Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 15, Number 3, 2009


Contents


Central Hemodynamics and Arterial Stiffness: Methodological, Clinical and Pharmaceutical Considerations
Executive Editor: T.G. Papaioannou


Editorial: Pp. 243-244


Non-Invasive Methods and Techniques for Central Blood Pressure Estimation: Procedures, Validation, Reproducibility and Limitations Pp. 245-253
T.G. Papaioannou, A.D. Protogerou, K.S. Stamatelopoulos, M. Vavuranakis and C. Stefanadis
[Abstract] [Purchase Article] [PMID: 19149616 PubMed - indexed for MEDLINE]


Is there any Additional Prognostic Value of Central Blood Pressure Wave Forms Beyond Peripheral Blood Pressure? Pp. 254-266
M. Sabovic, M.E. Safar and J. Blacher
[Abstract] [Purchase Article] [PMID: 19149615 PubMed - indexed for MEDLINE]


The Effect of Antihypertensive Drugs on Central Blood Pressure Beyond Peripheral Blood Pressure. Part I: (Patho)-Physiology, Rationale and Perspective on Pulse Pressure Amplification Pp. 267-271
A.D. Protogerou, T.G. Papaioannou, J.P. Lekakis, J. Blacher and M.E. Safar
[Abstract] [Purchase Article] [PMID: 19149617 PubMed - indexed for MEDLINE]


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 Pp. 272-289
A.D. Protogerou, G.S. Stergiou, C. Vlachopoulos, J. Blacher and A. Achimastos
[Abstract] [Purchase Article] [PMID: 19149618 PubMed - indexed for MEDLINE]


Anti-Inflammatory Drugs and Statins for Arterial Stiffness Reduction Pp. 290-303
K.M. Mäki-Petäjä and I.B. Wilkinson
[Abstract] [Purchase Article] [PMID: 19149619 PubMed - indexed for MEDLINE]


Actions of Selected Cardiovascular Hormones on Arterial Stiffness and Wave Reflections Pp. 304-320
W.W. Nichols and B.J. Epstein
[Abstract] [Purchase Article] [PMID: 19149620 PubMed - indexed for MEDLINE]


Red Wine, Arterial Stiffness and Central Hemodynamics Pp. 321-328
K. Karatzi, T.G. Papaioannou, C. Papamichael, J. Lekakis, C. Stefanadis and A. Zampelas
[Abstract] [Purchase Article] [PMID: 19149621 PubMed - indexed for MEDLINE]


Targeting Redox Signaling in the Vascular Wall: From Basic Science to Clinical Practice Pp. 329-342
C. Antoniades, A.S. Antonopoulos, J.K. Bendall and K.M. Channon
[Abstract] [Purchase Article] [PMID: 19149622 PubMed - indexed for MEDLINE]




Abstracts



[Back to top]
Editorial: Central Hemodynamics and Arterial Stiffness: Methodological, Clinical and Pharmaceutical Considerations

Arterial stiffness and central hemodynamics is a “hot” topic with increasing research and clinical interest. There is now ample evidence supporting that arterial stiffness and central hemodynamic indices have an independent predictive value for cardiovascular events and mortality. The present issue of Current Pharmaceutical Design is mainly focused on pathophysiology and treatment of arterial stiffness and central hemodynamics.

The development of new technologies for the non-invasive assessment of central blood pressure (BP) and arterial stiffness has allowed their widespread evaluation. Although several methods now exist for non-invasive estimation of central BP, current technologies are still under evaluation and several technical and methodological issues are debated. In this issue, several methods and technologies currently available for the assessment of central BP are reviewed. Methodological and technical procedures as well as their accuracy, reproducibility and limitations are presented and discussed [1].

The article of Sabovic, Safar and Blacher [2] aims to answer two crucial questions regarding the clinical value of central BP. First, is central BP better than brachial BP as a predictor of cardiovascular (CV) outcome?; and second, can the improvement of central BP result in concomitant reduction in CV events? For centuries, the assessment of BP was based exclusively on measurements of peripheral (brachial) BP. However, there is now a growing interest in the investigation of central (aortic) BP, since it is now accepted that central hemodynamics, reflected by central pressure wave forms and arterial stiffness, can provide new and better insight into the pathophysiology of cardiovascular disorders associated with ageing, hypertension, diabetes, as well as end-stage renal disease. The article of Sabovic et al., provide the pathophysiology and the predictive role of central pressure wave forms for cardiovascular events that are beyond peripheral BP. Crucially, they review data supporting the view that improvement of central BP can result to a reduction of cardiovascular events.

Protogerou et al., in the first part of their review [3] deal with the mechanisms underlying the genesis and recording of BP difference between central and peripheral arteries (pressure amplification). In addition, the rationale of differential effect of antihypertensive drugs on pressure amplification is discussed. Finally, the pathophysiological role of pressure amplification on CV disease as well as its clinical and research implications are presented. In the second part of their review, Protogerou et al. [4], summarize and discuss the so far available evidence regarding the specific class-effect of antihypertensive drugs on central BP beyond peripheral BP, as well as the potential underlying hemodynamic mechanisms. Also a head to head comparison of the effect of different classes of antihypertensive drugs on central BP is being made, while the effect of combination drug treatment on central BP is discussed. Finally, the authors attempt an extrapolation of the above evidence on the results and conclusions derived from large epidemiological studies based on peripheral BP recording [4].

There is a strong body of evidence demonstrating that arterial stiffness is an independent predictor of cardiovascular outcome. Mean arterial pressure and changes in the arterial wall properties are the main factors regulating stiffness; however it has become apparent that inflammation also plays an important role in arterial stiffening. Numerous small-scale interventional studies have demonstrated that inflammation-reduction either by traditional anti-inflammatory drugs or with cholesterol-reduction therapies, ameliorates arterial stiffness in numerous patient groups. Mäki-Petäjä and Wilkinson [5], explored the published data investigating the role of inflammation on arterial stiffening and review the results from the studies investigating the effect of anti-inflammatory drugs and statins on arterial stiffness. Finally, they discuss the potential mechanisms by which these drugs may reduce arterial stiffness.

The article of Nichols and Epstein [6] is aimed at highlighting the importance of arterial stiffness and wave reflections, reviewing the impact of various hormones on arterial structure and function, and also reviewing what is known about the impact of drug therapy on arterial properties and wave reflection [6].

Food and drinks or other nutritional factors that might influence arterial stiffness and central hemodynamics are of great importance, since there might be natural substances with beneficial influence on heart and vessel function like those found in red wine (mainly ethanol and antioxidants). The effect of red wine on central hemodynamics has been partially explored with divergent results. It seems that data regarding the possible consequences of acute and long – term intake on arterial stiffness, wave reflections and central BP are limited and sometimes unclear. Karatzi et al. [7], gathered and discuss all the existing data regarding the effects of red wine consumption on arterial stiffness and central hemodynamics.

Antoniades et al. [8], provide an overview of reactive oxygen species (ROS) physiology in human vessels. They describe the sources of vascular oxidative stress and seek to highlight the effects of ROS on vascular redox signaling and vascular homeostasis. Finally, the possible therapeutic strategies for targeting redox signaling in the vascular wall at a clinical level are discussed.

There is now a great body of evidence supporting the relation of arterial stiffness and central hemodynamics with cardiovascular risk and mortality. The ultimate objective in many clinical and experimental studies and a great future challenge is the investigation of drugs that can reduce central BP and arterial stiffness independently from the peripheral BP response, resulting to an additional reduction of cardiovascular risk and mortality.

References
[1] Papaioannou TG, Protogerou AD, Stamatelopoulos KS, Vavuranakis M, Stefanadis C. Non-invasive methods and techniques for central blood pressure estimation: procedures, validation, reproducibility and limitations. Curr Pharm Des 2009; 15(3): 245-253.

[2] Sabovic M, Safar ME, Blacher J. Is there any additional prognostic value of central blood pressure wave forms beyond peripheral blood pressure? Curr Pharm Des 2009; 15(3): 254-266.

[3] Protogerou AD, Papaioannou TG, Lekakis JP, Blacher J, Safar ME. The effect of antihypertensive drugs on central blood pressure beyond peripheral blood pressure. Part I: (Patho)-physiology, rationale and perspective on pulse pressure amplification. Curr Pharm Des 2009; 15(3): 267-271.

[4] Protogerou AD, Stergiou GS, Vlachopoulos C, Blacher J, Achimastos A. 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 Curr Pharm Des 2009; 15(3): 272-289.

[5] Mäki-Petäjä KM, Wilkinson IB. Anti-inflammatory drugs and statins for arterial stiffness reduction. Curr Pharm Des 2009; 15(3): 290-303.
[6] Nichols WW, Epstein BJ. Actions of selected cardiovascular hormones on arterial stiffness and wave reflections Curr Pharm Des 2009; 15(3): 304-320.

[7] Karatzi K, Papaioannou TG, Papamichael C, Lekakis J, Stefanadis C, Zampelas A. Red wine, arterial stiffness and central hemodynamics. Curr Pharm Des 2009; 15(3): 321-328.

[8] Antoniades C, Antonopoulos AS, Bendall JK, Channon KM. Targeting redox signaling in the vascular wall: From basic science to clinical practice. Curr Pharm Des 2009; 15(3): 329-342.


Theodore G. Papaioannou and
Christodoulos Stefanadis
1st Dept. of Cardiology
Hippokration Hospital
Medical School
National & Kapodistrian University of Athens
Greece
Fax: 0030 210 8254791
E-mail: theopap@mail.ntua.gr


[Back to top] [Purchase Article] [PMID: 19149616 PubMed - indexed for MEDLINE]
Non-Invasive Methods and Techniques for Central Blood Pressure Estimation: Procedures, Validation, Reproducibility and Limitations
T.G. Papaioannou, A.D. Protogerou, K.S. Stamatelopoulos, M. Vavuranakis and C. Stefanadis

Hypertension is a major risk factor for a wide range of cardiovascular diseases and is typically identified by measuring blood pressure (BP) at the brachial artery. Although such a measurement may accurately determine diastolic BP, it does not accurately reflect systolic BP. This is mainly attributed to the fact that blood pressure waveform is distorted as it travels outward from the heart due to the presence of wave reflections from the peripheral arteries. Due to this distortion, blood pressure measured at the brachial artery provides an inaccurate measure of central aortic systolic pressure. However, central systolic BP is an important factor determining cardiac function and work, while central diastolic BP may determine coronary flow. Consequently central (aortic and carotid) pressures are pathophysiologically more relevant than peripheral pressures and thus their non-invasive accurate estimation is challenging and clinically necessary. The purpose of this review is to present methods and techniques that are used for the estimation of central blood pressures and to describe and discuss issues regarding methodological procedures, reproducibility, validity and limitations.


[Back to top] [Purchase Article] [PMID: 19149615 PubMed - indexed for MEDLINE]
Is there any Additional Prognostic Value of Central Blood Pressure Wave Forms Beyond Peripheral Blood Pressure?
M. Sabovic, M.E. Safar and J. Blacher

For a long time the consideration of blood pressure was based exclusively on measurements of peripheral (brachial) blood pressure. However, there is now a growing interest in the investigation of central (aortic) pressure. There is increasing awareness that the central hemodynamics, reflected by central pressure wave forms and arterial stiffness, can provide new and better insight into the pathophysiology of cardiovascular disorders associated with ageing, hypertension, diabetes, as well as end-stage renal disease. Understanding the concept of arterial stiffness, elevated central blood pressure and pulse pressure has given a new view on the mechanisms of target organ damage and their prevention and treatment. Hence, the measurements of arterial stiffness and central blood pressure, and not only peripheral pressure, have been performed in a few recent interventional trials. Not surprisingly, it was found that observed disparity in cardiovascular events obtained by different antihypertensive drugs might be attributed to their diverse effect on central pressure wave forms, despite similar control of peripheral blood pressure. Putting all currently available data together it appears certainly that there is an additional prognostic value of central pressure wave forms beyond peripheral blood pressure. The aim of this article is to provide the pathophysiology and predictive role for cardiovascular events of central pressure wave forms that are beyond peripheral blood pressure. Crucially, we will review data supporting the view that improvement of central blood pressure can result in reduction of cardiovascular events. Lastly, the future perspectives in this exciting and promising field will be presented.


[Back to top] [Purchase Article][PMID: 19149617 PubMed - indexed for MEDLINE]
The Effect of Antihypertensive Drugs on Central Blood Pressure Beyond Peripheral Blood Pressure. Part I: (Patho)-Physiology, Rationale and Perspective on Pulse Pressure Amplification
A.D. Protogerou, T.G. Papaioannou, J.P. Lekakis, J. Blacher and M.E. Safar

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 antihype-tensive drugs affect peripheral and central BP differentially and alter pressure amplification. In the present review (Part I) we deal with the mechanisms underlying: (i) the genesis and recording of BP difference between central and peripheral arteries (pressure amplification), (ii) the rational of differential effect of antihypertensive drugs on pressure amplification, (iii) the pathophysiological role of pressure amplification on cardiovascular disease as well as its clinical and research implications.


[Back to top] [Purchase Article][PMID: 19149618 PubMed - indexed for MEDLINE]
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
A.D. Protogerou, G.S. Stergiou, C. Vlachopoulos, J. Blacher and A. Achimastos

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.


[Back to top] [Purchase Article] [PMID: 19149619 PubMed - indexed for MEDLINE]
Anti-Inflammatory Drugs and Statins for Arterial Stiffness Reduction
K.M. Mäki-Petäjä and I.B. Wilkinson

Arterial stiffness is a powerful predictor of cardiovascular outcome in various patient groups as well as in general population, and can directly accelerate the atherosclerotic process. Arterial stiffness is regulated by numerous factors. Traditionally, mean arterial pressure and structural changes in the components of arterial wall were thought to be main determinants of arterial stiffness, however it is now recognized that arterial stiffness is also regulated by the smooth muscle tone and that endothelium derived mediators, such as NO, contribute to the functional regulation of arterial stiffness. It has also become apparent that inflammation has an important role in the stiffening of the large arteries, possibly via changes in the composition of the arterial wall due to inflammatory cell infiltration or via endothelial dysfunction.

Recently, numerous small scale interventional studies have looked into the possibility of using anti-inflammatory and cholesterol-reduction therapies with anti-inflammatory properties as a means to reduce arterial stiffness and therefore cardiovascular risk. Anti-inflammatory therapies, such as corticosteroids and anti-TNF alpha therapy have been shown to reduce arterial stiffness in patients with chronic inflammatory conditions. In addition, statins and other cholesterol-reducing agents have been shown to have beneficial effects on wave reflection and aortic stiffness reduction in several patient groups.

This review aims to explore the studies investigating the role of inflammation on arterial stiffening and to review the results from the studies investigating the effect of anti-inflammatory drugs and statins for arterial stiffness reduction and finally, to discuss the potential mechanisms by which these drugs may reduce arterial stiffness.


[Back to top] [Purchase Article] [PMID: 19149620 PubMed - indexed for MEDLINE]
Actions of Selected Cardiovascular Hormones on Arterial Stiffness and Wave Reflections
W.W. Nichols and B.J. Epstein

The large conduit arteries of the thorax and abdomen are elastic while those in the arms and legs are muscular. Alterations in wall properties of elastic arteries occur over time and are usually permanent in nature; acute changes can, however, occur is response to a change in transmural pressure. Chronic alterations in properties of muscular arteries are minimal but changes (e.g vasoconstriction, vasodilation or tone) do occur in response to smooth muscle cell (SMC) stimulation. In general an increase in arterial stiffness (and wave reflection) increases systolic blood pressure (BP) and is detrimental while a decrease is beneficial. The augmentation in systolic BP increases left ventricular (LV) mass, wasted energy, tension-time index (TTI) and myocardial oxygen demand while the fall in diastolic BP decreases coronary artery perfusion causing a mismatch in ventricular/vascular coupling and an imbalance in the myocardial oxygen supply/demand ratio. Cardiovascular hormones such as renin, angiotensin, aldosterone, parathormone, sympathomimetic amines and endothelin induce vasoconstriction and increase arterial stiffness while insulin, thyroxine, testosterone, atrial natriuretic peptide (ANP), estrogen and nitric oxide (NO) have the opposite effect. The undesirable effects can be reversed with selected blocking agents. Vasodilator drugs have little direct active effect on large elastic arteries and unaugmented BP but can markedly reduce wave reflection amplitude and duration and augmentation index by decreasing stiffness of the muscular arteries and reducing transmission velocity of the reflected wave from the periphery to the heart. This decrease in amplitude and increase in travel time (or delay) of the reflected wave causes a generalized decrease in systolic BP, arterial wall stress, wasted LV energy and TTI.


[Back to top] [Purchase Article] [PMID: 19149621 PubMed - indexed for MEDLINE]
Red Wine, Arterial Stiffness and Central Hemodynamics
K. Karatzi, T.G. Papaioannou, C. Papamichael, J. Lekakis, C. Stefanadis and A. Zampelas

Red wine is considered to reduce cardiovascular risk and decrease peripheral systolic and diastolic blood pressure. Central aortic pressures are often more sensitive clinical and prognostic factors than peripheral pressures, while arterial stiffness is an independent prognostic factor for cardiovascular events.

Great efforts are being made to find natural sources of improving health. In order to clarify the mechanisms under which a widely used drink, like red wine, is affecting heart and vessels, we aimed to review the available data regarding the effects of red wine on arterial stiffness, wave reflections and central blood pressures.

The effect of red wine on central hemodynamics has been poorly explored with divergent results. Possible consequences of acute and long - term intake on arterial stiffness, wave reflections and central pressures are not clear. This might make someone skeptical when suggesting the consumption of a glass of red wine, although its cardioprotective actions (when moderately consumed) are already shown from epidemiological studies.


[Back to top] [Purchase Article] [PMID: 19149622 PubMed - indexed for MEDLINE]
Targeting Redox Signaling in the Vascular Wall: From Basic Science to Clinical Practice
C. Antoniades, A.S. Antonopoulos, J.K. Bendall and K.M. Channon

Oxidative stress is a key feature in vascular homeostasis. Reactive oxygen species (ROS) are produced by multiple enzymatic sources located in various anatomical structures of the vascular wall, such as the vascular endothelium, the smooth muscle cells and inflammatory cells infiltrating sub-endothelial space and the rest of the vascular wall. Although ROS behave as signaling molecules regulating important aspects of vascular physiology, their excess generation is harm-ful. Further to the cytotoxic effect of ROS in the vascular wall, they also activate various redox sensitive transcription pathways, regulating the expression of proinflammatory molecules with strong pro-atherogenic effects. The activation of redox-sensitive enzymatic systems in the vascular wall such as matrix metalloproteinases as well as the impairment of endothelial function have a significant impact on vascular elasticity and vascular mechanics in general. The impairment of vascular mechanics has a significant impact on vascular homeostasis, promoting atherogenesis. It is therefore crucial to regulate vascular redox signaling, by developing therapeutic strategies able to target the effectively intracellular ROS bioavailability. Statins, angiotensin converting enzyme inhibitors, thiazolidinediones, folates, tetrahydrobiopterin and other therapeutic strategies seem promising in targeting vascular redox signaling, although it is still unclear which of these treatments have the potential to effectively prevent atherogenesis. Future studies need to define the key redox sensitive pathways in the vascular wall in order to develop effective therapeutic strategies against atherosclerosis.