0Current Therapeutic Research
Volume 69, Number 3, June 2008
Effects of Barnidipine on Blood Pressure and Left Ventricular Diastolic Function in Patients with Hypertension and Metabolic Syndrome: A 12-Week, Open-Label Noncomparison Study
Fabio Angeli, MD1; Salvatore Repací, MD1; Claudia Borgioni, MD1; Mariagrazia Sardone, MD1; Aurelio Scotti, MD2; and Paolo Verdecchia, MD, FACC1
1Struttura Complessa di Cardiología, Unitä di Ricerca Clínica 'Cardiología Preventiva,' Ospedale "S. Maria della Misericordia," Perugia, Italy; and 2Scientific Department, Italfarmaco, S.p.A., Cinisello Balsamo, Milan, Italy
ABSTRACT
BACKGROUND: Barnidipine is one of a new generation of dihydropyridine calcium-channel blockers. Despite evidence of favorable effects on blood pressure (BP) and insulin sensitivity, this drug has rarely been tested in hypertensive patients with metabolic syndrome (MS).
objective: The aim of this study was to evaluate the effects of barnidipine on BP and left ventricular (LV) diastolic function in patients with hypertension and MS.
methods: Consecutive subjects aged 18 to 75 years with systolic BP (SBP) of 140 to 179 mm Hg and/or diastolic BP (DBP) of 90 to 109 mm Hg and MS (based on Adult Treatment Panel III criteria) were assessed for inclusion in the study. Lifestyle changes according to current guidelines were recommended and barnidipine monotherapy 10 mg daily was initiated. All patients entered a 2-week run-in period. After a 6-week treatment period, the daily dosage was doubled for the remainder of the study in patients whose BP remained uncontrolled (>l40/>90 mm Hg). We assessed the glycolipidic profile and LV structure and function using standard Doppler and tissue Doppler imaging (TDI) echocardiography before and after 12 weeks of treatment. Ambulatory BP records and electrocardiographic and echocardiographic tracings were coded and shipped to a central laboratory for blinded analysis. Possible adverse events (AEs) were recorded at predetermined intervals throughout the follow-up period and at unplanned intervals whenever an AE became known to the investigators.
results: Thirty-four consecutive patients were assessed for inclusion. Thirty consecutive patients (20 men, 10 women; mean [SD] age, 55.9 [10.3] years; 5 current smokers) were included in the study. At study entry, mean office SBP was 146 mm Hg, DBP was 87 mm Hg, and heart rate was 72 beats/min. At the study end, mean office SBP/DBP was <140/90 mm Hg in 20 patients (66.7%). From baseline to study end, 24-hour ambulatory BP decreased significantly by 12 and 8 mm Hg for SBP and DBP, respectively (both, P = 0.001). The smoothness index was 0.92 for SBP and
Accepted for publication March 28, 2008. doi:10.10l6/j.curtheres.2008.06.003
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0.82 for DBP. Fasting plasma glucose concentration decreased significantly from 110 to 104 mg/dL (P = 0.001). Total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol concentrations did not change significantly. From baseline to study end, there were no significant changes in LV structure or systolic function (LV mass, 50.7 vs 50.6 g/ht2 7; LV diastolic/systolic diameters, 47.50/29.80 vs 48.40/30.76 mm; wall motion score index, 1.0 vs 1.0; ejection fraction, 61% vs 60%), while the peak E/A velocity ratio on TDI increased from 1.078 to 1.245 (P = 0.009). No AEs (including AEs reflected by chemistry values) either unrelated or related to treatment were noted during the 12-week duration of the study.
conclusions: In these hypertensive patients with MS, a 12-week treatment period with barnidipine in addition to lifestyle modifications was associated with significant reductions in 24-hour BP and BP variability, reduction in plasma glucose concentration, and improvement in LV diastolic relaxation. No significant changes in lipid concentrations, LV structure, or systolic function were found. (Curr Ther Res Clin Exp. 2008;69:207-220) © 2008 Excerpta Medica Inc.
keywords: barnidipine, hypertension, metabolic syndrome, left ventricular hypertrophy, diastolic dysfunction.
INTRODUCTION
Metabolic syndrome (MS), a constellation of risk factors of metabolic origin, is strongly associated with the development of type 2 diabetes and cardiovascular disease.1'2 These factors may trigger a proinflammatory and prothrombotic state and identify individuals at elevated cardiovascular risk.3-5 The main features of MS are an increased risk for fatal and nonfatal cardiovascular complications, a 3- to 6-fold higher risk of developing diabetes, a higher risk of new-onset hypertension, and a frequent association with subclinical organ damage (eg, microalbuminuria, arterial stiffening, left ventricular [LV] hypertrophy, and diastolic dysfunction).1'4 Tissue Doppler imaging (TDI), a relatively recent application of the Doppler principle, is increasingly used as a tool to investigate diastolic function. The TDI parameters of diastolic function are relatively unaffected by preload and heart rate (HR) and hence more valuable in distinguishing normal from abnormal and pseudonormal filling as compared with traditional Doppler parameters.6-8
The 2007 joint guidelines of the European Society of Hypertension and the European Society of Cardiology for the management of patients with hypertension included MS in the list of cardiovascular risk factors and decision criteria to establish whether or not to begin drug treatment in hypertensive patients.9 We searched MEDLINE for clinical studies which met all of the following pre-specified criteria: (1) effect of antihypertensive drugs in patients with MS; (2) publication before December 31, 2007 in peer-reviewed journals; (3) inclusion of patients with hypertension or high cardiovascular risk; and (4) measurement of blood pressure (BP) at baseline and follow-up. Although rigorous BP control is envisaged in patients with MS,9'10 there is a paucity of intervention trials in hypertensive patients with MS.10
The aim of this study was to investigate, in a sample of patients with mild to moderate hypertension with concomitant MS, the 24-hour antihypertensive effectiveness of
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barnidipine,*11"15 a third-generation calcium-channel blocker indicated for the treatment of hypertension. Similar to other dihydropyridine calcium antagonists, barnidipine has been reported to have a neutral tolerability profile with regard to insulin sensitivity,15 indicating it might be particularly suitable for patients with MS, dyslipidemia, and impaired fasting glucose.
PATIENTS AND METHODS
This 12-week, open-label, noncomparative study was carried out in patients attending our Clinic Research Unit of Preventive Cardiology in Perugia, Italy. Our institutional ethical committee approved the study (PROTOCOL DS/VAS/01) in March 2006, and all participants gave their written informed consent to participate in the study.
We assessed patients aged 18 to 75 years with mild to moderate essential hypertension (defined as systolic BP [SBP] of 140-179 mm Hg and/or diastolic BP [DBP] of 90109 mm Hg) and a diagnosis of MS according to the Adult Treatment Panel III criteria.1 All patients needed to meet predetermined inclusion and exclusion criteria.
Female patients needed to be either postmenopausal for >1 year, surgically sterile, or using effective contraceptive methods. All patients required a diagnosis of hypertension and MS with >3 of the following factors present: waist circumference >102 cm in men and >88 cm in women; triglycerides >150 mg/dL; high-density lipoprotein cholesterol (HDL-C) <40 mg/dL in men and <50 mg/dL in women; BP >130/>85 mm Hg; or fasting plasma glucose >110 mg/dL.
Patients were excluded for any of the following reasons: secondary form of hypertension; concomitant administration of BP-lowering drugs; Keith-Wagener grade III of IV9 hypertensive retinopathy; history of hypertensive encephalopathy or cerebrovascular accident; transient ischemic cerebral attack; coronary bypass surgery or any percutaneous coronary intervention during the 6 months prior to the first study visit; present or past diagnosis of heart failure (New York Heart Association class II—IV); myocardial infarction, angina pectoris (treated with drugs different from oral or topical nitrates in stable doses); presence of potentially life-threatening arrhythmia or symptomatic arrhythmia; serum sodium <136 mEq/L, serum potassium <3.5 mEq/L or >5.5 mEq/L; major gastrointestinal tract surgery (eg, gastrectomy, gastroenterostomy, bowel resection); active or previously active inflammatory bowel disease during the 12 months prior to the first study visit; active gastritis, duodenal or gastric ulcers, or gastrointestinal/rectal bleeding during the 3 months prior to the first study visit; history of pancreatic injury or pancreatitis or evidence of impaired pancreatic function/ injury, as indicated by abnormal lipase or amylase activity; evidence of hepatic injury, as determined by either of the following—aspartate aminotransferase or alanine aminotransferase activity >3 times the upper limit of normal at the first study visit or a history of hepatic encephalopathy, esophageal varices, or portocaval shunt; evidence of renal impairment, as determined by any one of the following—serum creatinine >1.7 mg/dL for women and >2.0 mg/dL for men at first visit or history of dialysis or nephrotic syndrome; history or evidence of drug or alcohol abuse within the last
*Trademark: Vasexten® (Italfarmaco, S.p.A., Cinisello Balsamo, Milan, Italy).
12 months; pregnancy or breastfeeding; any surgical or medical condition that, in the opinion of the investigator, might place the patient at increased risk from his/her participation in the study or was likely to prevent the patient from complying with the requirements of the study or completing the study; concomitant treatment with drugs potentially interfering with barnidipine (eg, antiprotease drugs, ketoconazole, itraconazole, erythromycin, clarithromycin); history of noncompliance to medical regimens or unwillingness to comply with the study protocol; or participation in any investigational drug trial within 1 month of the first study visit.
All patients were initially advised to make lifestyle modifications, where appropriate, according to current guidelines.9 After a 2-week run-in period during which previous antihypertensive drugs were discontinued, patients entered the active phase of the study, which lasted 12 weeks. Diuretics and P-blockers were discontinued because they are associated with increased risk of developing diabetes.16 Barnidipine monotherapy was administered between 7:00 am and 9:00 pm at the initial daily dose of 10 mg. The dosage was doubled to 20 mg daily in those patients whose hypertension remained uncontrolled (SBP >140 mm Hg and/or DBP >90 mm Hg) at the end of 6 weeks of treatment. All other drugs that did not affect BP were not changed during the study.
BP was measured by the same physician for all patients with a standard mercury sphygmomanometer in a quiet, comfortable room with temperature verified to be in the range of 18°C to 27°C. Patients were seated and relaxed for >10 minutes before BP was measured on the nondominant arm.
HR was obtained from the radial artery. The means of 3 consecutive measurements were used for the statistical analysis of both BP and HR.
All laboratory testing (creatinine, potassium, plasma glucose, total cholesterol, HDL-C, low-density lipoprotein cholesterol [LDL-C], triglycerides) was carried out after an overnight fast at the beginning of the study and after 12 weeks of treatment.
Ambulatory BP was recorded using an oscillometric device (SpaceLabs 90207, SpaceLabs, Redmond, Washington) set to take a reading every 15 minutes throughout the 24-hour monitoring period. Ambulatory BP monitoring was performed at the beginning of the study and after 12 weeks of treatment. Mean 24-hour, daytime (6:00 am-10:00 pm), and nighttime (10:00 pm-6:00 am) BP were determined. BP variability was estimated using the SD of daytime and nighttime SBP and DBP. The smoothness index was computed to analyze the stability of BP reduction over the 24-hour monitoring period.17
A standard 12-lead electrocardiogram (ECG) was recorded in all patients at 25 mm/s and 1 mV/cm calibration. LV hypertrophy was diagnosed using a prognostically validated score18 developed in our laboratory,19 which requires positivity of >1 of the following 3 criteria: (1) modified Cornell voltage (ECG amplitude SV3 + RaVL >2.4 mV in men, >2.0 mV in women); (2) typical LV strain (inverted T wave with asymmetric branches associated with a flat or down-sloping ST segment, with >0.05 mV depression 80 ms after the J point); and (3) a Romhilt-Estes point score of >5.19
LV structure and systolic function were evaluated by standard 2D-guided M-Mode echocardiography. Only frames with optimal visualization of interfaces and show-
F. ANGEL.I ET AL
ing simultaneous visualization of septum, LV internal diameter, and posterior wall were used for reading. LV mass was calculated using a standard formula validated by Devereux et al20 and corrected by height in meters at the power of 2.7 in order to correct for overweight and obesity.21 LV hypertrophy was defined by an LV mass >51.0 g/(height in meters)2-7.21 Diastolic function was evaluated through standard Doppler imaging (peak E area, peak A area, peak E/A area ratio, E velocity, A velocity, E/A velocity ratio) and TDI.6,7 TDI targeted to the lateral mitral valve anulus was used to analyze early and late diastolic anular motion (Ea and Aa, respectively).6'7
All 24-hour ambulatory BP records, ECG, and echocardiography tracings were coded and shipped to a central laboratory for analysis. Readers were unaware of the clinical characteristics of the patients or their treatment.
Possible adverse events (AEs) were recorded at predetermined intervals throughout the follow-up period and at unplanned intervals whenever an AE became known to an investigator.
Statistical Analysis
Statistical analysis was performed using SPSS version 14 (SPSS Inc., Chicago, Illinois) and STATA version 8 (StataCorp LP, College Station, Texas). Parametric data were reported as mean (SD). Comparisons between pretreatment and treatment values were made using the t test for paired samples (continuous variables) and the %2 test (categorical variables) when applicable. A 2-sided a of 0.05 was used; therefore, P < 0.05 was considered statistically significant.
RESULTS
Of 34 hypertensive patients screened, 4 did not meet the inclusion criteria and were excluded from the study. The remaining 30 patients (20 men, 10 women; mean [SD] age, 55.9 [10.3] years; 5 current smokers), 15 of whom had never been treated for hypertension, were included in the study (Table I). All 30 patients completed the study.
At study entry (visit 1), mean (SD) office SBP was 146 (10) mm Hg, DBP was 87 (11) mm Hg, and HR was 72 (10) beats/min. At the end of the 2-week run-in period (visit 2, baseline), SBP was 153 (6) mm Hg, DBP was 92 (5) mm Hg, and HR was 74 (8) beats/min (Table II). Ten patients (33.3%) received lipid-lowering drugs during the study. At entry, none of the study patients were being treated with insulin or glucose-lowering drugs. During the study, no changes in glucose or lipid-lowering drugs were prescribed. At baseline, 14 patients (46.7%) had impaired fasting plasma glucose (>100 mg/dL) and 3 (10.0%) had diabetes mellitus.
Effect of barnidipine on blood Pressure
The changes in office BP during the study are reported in Table II and Figure 1. At week 6 (visit 3), 12 patients (40.0%) had not achieved adequate BP control and, therefore, their daily dosage of barnidipine was doubled to 20 mg. At week 12 (visit 4), mean office BP was <140/90 mm Hg in 20 patients (66.7%). Mean SBP and DBP decreased significantly from baseline (-22 and -12 mm Hg, respectively; both, P = 0.001). Mean HR did not change significantly during the course of the study.
Table I. Baseline demographic and clinical characteristics of patients with hypertension and metabolic syndrome (N = 30).*
Characteristic Value
Age, mean (SD), y 55.9 (10.3)
Sex, no. (%)
Male 20 (66.7)
Female 10 (33.3)
BSA, mean (SD), m2 1.99 (0.19)
Current smoker, no. (%) 5 (16.7)
History of dyslipidemia, no. (%) 10 (33.3)
Antihypertensive treatment at baseline, no. (%) 15 (50.0)
BSA = body surface area.
*No significant between-group differences were found.
Table II. Effects of treatment with barnidipine on office blood pressure and laboratory findings in patients with hypertension and metabolic syndrome treated with barnidipine once daily (N = 30). Data are mean (SD) unless otherwise indicated.
Visit 1 Visit 2 Visit 3 Visit 4
Variable (Week -2) (Week 0) (Week 6) (Week 12) p*
Office monitoring
SBP, mm Hg 146 (10) 153 (6) 127 (11) 131 (9) 0.001
DBP, mm Hg 87 (11) 92 (5) 81 (8) 80 (10) 0.001
HR, beats/min 72 (10) 74(8) 70 (9) 69 (8) 0.084
Laboratory findings
Creatinine, mg/dL - 1.05 (0.13) - 1.05 (0.13) 0.98
Plasma glucose, mg/dL - 110 (24) - 104 (26) 0.001
IFG, no. (%)t - 17 (56.7) - 16 (53.3) 0.80
Total cholesterol, mg/dL - 202 (30) - 202 (32) 0.99
HDL cholesterol, mg/dL - 53 (13) - 56 (12) 0.19
LDL cholesterol, mg/dL - 112 (31) - 114 (27) 0.60
Triglycerides, mg/dL - 176 (98) - 168 (104) 0.66
SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate; IFG = glucose; HDL = high-density lipoprotein; LDL = low-density lipoprotein. ♦Week 12 versus week 0. +Serum glucose concentration >100 mg/dL.
impaired fasting
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160 150 140 130 120 110 100 90 80 70 60
SBP DBP HR
Visit 1 (Week -2)
Visit 2 (Week 0)
Visit 3 (Week 6)
Visit 4 (Week 12)
Figure 1. Changes in office systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR) after 12 weeks of treatment with barnidipine (10-20 mg QD) in patients with hypertension and metabolic syndrome (N = 30). Treatment was started at visit 2 after a run-in period of 2 weeks. *P = 0.001 versus baseline.
From baseline to study end, 24-hour ambulatory SBP and DBP decreased significantly (-12 and -8 mm Hg, respectively; both, P = 0.001), while ambulatory HR did not change significantly (Table III and Figure 2).
Mean (SD) SBP variability decreased significantly from 13 (3) mm Hg to 11 (3) mm Hg (P = 0.043) during the daytime and from 12 (3) mm Hg to 10 (3) mm Hg (P = 0.040) during the nighttime. DBP variability did not change significantly. The smoothness index was 0.82 for ambulatory SBP and 0.92 for ambulatory DBP.
Metabolic parameters
From baseline to week 12, there were no significant changes in total cholesterol (202 {30] vs 202 [32] mg/dL, respectively), HDL-C (53 [13] vs 56 [12] mg/dL), LDL-C (112 [31] vs 114 [27] mg/dL), or triglycerides (176 [98] vs 168 [104] mg/dL). Mean fasting plasma glucose concentration decreased 6 mg/dL from baseline (110 [24] vs 104 [26]; P = 0.001) (Table II).
Table III. Effects of treatment with barnidipine on 24-hour ambulatory blood pressure in patients with hypertension and metabolic syndrome (N = 30). Data are mean (SD).
Variable Visit 2 (Week 0) Visit 4 (Week 12) P
24-Hour monitoring
SBP, mm Hg 134 (10) 122 (10) 0.001
DBP, mm Hg 85 (8) 77 (7) 0.001
HR, beats/min 70 (10) 73 (9) 0.25
Daytime (6 am-8 pm) monitoring
SBP, mm Hg 139 (10) 126 (9) 0.001
DBP, mm Hg 90 (8) 81 (7) 0.001
HR, beats/min 73 (11) 75 (11) 0.24
Nighttime BP (8 pm-6 am) monitoring
SBP, mm Hg 123 (12) 114 (13) 0.001
DBP, mm Hg 74 (10) 69 (10) 0.017
HR, beats/min 65 (9) 67 (10) 0.22
BP variability
Daytime SBP, mm Hg 13 (3) 11 (3) 0.043
Daytime DBP, mm Hg 11 (2) 10 (3) 0.25
Nighttime SBP, mm Hg 12 (3) 10 (3) 0.040
Nighttime DBP, mm Hg 10 (2) 9 (4) 0.72
SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate.
left ventricular structure and function
At baseline, LV hypertrophy was detected by standard ECG in 4 patients (13.3%). There were no significant changes in any of the ECG parameters of LV hypertrophy at the end of the study. Similarly, there were no significant changes in LV structure or systolic function, as detected by standard 2D-guided M-Mode echocardiography. No significant changes were found in the ejection fraction, left atrial diameter, or LV diameters (Table IV).
The mean (SD) Ea/Aa ratio on TDI increased significantly from 1.078 (0.328) at baseline to 1.245 (0.231) at week 12 (P = 0.009), while no significant changes were found with standard transmittal Doppler flow parameters (peak E velocity, peak A velocity and their ratio) (Figure 3).
Tolerability
No AEs (including AEs reflected by chemistry values) either unrelated or related to treatment were noted during the 12-week duration of the study. In particular, there were no cases of ankle edema.
-♦- SBP-Baseline SBP-12 weeks
Figure 2. Twenty-four-hour ambulatory systolic and diastolic blood pressure (SBP and DBP) profile before and after 12 weeks of treatment with barnidipine (10-20 mg QD) in patients with hypertension and metabolic syndrome (N = 30). Both SBP and DBP were decreased significantly (both, P = 0.001).
Table IV. Changes in electrocardiographic (ECG) and echocardiographic parameters after 12 weeks of treatment with barnidipine in patients with hypertension and metabolic syndrome (N = 30). Data are mean (SD) unless otherwise indicated.
Visit 2 Visit 4
Variable (Week 0) (Week 12) P
LV hypertrophy-Cornell/strain, no. (%) 4 (13.3) 4 (13.3) 0.99
Cornell voltage, mV 15.5 (7.2) 15.8 (8.4) 0.70
Sokolow-Lyon voltage, mV 19.2 (5.9) 19.1 (6.2) 0.82
Typical strain, % 3.3 3.3 0.90
Echocardiography
LVM, g/ht2-7 50.7 (12.6) 50.6 (13.8) 0.88
LVM/ht2-7 >51, no. (%) 15 (50.0) 12 (40.0) 0.06
Left atrial diameter, mm 36.8 (5.2) 36.6 (4.7) 0.53
LV systolic diameter, mm 29.80 (4.65) 30.76 (4.23) 0.12
LV diastolic diameter, mm 47.50 (5.12) 48.40 (5.41) 0.10
LV systolic function
WMSI 1.0 1.0 0.99
Ejection fraction, % 61 (10) 60 (8) 0.50
LV diastolic function by standard PD
Peak E velocity, m/s 0.59 (0.11) 0.60 (0.10) 0.37
Peak A velocity, m/s 0.67 (0.11) 0.66 (0.14) 0.72
Peak E velocity/Peak A velocity ratio 0.91 (0.28) 0.95 (0.23) 0.24
LV diastolic function by TDI
Peak E velocity, m/s 0.092 (0.023) 0.091 (0.014) 0.71
Peak A velocity, m/s 0.090 (0.024) 0.076 (0.020) 0.001
Peak E velocity/Peak A velocity ratio 1.078 (0.328) 1.245 (0.231) 0.009
LV = left ventricular; LVM = left ventricular mass; WMSI = wall motion score index; PD = pulsed Doppler; TDI = tissue Doppler imaging.
DISCUSSION
The present study suggests that a 12-week treatment period with barnidipine 1020 mg daily provided a consistent 24-hour BP-lowering effect in these patients with hypertension and concomitant MS. Office BP normalization was achieved in 66.7% of patients, and 24-hour ambulatory SBP/DBP decreased by 12/8 mm Hg. BP control was sustained and constant over the 24-hour monitoring period, as suggested by the smoothness indexes17 of 0.82 and 0.92 for SBP and DBP, respectively, and the significant reduction in daytime and nighttime BP variability. There were significant improvements in LV relaxation, as assessed by TDI, and a small but significant reduction in plasma glucose concentration from baseline.
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Visit 2 (Week 0)
Visit 4 (Week 12)
Figure 3. Effect of treatment with barnidipine (10-20 mg QD) on diastolic function evaluated using tissue Doppler imaging echocardiography. Early and late diastolic anular motion (Ej/Aj,) ratio before and after 12 weeks of treatment are reported with SD. *P = 0.009.
Drug Treatment of Hypertensive Patients with metabolic syndrome
The growing importance of MS in the decision-making process in patients with essential hypertension was recognized in the 2007 joint guidelines of the European Society of Hypertension and the European Society of Cardiology.9 The document suggests that MS, even in the absence of other risk factors, is a reason to begin drug treatment in hypertensive patients with stage 1 hypertension. Even in patients with highnormal BP (SBP 130-139 mm Hg or DBP 95-99 mm Hg), MS is identified as a reason to consider drug treatment. The same document states that diuretics and (3-blockers should be avoided in hypertensive patients at high risk of developing diabetes mellitus, such as those with MS.
The present study, specifically designed for hypertensive patients with MS, may provide further insights into the management of these patients. Barnidipine administered once daily was associated with significant, sustained 24-hour BP control. The importance of achieving adequate 24-hour BP control is supported by the large body of evidence that supports the strong prognostic value of ambulatory BP6,22 and by the evidence that in-treatment ambulatory BP levels are superior to pretreatment levels in identifying patients at increased cardiovascular risk.23 At any level of ambulatory BP, lesser BP variability during the day and night is also associated with a lesser risk of future cardiovascular disease.24'25 In this context, it is noteworthy that barnidipine treatment was associated with a significant reduction in BP variability in the present study.
Metabolic Effects
There was a small, albeit statistically significant, reduction in plasma glucose concentration and no significant effects on lipid concentrations. These results are consistent with a previous study by Kosegawa et al,15 who noted improvement in insulin sensitivity (increased glucose infusion rate from 3-91 [0.43] to 5.29 [0.43] mg/kg • min-1; P = 0.028) after barnidipine administration in hypertensive patients. Improved blood flow to pancreatic islets resulting from arteriolar vasodilatation might have been one mechanism of improved insulin sensitivity.15
Cardiac Effects
There were no significant effects on the ECG markers of LV hypertrophy or the echocardiographic indexes of LV structure. It is likely that the duration of the study and the inclusion criteria, which were not based on LV hypertrophy, precluded identifying detectable effects on hypertrophy regression. However, we noted for the first time a significant improvement in the TDI parameters of diastolic function (peak E velocity/peak A velocity) during treatment. In several clinical conditions, including hypertension, heart failure, and acute myocardial infarction, LV diastolic dysfunction detected by TDI predicted major cardiovascular events and mortality.26
The main limitation of this study is inherent in its open-label and noncomparative design. To partially overcome this limitation, great care was taken to ensure a central blind assessment of the main outcome measures, including ECG, echocardiography, and 24-hour ambulatory BP. Further large, blinded, controlled studies are needed to confirm these effects of barnidipine on LV diastolic functions and metabolic profile. No sample size calculation was done, either a priori or post hoc protocol.
CONCLUSIONS
We found that lifestyle modifications and a 12-week treatment period with barnidipine monotherapy according to current guidelines in these hypertensive patients with MS were associated with a significant reduction in 24-hour BP and BP variability, with concomitant reduction in plasma glucose concentration and improvement in LV diastolic relaxation. No significant changes in lipid concentrations, LV structure, or systolic function were observed.
ACKNOWLEDGMENTS
The barnidipine used in this study was provided by the manufacturer, Italfarmaco, S.p.A., Cinisello Balsamo, Milan, Italy.
The authors' research was supported by the Associazione Umbra Cuore e Ipertensione. We gratefully thank Francesca Saveri for secretarial assistance.
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26. Yu CM, Sanderson JE, Marwick TH, Oh JK. Tissue Doppler imaging a new prognosticator for cardiovascular diseases J Am Coll Cardiol 2007;49:1903-1914.
address correspondence to: Fabio Angeli, MD, Struttura Complessa di Cardiología, Unitá di Ricerca Clinica 'Cardiología Preventiva,' Ospedale "S. Maria della Misericordia," Piazzale G. Menghini, 06132 Perugia, Italy. E-mail: fangeli@cardionet.it
