Blood pressure and low-density lipoprotein-cholesterol lowering for prevention of strokes and cognitive decline: a review of available trial evidence.

BACKGROUND AND OBJECTIVES: It is well established by a large number of randomized controlled trials that lowering blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) by drugs are powerful means to reduce stroke incidence, but the optimal BP and LDL-C levels to be achieved are largely uncertain. Concerning BP targets, two hypotheses are being confronted: first, the lower the BP, the better the treatment outcome, and second, the hypothesis that too low BP values are accompanied by a lower benefit and even higher risk. It is also unknown whether BP lowering and LDL-C lowering have additive beneficial effects for the primary and secondary prevention of stroke, and whether these treatments can prevent cognitive decline after stroke. RESULTS: A review of existing data from randomized controlled trials confirms that solid evidence on optimal BP and LDL-C targets is missing, possible interactions between BP and LDL-C lowering treatments have never been directly investigated, and evidence in favour of a beneficial effect of BP or LDL-C lowering on cognitive decline is, at best, very weak. CONCLUSION: A new, large randomized controlled trial is needed to determine the optimal level of BP and LDL-C for the prevention of recurrent stroke and cognitive decline.

Is nurse-measured blood pressure a valid substitute for ambulatory blood pressure monitoring?

BACKGROUND: Because ambulatory blood pressure monitoring (ABPM) is not available everywhere, the objective of the study was to determine whether nurse-measured blood pressure could be an acceptable substitute to ABPM. METHODS: We analyzed the data of 2385 consecutive patients referred to our hypertension clinic for the performance of ABPM. Before ambulatory monitoring was performed, a nurse-measured BP was obtained three times using a Y-tube connecting the sphygmomanometer and the recorder. We compared the mean value of the three nurse-measured blood pressures with that of the 12h daytime ambulatory monitoring, considered as the reference. RESULTS: The difference between the nurse-measured and the ambulatory blood pressure was small but statistically significant, indicating that nurse-measured blood pressure tends to overestimate both diastolic and systolic blood pressure. The difference between the nurse blood pressure and ABPM was greater among treated hypertensive patients than untreated patients. To diagnose hypertension, defined as a blood pressure of over 140/90mmHg by ABPM, the positive predictive value of the nurse blood pressure was 0.81 and the negative predictive value 0.63. However, these predictive values could be improved with less stringent cut-off values of blood pressure. Thus, for a diastolic blood pressure above 100mmHg, the positive predictive value of nurse blood pressure was 0.55 and the negative predictive value 0.91. These figures were relatively similar for previously treated and untreated patients. CONCLUSION: Nurse blood pressure is less accurate than ABPM in diagnosing hypertension, defined as a blood pressure of over 140/90mmHg. It could, however, be an acceptable substitute, especially to exclude people who do not need to be treated, in situations where lower resources require a less rigorous definition of hypertension.

Development of Implantable Flow-Through Left Ventricular Pressure Telemetric Transmitter for small Rodent Animals

Objective: Although 24-hour arterial blood pressure can be monitored in a free-moving animal using pressure telemetric transmitter mostly from Data Science International (DSI), accurate monitoring of 24-hour mouse left ventricular pressure (LVP) is not available because of its insufficient frequency response to a high frequency signal such as the maximum derivative of mouse LVP (LVdP/dtmax and LVdP/dtmin). The aim of the study was to develop a tiny implantable flow-through LVP telemetric transmitter for small rodent animals, which can be potentially adapted for human 24 hour BP and LVP accurate monitoring. Design and Method: The mouse LVP telemetric transmitter (Diameter: _12 mm, _0.4 g) was assembled by a pressure sensor, a passive RF telemetry chip, and to a 1.2F Polyurethane (PU) catheter tip. The device was developed in two configurations and compared with existing DSI system: (a) prototype-I: a new flow-through pressure sensor with wire link and (b) prototype-II: prototype-I plus a telemetry chip and its receiver. All the devices were applied in C57BL/6J mice. Data are mean_SEM. Results: A high frequency response (>100 Hz) PU heparin saline-filled catheter was inserted into mouse left ventricle via right carotid artery and implanted, LV systolic pressure (LVSP), LVdP/dtmax, and LVdP/dtmin were recorded on day2, 3, 4, 5, and 7 in conscious mice. The hemodynamic values were consistent and comparable (139_4 mmHg, 16634_319, - 12283_184 mmHg/s, n¼5) to one recorded by a validated Pebax03 catheter (138_2mmHg, 16045_443 and -12112_357 mmHg/s, n¼9). Similar LV hemodynamic values were obtained with Prototype-I. The same LVP waveforms were synchronically recorded by Notocord wire and Senimed wireless software through prototype-II in anesthetized mice. Conclusion: An implantable flow-through LVP transmitter (prototype-I) is generated for LVP accurate assessment in conscious mice. The prototype-II needs a further improvement on data transmission bandwidth and signal coupling distance to its receiver for accurate monitoring of LVP in a freemoving mouse.

Structural development of the Tso Morari ultra-high pressure nappe of the Ladakh Himalaya

A continental subduction-related and multistage exhumation process for the Tso Morari ultra-high pressure nappe is proposed. The model is constrained by published thermo-barometry and age data, combined with new geological and tectonic maps. Additionally, observations on the structural and metamorphic evolution of the Tso Morari area and the North Himalayan nappes are presented. The northern margin of the Indian continental crust was subducted to a depth of >90 km below Asia after continental collision some 55 Ma ago. The underthrusting was accompanied by the detachment and accretion of Late Proterozoic to Early Eocene sediments, creating the North Himalayan accretionary wedge, in front of the active Asian margin and the 103-50 Ma Ladakh arc batholith. The basic dikes in the Ordovician Tso Morari granite were transformed to eclogites with crystallization of coesite, some 53 Ma ago at a depth of >90 kin (>27 kbar) and temperatures of 500 to 600 degrees C. The detachment and extrusion of the low density Tso Morari nappe, composed of 70% of the Tso Morari granite and 30% of graywackes with some eclogitic dikes, occurred by ductile pure and simple shear deformation. It was pushed by buoyancy forces and by squeezing between the underthrusted Indian lithosphere and the Asian mantle wedge. The extruding Tso Morari nappe reached a depth of 35 km at the base of the North Himalayan accretionary wedge some 48 Ma ago. There the whole nappe stack recrystallized under amphibolite facies conditions of a Barrovian regional metamorphism with a metamorphic field gradient of 20 degrees C/km. An intense schistosity with a W-E oriented stretching lineation L, and top-to-the E shear criteria and crystallization of oriented sillimanite needles after kyanite, testify to the Tso Morari nappe extrusion and pressure drop. The whole nappe stack, comprising from the base to top the Tso Morari, Tetraogal, Karzok and Mata-Nyimaling-Tsarap nappes, was overprinted by new schistosities with a first N-directed and a second NE-directed stretching lineation L-2 and L-3 reaching the base of the North Himalayan accretionary wedge. They are characterized by top-to-the S and SW shear criteria. This structural overprint was related to an early N- and a younger NE-directed underthrusting of the Indian plate below Asia that was accompanied by anticlockwise rotation of India. The warping of the Tso Morari dome started already some 48 Ma ago with the formation of an extruding nappe at depth. The Tso Morari dome reached a depth of 15 km about 40 Ma ago in the eastern Kiagar La region and 30 Ma ago in the western Nuruchan region. The extrusion rate was of about 3 cm/yr between 53 and 48 Ma, followed by an uplift rate of 1.2 mm/yr between 48 and 30 Ma and of only 0.5 mm/yr after 30 Ma. Geomorphology observations show that the Tso Morari dome is still affected by faults, open regional dome, and basin and pull-apart structures, in a zone of active dextral transpression parallel to the Indus Suture zone.

Blood pressure and renin-angiotensin system resetting in transgenic rats with elevated plasma Val5-angiotensinogen.

OBJECTIVE: : Increases in plasma angiotensinogen (Ang-N) due to genetic polymorphisms or pharmacological stimuli like estrogen have been associated with a blood pressure (BP) rise, increased salt sensitivity and cardiovascular risk. The relationship between Ang-N, the resetting of the renin-angiotensin system, and BP still remains unclear. Angiotensin (Ang) II-induced genetic hypertension should respond to lisinopril treatment. METHODS: : A new transgenic rat line (TGR) with hepatic overexpression of native (rat) Ang-N was established to study high plasma Ang-N. The transgene contained a mutation producing Val-Ang-II, which was measured separately from nontransgenic Ile-Ang-II in plasma and renal tissue. RESULTS: : Male homozygous TGR had increased plasma Ang-N (∼20-fold), systolic BP (ΔBP + 26 mmHg), renin activity (∼2-fold), renin activity/concentration (∼5-fold), total Ang-II (∼2-fold, kidney 1.7-fold) but decreased plasma renin concentrations (-46%, kidney -85%) and Ile-Ang-I and II (-93%, -94%) vs. controls. Heterozygous TGR exhibited ∼10-fold higher plasma Ang-N and 17 mmHg ΔBP. Lisinopril decreased their SBP (-23 vs. -13 mmHg in controls), kidney Ang-II/I (∼3-fold vs. ∼2-fold) and Ile-Ang-II (-70 vs. -40%), and increased kidney renin and Ile-Ang-I (>2.5-fold vs. <2.5-fold). Kidney Ang-II remained higher and renin lower in TGR compared with controls. CONCLUSION: : High plasma Ang-N increases plasma and kidney Ang-II levels, and amplifies the plasma and renal Ang-II response to a given change in renal renin secretion. This enzyme-kinetic amplification dominates over the Ang-II mediated feedback reduction of renin secretion. High Ang-N levels thus facilitate hypertension via small increases of Ang II and may influence the effectiveness of renin-angiotensin system inhibitors.

Pulse wave analysis of aortic pressure: diastole should also be considered.

BACKGROUND: : The systolic augmentation index (sAix), calculated from the central aortic pulse wave (reconstructed from the noninvasive recording of the radial pulse with applanation tonometry), is widely used as a simple index of central arterial stiffness, but has the disadvantage of also being influenced by the timing of the reflected with respect to the forward pressure wave, as shown by its inverse dependence on heart rate (HR). During diastole, the central aortic pulse also contains reflected waves, but their relationship to arterial stiffness and HR has not been studied. METHODS: : In 48 men and 45 women, all healthy, with ages ranging from 19 to 70 years, we measured pulse wave velocity (PWV, patients supine), a standard evaluator of arterial stiffness, and carried out radial applanation tonometry (patients sitting and supine). The impact of reflected waves on the diastolic part of the aortic pressure waveform was quantified in the form of a diastolic augmentation index (dAix). RESULTS: : Across ages, sexes, and body position, there was an inverse relationship between the sAix and the dAix. When PWV and HR were added as covariates to a prediction model including age, sex and body position as main factors, the sAix was directly related to PWV (P < 0.0001) and inversely to HR (P < 0.0001). With the same analysis, the dAix was inversely related to PWV (P < 0.0001) and independent of HR (P = 0.52). CONCLUSION: : The dAix has the same degree of linkage to arterial stiffness as the more conventional sAix, while being immune to the confounding effect of HR. The quantification of diastolic aortic pressure augmentation by reflected waves could be a useful adjunct to pulse wave analysis.

Profound impact of uncomplicated pregnancy on diastolic, but not systolic pulse contour of aortic pressure

RESUME: L'objectif de cette étude était de déterminer l'impact de la grossesse non compliquée sur l'onde de pouls de la pression aortique centrale. Méthode 66 femmes au total avec une grossesse simple ont été réparties en trois groupes selon le stade de leur gestation: premier trimestre (T1, n=22), deuxième trimestre (T2, n=20) et troisième trimestre (T3, n=24). Le groupe contrôle (C, n=21) était constitué de femmes non enceintes, en bonne santé habituelle, prenant une contraception oestroprogestative. La tonométrie d'aplanation a été utilisée pour l'acquisition des ondes de pouls centrale un appareil disponible dans le commerce (SphygmoCor) permet l'enregistrement de l'onde de pouls périphérique avec un tonomètre d'aplanation de l'artère radiale au niveau du poignet, puis effectue sa transformation en sa forme centrale, grâce à une analyse de Fourrier et une fonction de transfert. L'influence des ondes réfléchies sur l'onde de pouls a été déterminée non seulement pendant la systole (augmentation systolique), comme on procède habituellement dans l'analyse de l'onde de pouls, mais aussi pendant la diastole (augmentation diastolique). Résultats Au cours de la grossesse, les pressions centrales systolique et diastolique sont restées inchangées et comparables aux valeurs mesurées chez les femmes qui ne sont pas enceintes. Dans le groupe contrôle, l'augmentation systolique s'élevait à 8.1±7.5% de la pression de pouls ; il n'y avait pas de différence statistiquement significative avec les valeurs obtenues chez les femmes enceintes, et ce, à n'importe quel stade de la grossesse (T1 : 4.6±11.4%, T2: 5.0±9.3%, T3 : 4.7±8.1%). Par contre, l'amplitude de l'augmentation diastolique diminuait avec la progression de la grossesse (C 6.5±2.4%, T1 : 5.2±3.1%, T2 : 3.8±2.6%; P=0.002 versus C; T3 : 2.3±2.0%; P<0.0001 versus C et P=0.004 versus T 1). Conclusion La grossesse ne modifie pas la forme de l'onde de pouls systolique centrale, ce qui implique de la part du système cardiovasculaire une adaptation fine à la demande croissante de flux sanguin, et ce, à tous les stades de la grossesse. Par contre, l'amplitude de l'onde de réflexion atteignant l'aorte pendant la diastole diminue progressivement au cours de la grossesse. Perspectives De récentes études montrent qu'une valeur anormalement haute de l'augmentation systolique de la pression centrale, comme on peut la déterminer avec la tonométrie d'aplanation, pourrait être un indice de trouble hypertensif de la grossesse débutant. Cette technique simple pourrait être d'autant plus facile à mettre en oeuvre si les valeurs normales pour l'augmentation systolique étaient indépendantes du stade de la grossesse, comme le suggèrent nos résultats, du moins pour les mesures prises en position assise.

Blood pressure response to central and/or peripheral inhibition of phenylethanolamine N-methyltransferase in normotensive and hypertensive rats

We studied the effects on blood pressure and heart rate of two different phenylethanolamine N-methyltransferase (PNMT) inhibitors in normotensive, in two-kidney renal hypertensive, and in deoxycorticosterone-salt (DOC-salt) hypertensive rats. One compound (SK&F 64139) blocks the conversion of norepinephrine to epinephrine in both the central and the peripheral nervous system, whereas the other (SK&F 29661) does not cross the blood-brain barrier and therefore is active mostly in the adrenal glands. In the rats given SK&F 29661, practically no acute blood pressure changes were in the adrenal glands. In the rats given SK&F 64139 induced only a minor blood pressure and heart rate response in normotensive and two-kidney renal hypertensive rats. However, in DOC-salt hypertensive rats, it reduced arterial pressure to approximately normal levels and concomitantly slowed pulse rate. There was a close correlation between the magnitude of the blood pressure response observed in all SK&F 64139-treated animals and the control plasma norepinephrine (4 = -0.795, P less than 0.001) and epinephrine (r = -0.789, P less than 0.001) levels. These results suggest an important role for central epinephrine in regulating the peripheral sympathoadrenomedullary and the baroreceptor reflex activity, particularly when the maintenance of the high blood pressure is not renin-dependent.

Evaluation de l'efficacite antihypertensive de l'isradipine SRO par enregistrement tensionnel en ambulatoire. [Evaluation of the antihypertensive efficacy of isradipine SRO as assessed by ambulatory blood pressure determination]

The calcium channel blocker isradipine has become recently available in a form with delayed release (isradipine SRO). The anti-hypertensive efficacy and tolerance of this preparation at a single daily dose of 5 mg was studied in 40 patients with uncomplicated essential hypertension over a period of 6 weeks. Blood pressure during office visits decreased under Isradipine SRO from 164/105 +/- 16/7 to 144/93 +/- 12/7 mmHg (mean +/- 1 standard deviation p < 0.001). Using ambulatory blood pressure recording we could show that antihypertensive efficacy of the new galenic form persisted over 24 hours. During the day the blood pressure dropped from 150/95 +/- 13/7 to 141/91 +/- 13/7 mmHg (p < 0.001), during the night from 131/85 +/- 13/3 to 121/81 +/- 15/9 mmHg (p < 0.001). Heart-rate was not changed by treatment and the drug was well tolerated. Isradipine SRO at a single dose is thus well suited for antihypertensive treatment.

Step count is associated with lower nighttime systolic blood pressure and increased dipping.

BACKGROUND: Higher nighttime blood pressure (BP) and the loss of nocturnal dipping of BP are associated with an increased risk for cardiovascular events. However, the determinants of the loss of nocturnal BP dipping are only beginning to be understood. We investigated whether different indicators of physical activity were associated with the loss of nocturnal dipping of BP. METHODS: We conducted a cross-sectional study of 103 patients referred for 24-hour ambulatory monitoring of BP. We measured these patients' step count (SC), active energy expenditure (AEE), and total energy expenditure simultaneously, using actigraphs. RESULTS: In our study population of 103 patients, most of whom were hypertensive, SC and AEE were associated with nighttime systolic BP in univariate (SC, r = -0.28, P < 0.01; AEE, r = -0.20, P = 0.046) and multivariate linear regression analyses (SC, coefficient beta = -5.37, P < 0.001; AEE, coefficient beta = -0.24, P < 0.01). Step count was associated with both systolic (r = 0.23, P = 0.018) and diastolic (r = 0.20, P = 0.045) BP dipping. Nighttime systolic BP decreased progressively across the categories of sedentary, moderately active, and active participants (125mm Hg, 116mm Hg, 112mm Hg, respectively; P = 0.002). The degree of BP dipping of BP increased progressively across the same three categories of activity (respectively 8.9%, 14.6%, and 18.6%, P = 0.002, for systolic BP and respectively 12.8%, 18.1%, and 22.2%, P = 0.006, for diastolic BP). CONCLUSIONS: Step count is continuously associated with nighttime systolic BP and with the degree of BP dipping independently of 24-hour mean BP. The combined use of an actigraph for measuring indicators of physical activity and a device for 24-hour measurement of ambulatory BP may help identify patients at increased risk for cardiovascular events in whom increased physical activity toward higher target levels may be recommended.

Blood pressure treatment in acute ischemic stroke: a review of studies and recommendations.

PURPOSE OF REVIEW: Elevated blood pressure (BP) is frequent in patients with acute ischemic stroke. Pathophysiological data support its usefulness to maintain adequate perfusion of the ischemic penumba. This review article aims to summarize the available evidence from clinical studies that examined the prognostic role of BP during the acute phase of ischemic stroke and intervention studies that assessed the efficacy of active BP alteration. RECENT FINDINGS: We found 34 observational studies (33,470 patients), with results being inconsistent among the studies; most studies reported a negative association between increased levels of BP and clinical outcome, whereas a few studies showed clinical improvement with higher BP levels, clinical deterioration with decreased BP, or no association at all. Similarly, the conclusions drawn by the 18 intervention studies included in this review (1637 patients) were also heterogeneous. Very recent clinical data suggest a possible beneficial effect of early treatment with some antihypertensives on late clinical outcome. SUMMARY: Observational and interventional studies of management of acute poststroke hypertension yield conflicting results. We discuss different explanations that may account for this and discuss the current guidelines and pathophysiological considerations for the management of acute poststroke hypertension.

Effect on blood pressure and the renin-angiotensin system of repeated doses of the converting enzyme inhibitor CGS 14824A.

A new, orally active angiotensin converting enzyme (ACE) inhibitor, CGS 14824A, was evaluated in 12 healthy male volunteers. Two groups each of 6 volunteers were given 5 or 10 mg once daily p.o. for 8 days. Four hours after the first and the last morning doses, plasma angiotensin II, aldosterone and plasma converting enzyme activity had fallen, while blood angiotensin I and plasma renin activity had risen. Throughout the study, more than 90% inhibition of ACE was found immediately before giving either the 5 or 10 mg dose and 50% blockade was still present 72 h following the last dose. Based on the determination of ACE, there was no evidence of drug accumulation. No significant change in blood pressure or heart rate was observed during the course of the study. CGS 14824A was an effective, orally active, long-lasting and well tolerated converting enzyme inhibitor.

Nitric ocide mediates the blood pressure response to mental stress in humans

Objectif : Le monoxyde d'azote (NO) régule la pression artérielle en modulant le tonus vasculaire périphérique et l'activité sympathique vasoconstrictrice. La synthèse du NO est altérée dans plusieurs maladies cardiovasculaires importantes. La perte de l'effet vasodilatateur du NO et de son effet freinateur sur la décharge sympathique pourrait entraîner une réponse vasopressive exagérée au stress mental. Méthodes : Nous avons donc comparé les réponses sympathique (activité nerveuse musculaire sympathique) et hémodynamique au stress mental pendant une perfusion isotonique de NaCI et lors de l'administration d'un inhibiteur systémique de la NO- synthase (NG-monomethyl-L-arginine, L-NMMA). Résultats : Le résultat principal est que le stress mental qui pendant la perfusion saline augmente l'activité nerveuse sympathique d'environ 50% et la pression artérielle moyenne d'environ 15%, n'a eu aucun effet sympathoexcitateur et vasopresseur détectable lors de la perfusion de L-NMMA. Ces observations ne sont pas liées à une atteinte généralisée de la réponse hémodynamique et/ou sympathique lors de la perfusion de L-NMMA, car ces réponses étaient conservées lors de l'immersion de la main dans de l'eau glacée. Conclusions : Le stress mental induit des effets vasopresseurs et sympathoexcitateurs chez l'homme qui sont médiés par le NO. Ces résultats laissent penser que, contrairement à ce qui a été généralement supposé, le NO peut dans certaines circonstances augmenter la pression artérielle in vivo.