Apostolos Achimastos

The Effect of Antihypertensive Drugs on Central Blood Pressure Beyond Peripheral Blood Pressure. Part II: Evidence for Specific Class-Effects of Antihypertensive Drugs on Pressure Amplification

The blood pressure (BP) waveform varies substantially between the peripheral conduit (brachial) and the central elastic (aorta) arteries mainly do a gradual increase of systolic BP, as the wave propagates distally. This phenomenon is called BP amplification and is principally generated by the presence of arterial stiffness gradient and wave reflections along the arterial bed. More and more clinical studies suggest that central BP may provide additional information regarding cardiovascular risk beyond peripheral BP. Arterial properties and thus pressure amplification, are modulated by age, cardiovascular risk factors, vasoactive substances and drugs. Recent evidence suggests, beyond any doubt, that antihypertensive drugs affect peripheral and central BP differentially and alter pressure amplification. The aim of the present review (Part II) is to summarize the available evidence regarding: (i) the specific class-effect of antihypertensive drugs on central BP beyond peripheral BP, as well as the potential underlying hemodynamic mechanisms, (ii) head to head comparison of the effect of different classes of antihypertensive drugs on central BP, (iii) the effect of combination drug treatment on central BP. Finally to attempt an interpretation of the clinical trials in hypertension, which classically record brachial BP, based on the results of studies which assessed central BP. Several conclusions were drawn. First, it is clear that there are important differences between the classes of antihypertensive drugs regarding their effects on BP amplification. Second, it seems that the newer antihypertensive drugs [angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers and dihydropyridine calcium blockers], as well as nitrates, have a more beneficial effect on BP amplification than the older drugs (diuretics and BBs). Third, there is compelling evidence regarding the detrimental effect of BBs (mainly atenolol) on central BBs and convincing evidence that ACEIs increase BP amplification.

Blood pressure response under chronic antihypertensive drug therapy: the role of aortic stiffness in the REASON (Preterax in Regression of Arterial Stiffness in a Controlled Double-Blind) study.

OBJECTIVES We sought to evaluate the role of arterial stiffness on blood pressure (BP) response to drug treatment. BACKGROUND Increased arterial stiffness (pulse wave velocity [PWV]) is associated with increased systolic blood pressure (SBP). Antihypertensive drug therapy achieves better control of diastolic blood pressure (DBP) than SBP does, implying that increased PWV might be a predictor of the SBP response to treatment. METHODS The REASON (Preterax in Regression of Arterial Stiffness in a Controlled Double-Blind) study is a randomized, double-blind trial comparing atenolol versus perindopril/indapamide; 375 patients with hypertension, with BP and PWV measurements at baseline and after 12 months of treatment, were divided into 3 tertiles according to baseline PWV and included in a post-hoc analysis. RESULTS After 12 months of treatment, BP differed significantly between PWV tertiles (the third having the lowest response, p < 0.05). Factors related to smaller BP decline were low baseline BP, high baseline PWV, need for a double dose of treatment, use of atenolol (only for SBP response), and age (only for DBP). Although DBP control did not differ in the PWV tertiles, SBP control was significantly associated with PWV level (p = 0.001) as well as with the use of perindopril/indapamide (p < 0.001). The predictive value of PWV on BP response was independent of age, sex, mean BP, and cardiovascular risk factors. CONCLUSIONS Baseline PWV is a significant predictor of BP response to antihypertensive treatment, independent from age, the need for increasing drug dosage, and the presence of cardiovascular risk factors. Achievement of SBP control appears to be influenced by aortic stiffness as well as by angiotensin-converting enzyme inhibition.

Additive hypotensive effect of angiotensin-converting enzyme inhibition and angiotensin-receptor antagonism in essential hypertension

The study was designed to assess the antihypertensive effect of combined angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 receptor (AT1) antagonism in patients with essential hypertension. Twenty patients with uncontrolled ambulatory diastolic blood pressure (BP) after 6 weeks of ACE inhibitor monotherapy (benazepril, 20 mg, o.d.) were randomized to receive double-blind valsartan, 80 mg, o.d. (AT1 antagonist) or matching placebo for 5 weeks while continuing to receive background benazepril. Then patients crossed over to the alternative regimen for a second 5-week period. The 24-h ambulatory BP was monitored on the final day of the benazepril monotherapy period and on the final day of each double-blind treatment period. Valsartan added to benazepril produced a significant antihypertensive effect with a benefit over placebo of 6.5 +/- 12.6/4.5 +/- 8.0 mm Hg (systolic/diastolic) for average awake ambulatory BP (p < 0.05), 7.1 +/- 9.4/5.6 +/- 6.5 mm Hg for asleep BP (p < 0.01), and 6.8 +/- 9.7/4.9 +/- 6.8 mm Hg for average 24-h ambulatory BP (p < 0.01). Pulse rate was unaffected. Plasma active renin was higher on the benazepril-valsartan combination compared with benazepril-placebo (p < 0.05). There was no change in routine biochemical variables when valsartan was added to benazepril. Six patients reported mild dizziness or fatigue (three also with placebo). These data suggest that in hypertensive patients uncontrolled with an ACE inhibitor, the addition of an AT1 antagonist provides a powerful and safe antihypertensive drug combination.

Comparison of oral MK 421 and propranolol in mild to moderate essential hypertension and their effects on arterial and venous vessels of the forearm.

The efficacy of MK 421 and propranolol was compared in 48 patients with mild to moderate hypertension. Each patient was randomly assigned to receive 1 of the drugs for 12 weeks. Additionally, a subgroup of 28 patients underwent studies of forearm arterial and venous circulation by means of pulsed Doppler and mercury-in-silastic plethysmography. Both drugs reduced supine and standing blood pressure (BP) (p less than 0.001). Propranolol reduced heart rate (p less than 0.001), while MK 421 did not change it. Brachial artery diameter, blood velocity and flow increased after MK 421 (p less than 0.001), but were not changed after propranolol therapy. Forearm vascular resistance decreased after MK 421 (p less than 0.001) and after propranolol (p less than 0.05). Forearm venous tone was unaffected on MK 421, but increased after propranolol (p less than 0.01). Thus, in moderate hypertension, 3 months of treatment with MK 421 or propranolol similarly decrease BP, but affect the forearm circulation differently: MK 421 dilates both the brachial artery and the arterioles of the forearm, but does not affect the venous vessels, and propranolol causes little arterial change but increases the forearm venous tone.

Left-ventricular hypertrophy is associated better with 24-h aortic pressure than 24-h brachial pressure in hypertensive patients: the SAFAR study.

Objective: To test the hypothesis that left-ventricular hypertrophy (LVH) is better associated with aortic, than brachial, 24-h average blood pressure (BP) in individuals with hypertension. Background: The office aortic BP is associated better with organ damage, such as LVH, than the office brachial BP; whether the 24-h average aortic BP associates better with LVH, than the 24-h average brachial BP, has never been tested. Methods: Aortic ambulatory BP monitoring (ABPM) was performed with a novel validated oscillometric cuff-based BP recording device, also used for simultaneous brachial ABPM, and the application of pulse wave analysis method. Office brachial and aortic BP were assessed with validated oscillometric recording device and pulse wave analysis, respectively; left-ventricular mass was measured by ultrasound. Results: Regression analysis performed in 229 individuals (aged 54.3 ± 14.6 years; 56% men; 75% hypertensive patients) showed that the 24-h average aortic SBP was significantly better associated with left-ventricular mass index and LVH than the 24-h average brachial, as well as, office (brachial or aortic) SBP, independently of age, sex, obesity or treatment. Receiver operator characteristics curve analysis showed a higher discriminatory ability of 24-h average aortic than brachial SBP to detect the presence of LVH (area under the curve: 0.73 versus 0.69; P = 0.007). A high degree of interindividual overlap regarding aortic 24-h average SBP level was found in individuals in whom the corresponding brachial measurements denoted different hypertension levels. Conclusion: These data suggest that aortic ABPM, when compared to brachial ABPM, improves the individualized assessment of the BP-associated heart damage.

The Combination of Nebivolol plus Pravastatin is Associated with a More Beneficial Metabolic Profile Compared to that of Atenolol plus Pravastatin in Hypertensive Patients with Dyslipidemia: A Pilot Study

Nebivolol, a selective β1-lipophilic blocker, achieves blood pressure control by modulating nitric oxide release in addition to b-blockade. This dual mechanism of action could result in minimum interference with lipid metabolism compared to atenolol, a classic (β1-selective blocker. Hypertensive patients commonly exhibit lipid abnormalities and frequently require statins in combination with the anti-hypertensive therapy. We conducted this trial in order to clarify the effect on the metabolic profile of β-blocker therapy with atenolol or nebivolol alone, or in conjunction with pravastatin. Thirty hypertensive hyperlipidemic men and women (total cholesterol >240 mg/dL [6.2 mmol/L], low-density lipoprotein cholesterol >190 mg/dL [4.9 mmol/L], triglycerides <500 mg/dL [5.6 mmol/L]) were separated in two groups. One group consisted of 15 subjects on atenolol therapy (50 mg daily), and the other group included 15 subjects on nebivolol therapy (5 mg daily). After 12 weeks of (-blocker therapy, pravastatin (40 mg daily) was added in both groups for another 12 weeks. Atenolol significantly increased triglyceride levels by 19% (P = .05), while nebivolol showed a trend to increase high-density lipoprotein cholesterol by 8% (NS) and to decrease triglyceride levels by 5% (NS). Atenolol significantly increased lipoprotein(a) by 30% (P = .028). Fibrinogen levels were equally and not significantly decreased in both groups by 9% and 7%, respectively. Furthermore, atenolol and nebivolol decreased serum high-sensitivity C-reactive protein levels by 14% (P = .05) and 15% (P = .05), respectively. On the other hand, both atenolol and nebivolol showed a trend to increase homocysteine levels (NS) by 13% and 11%, respectively. Although uric acid levels remained the same, atenolol significantly increased the fractional excretion of uric acid by 33% (P = .03). Following nebivolol administration, glucose levels remained the same, while insulin levels were reduced by 10% and the HOMA index (fasting glucose levels multiplied by fasting insulin levels and divided by 22.5) was reduced by 20% (P = .05). There were no significant differences between the two patient groups in the measured parameters after the administration of (-blockers, except for triglycerides (P < .05) and the HOMA index (P = .05). The addition of pravastatin to all patients (n = 30) decreased total cholesterol by 21% (P < .001), low-density lipoprotein cholesterol by 28% (P < .001), apolipoprotein-B by 22% (P < .001), apolipoprotein-E by 15% (P = .014) and lipoprotein(a) levels by 12% (P = .023). Moreover, homocysteine levels and C-reactive protein were reduced by 17% (P = .05) and 43% (P = .05), respectively. We conclude that nebivolol seems to be a more appropriate therapy in hypertensive patients with hyperlipidemia and carbohydrate intolerance. Finally, the addition of pravastatin could further correct the well-established predictors of cardiovascular events.

Fever of unknown origin: Discrimination between infectious and non-infectious causes

OBJECTIVE The present study aimed to develop and evaluate a simple diagnostic model that could aid physicians to discriminate between infectious and non-infectious causes of fever of unknown origin (FUO). DESIGN/SETTING/SUBJECTS Patients with classical FUO were studied in two distinct, prospective, observational phases. In the derivation phase that lasted from 1992 to 2000, 33 variables regarding demographic characteristics, history, symptoms, signs, and laboratory profile were recorded and considered in a logistic regression analysis using the diagnosis of infection as a dependent variable. In the validation phase, the discriminatory capacity of a score based on the derived predictors of infection was calculated for FUO patients assessed from 2001 to 2007. RESULTS Data from 112 individuals (mean age 56.5+/-11.2 years) were analyzed in the derivation cohort. The final diagnoses included infections, malignancies, non-infectious inflammatory diseases, and miscellaneous conditions in 30.4%, 10.7%, 33% and 5.4% of subjects, whereas 20.5% of cases remained undiagnosed. C-reactive protein>60 mg/L (odds ratio 6.0 [95% confidence intervals 2.5, 9.8]), eosinophils<40/mm(3) (4.1 [2.0, 7.3]) and ferritin<500 microg/L (2.5 [1.3, 5.2]) were independently associated with diagnosis of infection. Among the 100 patients of the validation cohort, the presence of > or =2 of the above factors predicted infection with sensitivity, specificity, and positive and negative predictive values of 91.4%, 92.3%, 86.5%, and 95.2%, respectively. CONCLUSIONS The combination of C-reactive protein, ferritin and eosinophil count may be useful in discriminating infectious from non-infectious causes in patients hospitalised for classical FUO.

Arterial stiffness and central hemodynamics in treated hypertensive subjects according to brachial blood pressure classification.

Background International recommendations have classified brachial blood pressure (BP) in subgroups enabling better cardiovascular risk stratification. Central BP is an independent predictor of cardiovascular risk, differing from brachial BP through the predominant influence of arterial stiffness and wave reflections. Central BP has never been studied in relation to international guidelines for brachial BP classification. Methods In 580 chronically treated hypertensive subjects we measured: carotid–femoral pulse wave velocity (PWV), carotid artery augmentation index (AI) and carotid blood pressures, using applanation tonometry and pulse wave analysis, and using brachial BP for carotid pressure wave calibration. Results For each given brachial value, carotid systolic blood pressure (SBP) and PP were significantly lower than the corresponding brachial SBP and PP. This pressure amplification was significantly lower in the ‘optimal’ and ‘normal’ BP ranges (6.8–7.4 mmHg) than in the higher BP ranges (10.1–11.3 mmHg), mainly depending on heart rate (HR) and PWV levels. PWV gradually increased as a function of brachial BP classification and was a significant predictor of this classification independently of age, drug treatment, atherosclerotic lesions and even mean BP. Finally, PWV was a highly sensitive marker of the effective BP control throughout all decades of age. Conclusion Under chronic antihypertensive therapy, central BP does not strictly parallel the corresponding brachial BP classification, depending on differences in aortic stiffness and HR. Whether aortic PWV might predict the brachial BP classification and/or the presence of effective BP control, as suggested in this study, needs further confirmation.

Statins: another class of antihypertensive agents?

The assessment of global cardiovascular risk is an essential step in the management of atherosclerotic disease prevention. Among the risk factors to be addressed are hypertension and hyperlipidaemia; these commonly coexist. A neutral or lipid-friendly antihypertensive agent is probably useful in the presence of lipid abnormalities. Similarly, statins have been shown to decrease cardiovascular risk in hypertensive patients. There is also experimental and clinical evidence that statins have blood pressure (BP)-lowering effects. In this review, we discuss the beneficial effects of statins on BP, and provide an overview of the underlying pathophysiology. We also consider the evidence justifying the use of statins in the management of hypertensive patients.

Intravascular volume, extracellular fluid volume, and total body water in obese and nonobese hypertensive patients.

Intraarterial blood pressure, plasma volume, extracellular and interstitial (IFV) fluid volumes, and total and intracellular (IBV) body water were evaluated in 50 men: 16 obese hypertensive patients, 16 nonobese hypertensive patients, and 18 normal subjects of similar age. In obese hypertensive subjects, the IBW/IFV ratio was significantly increased (p less than 0.01) in comparison with both control subjects and nonobese hypertensive patients. After body weight reduction, blood pressure (p less than 0.01), heart rate (p less than 0.05), and the IBW/IFV ratio (p less than 0.01) significantly decreased. The decrease in the ratio was due to an absolute increase in the interstitial fluid volume, related to a shift of fluid volume from the intracellular to the interstitial space. Thus, obese hypertensive patients have an increased water cell content, causing an altered partition between the intracellular and the interstitial spaces.