains; Hypertension; Circadian rhythm
Hypertension  2008;53(2):363-369.
Blood pressure normally decreases during the night. Absence of this phenomenon (non-dipping) is associated with increased cardiovascular risk. Altered autonomic and endocrine circadian rhythms are suspected to play a role. Patients with peripheral autonomic failure offer a unique opportunity to study this phenomenon because approximately 50% develop supine hypertension despite very low autonomic function. The purpose of this study was to define the prevalence of dipping in these patients, and to determine if dipping is associated with less severe autonomic impairment, or exaggerated nocturnal sodium excretion. We collected blood pressure and urine from 8PM-8AM in 41 peripheral autonomic failure patients with supine hypertension. Dipping (systolic BP fall ≥ 10% during 12AM-6AM from baseline [8PM–10PM]) occurred in 34% of patients, with an average decrease of −44±4mm Hg at 4 AM. Systolic BP, averaged from 12AM-6AM, decreased to normotensive levels in 50% (n=7) of dippers and 15% (n=4) of non-dippers. There were no significant differences in severity of autonomic failure, nocturnal diuresis or natriuresis (0.18±0.01 in dippers vs. 0.18±0.01mEq/mg creatinine in non-dippers; p=0.522) between groups. At 8AM, orthostatic hypotension was similar between groups (−84/−35±9/4 in dippers vs. −93/−39±6/3 in non-dippers, p=0.356 for SBP). In conclusion, dipping was observed in a third of patients with peripheral autonomic failure, so that a significant percentage of patients would not require treatment for supine hypertension. Dipping was not associated with increased nocturnal urinary sodium or volume excretion, or less severe autonomic failure. Thus, mechanisms independent of autonomic pathways contribute to BP dipping in these patients.
PMCID: PMC2665259  PMID: 19047577
dipping; supine hypertension; autonomic failure; circadian rhythm; autonomic nervous system; natriuresis

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