Hemodynamic measurements in coronary, valvular, and peripheral vascular disease : the role of the medical engineer in a cardiovascular department of a non-academic heart center

(1)

Hemodynamic measurements in coronary, valvular, and

peripheral vascular disease : the role of the medical engineer

in a cardiovascular department of a non-academic heart

center

Citation for published version (APA):

Veer, van 't, M. (2008). Hemodynamic measurements in coronary, valvular, and peripheral vascular disease : the role of the medical engineer in a cardiovascular department of a non-academic heart center. Technische

Universiteit Eindhoven. https://doi.org/10.6100/IR638545

DOI:

10.6100/IR638545

Document status and date: Published: 01/01/2008 Document Version:

Publisher’s PDF, also known as Version of Record (includes final page, issue and volume numbers) Please check the document version of this publication:

• A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. People interested in the research are advised to contact the author for the final version of the publication, or visit the DOI to the publisher's website.

• The final author version and the galley proof are versions of the publication after peer review.

• The final published version features the final layout of the paper including the volume, issue and page numbers.

Link to publication

General rights

Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain

• You may freely distribute the URL identifying the publication in the public portal.

If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement:

www.tue.nl/taverne

Take down policy

If you believe that this document breaches copyright please contact us at:

openaccess@tue.nl

providing details and we will investigate your claim.

(2)

in coronary, valvular, and

peripheral vascular disease

The role of the Medical Engineer in a cardiovascular

department of a non-academic heart center

(3)

Copyright c 2008 by M. van ’t Veer

All rights reserved. No part of this book may be reproduced, stored in a database or retrieval system, or published, in any form or in any way, electronically, mechanically, by print, photoprint, microfilm, or any other means without prior written permission of the author.

Cover design by Oranje Vormgevers, Eindhoven, The Netherlands. After the idea of Mariska van ’t Veer, Wageningen, The Netherlands

Printed by Drukkerij De Budelse, Budel, The Netherlands.

The research described in this thesis was financially supported by educational grants of Stichting Vrienden van het Hart, Eindhoven, The Netherlands; RADI Medical Systems, Uppsala, Sweden; Medtronic, Heerlen, The Netherlands ; Cordis, Roden, The Netherlands; and of the Wetenschappelijk Fonds Catharina Ziekenhuis, Eindhoven, The Netherlands.

(4)

in coronary, valvular, and

peripheral vascular disease

The role of the Medical Engineer in a cardiovascular

department of a non-academic heart center

PROEFSCHRIFT

ter verkrijging van de graad van doctor aan de Technische Universiteit Eindhoven,

op gezag van de Rector Magnificus, prof.dr.ir. C.J. van Duijn, voor een commissie aangewezen door het College voor Promoties

in het openbaar te verdedigen op donderdag 18 december 2008 om 16.00 uur

door

Marcel van ’t Veer

(5)

en

prof.dr.ir. F.N. van de Vosse

Copromotor: dr.ir. M.C.M. Rutten

(6)

Men zegt dat geluk geen meervoud heeft. Ik vind van wel.

(7)

(8)

1 Introduction 1 1.1 Hemodynamic measurements in the

cardiovascular system . . . 1

1.2 The Medical Engineer . . . 2

1.3 Outline of this thesis . . . 3

2 Degenerative diseases of the cardiovascular system 5 2.1 Coronary artery disease . . . 5

2.1.1 Pathophysiology . . . 5

2.1.2 Anatomic assessment of the coronary circulation . . . 6

2.1.3 Physiologic assessment of the coronary circulation . . . 6

2.1.4 Treatment . . . 9

2.2 Valvular disease. The aortic valve . . . 10

2.2.1 Clinical assessment . . . 11

2.2.2 Treatment . . . 11

2.3 Peripheral vascular disease. The Abdominal Aortic Aneurysm . . . 13

2.3.1 Anatomic assessment. The diameter criterium . . . 13

2.3.2 Physiologic assessment. Hemodynamic measurements . . . 14

3 Hemodynamic evaluation of coronary stents 15 3.1 Introduction . . . 16 3.2 Methods . . . 16 3.2.1 Study population . . . 16 3.2.2 Interventional protocol . . . 18 3.2.3 Hemodynamic analysis . . . 18 3.2.4 Angiographic analysis . . . 19 3.2.5 Statistical analysis . . . 20 3.3 Results . . . 20

3.3.1 Baseline characteristics and procedural results . . . 20

3.3.2 Clinical follow-up at 6 months . . . 20

3.3.3 Angiographic follow-up at 6 months . . . 22

3.3.4 Hemodynamic follow-up and WSS at 6 months . . . 22

3.4 Discussion . . . 22

(9)

3.4.1 Limitations . . . 26

3.5 Conclusions . . . 26

4 Influence of orientation of mechanical bi-leaflet valve prosthesis on coronary perfusion pressure 31 4.1 Introduction . . . 32

4.2 Materials and Methods . . . 33

4.2.1 Study population . . . 33

4.2.2 Echocardiography . . . 34

4.2.3 Surgical procedure . . . 34

4.2.4 Catheterisation at follow-up . . . 34

4.2.5 Data analysis and statistical analysis . . . 36

4.3 Results . . . 36 4.3.1 Procedural results . . . 36 4.3.2 Echocardiographic results . . . 38 4.3.3 Hemodynamic measurements . . . 38 4.4 Discussion . . . 40 4.4.1 Limitations . . . 42 4.5 Conclusion . . . 42

5 Continuous infusion thermodilution for assessment of coronary flow: Theoretical background and in-vitro validation 43 5.1 Introduction . . . 44

5.2 Methodology . . . 45

5.2.1 Theoretical background and measurement principle . . . 45

5.2.2 In-vitromodel and instrumental set-up . . . 46

5.2.3 Measurement protocol . . . 47

5.3 Results . . . 49

5.3.1 Temperature course of guide wire pullback . . . 49

5.3.2 Flow measurement at fixed position . . . 49

5.5 Conclusion . . . 54

5.5.1 Clinical implications . . . 54

6 Continuous infusion thermodilution for assessment of coronary flow: Animal study 55 6.1 Introduction . . . 56

6.2 Theoretical background and aim . . . 56

6.3.1 Animal instrumentation . . . 57 6.3.2 Cardiac catheterisation . . . 57 6.3.3 Experimental protocol . . . 59 6.3.4 Measurement procedure . . . 59 6.3.5 Statistical analysis . . . 62 6.4 Results . . . 62

(10)

6.4.1 Hemodynamic characteristics and procedural results . . . 62 6.4.2 Flow measurements . . . 62 6.5 Discussion . . . 66 6.5.1 Limitations . . . 67 6.5.2 Clinical implications . . . 68 6.6 Conclusion . . . 68

7 Continuous infusion thermodilution for assessment of coronary flow: Human study 71 7.1 Introduction . . . 72

7.2 Theoretical background and aim . . . 72

7.3.1 Patient selection . . . 72

7.3.2 Cardiac catheterisation and experimental protocol . . . 73

7.3.3 Measurement procedure . . . 75

7.3.4 Statistical analysis . . . 77

7.4 Results . . . 77

7.4.1 Baseline characteristics and procedural results . . . 77

7.4.2 Flow measurements . . . 78

7.5.2 Clinical implications . . . 83

8 Biomechanical properties of abdominal aortic aneurysms assessed by simultaneously measured pressure and volume changes in humans 85 8.1 Introduction . . . 86

8.2 Methods . . . 87

8.2.1 Study population . . . 87

8.2.2 Magnetic Resonance Imaging . . . 87

8.2.3 Pressure measurement . . . 87

8.2.4 Detection of volume changes . . . 88

8.2.5 Biomechanical properties of the AAA . . . 88

8.3 Results . . . 89

8.3.1 Baseline characteristics and clinical results . . . 89

8.3.2 Aneurysmal volume change and mechanical properties . . . 89

8.3.3 Invasive and non-invasive blood pressure . . . 90

9 General discussion and conclusions 97 9.1 Hemodynamic measurements . . . 97

9.2 The Medical Engineer . . . 100

(11)

References 102 Summary 113 Samenvatting 117 Dankwoord 121 Curriculum Vitae 123 Publications 125

(12)

Introduction

1.1 Hemodynamic measurements in the

cardiovascular system

Development in health care is mainly focussed on improving patient care. Technical improvements in this field have led to better methods for diagnosis and treatment of many diseases. As an example, vast improvements in imaging techniques have contributed to the ability to analyze anatomic structures in more detail as well as to perform several functional measurements. Furthermore, ongoing developments and miniaturization of sensors enable (invasive) hemodynamic measurements throughout the cardiovascular system.

For the cardiovascular system both imaging techniques and hemodynamic mea-surements play a central role in the diagnosis and treatment of a number of pathologic conditions. One such condition is atherosclerotic coronary artery disease (CAD). Presently, the coronary angiogram is most often used to detect coronary abnormalities. However, the angiogram only offers an anatomic view of the extent of the coronary artery disease. Hence, the functional severity cannot be assessed using angiography alone. Guide wire mounted sensors have enabled functional assessment of epicardial coronary artery disease, but challenges remain to assess microvascular dysfunction.

Functional assessment is also embedded in daily practice to assess valvular disease. Doppler-echocardiography is used to perform physiologic measurements in addition to anatomic measurements of structures in the heart. This allows the physician to non-invasively estimate the functional severity of valvular pathology and to assess the function of a valvular prosthesis at follow-up whenever valve replacement has taken place. The question whether different methods of aortic valve replacement have effect on coronary physiology cannot directly be answered using standard techniques and requires dedicated hemodynamic measurements.

Comparable to detection of CAD, a purely anatomy-based approach is used in the determination of peripheral vascular disease as well. A relatively common vascular

(13)

disorder is an abdominal aortic aneurysm (AAA). The risk of a AAA is rupture, associated with a high mortality rate. Rupture risk stratification of AAAs is often based on measurement of maximal diameter alone determined from computed tomography (CT), ultrasound (US), or magnetic resonance imaging (MRI) scans. Such a anatomy-based cut-off value does not take hemodynamic and bio-mechanical parameters into account. To determine these parameters both imaging of the AAA and hemodynamic measurements are required.

New methods for diagnosis and treatment improve healthcare but also raise new research questions. Hemodynamic measurements in combination with standard diagnostic methods are complementary to answer such questions, specifically in the cardiovascular disease.

1.2 The Medical Engineer

Generally, advanced techniques for acquiring and analyzing data have made health care increasingly complex. Medical engineers might have an additive value in the analyses of the extensive amounts of acquired data using mathematical models to, e.g., understand underlying (pathologic) processes of a disease/phenomenon or predict the outcome of an intervention. As a consequence, these engineers should have profound knowledge of the biologic and physiologic side of the problem as well as the capabilities to understand the physical processes and the way these processes are described using mathematical models. From this perspective there is a need for medical engineers that are capable of objectively processing data using mathematical or computer aided models to support clinical decision making.

The Department of Biomedical Engineering of the Eindhoven University of Tech-nology educates (bio)medical engineers. Besides engineering skills, like planning, performing, and evaluating scientific experiments, a medical engineer learns to quantify and objectify patient data as well. Additionally, model based problem solving is part of the basic skills.

The training of a medical engineer, however, has special demands for communi-cation, research methods, and interpretation of obtained results. The communication skills are opportune e.g., towards physicians to translate medical research questions into engineering ones (and vice versa). Medical research questions often ensue from practical issues in daily practice whereas biomedical questions mostly aim to answer research questions that deal with the fundamental underlying processes. To be able to function as a bridge between clinical research and more fundamental science, a medical engineer should have the above mentioned engineering competencies at his disposal but also sufficient clinical knowledge.

In performing research at the cutting edge of life sciences and engineering, also ethical issues play an important role in the choice for research methods. Moreover, especially in a non-academic hospital with high patient load, proper planning of experiments is needed to minimize interference with daily practice.

(14)

1.3 Outline of this thesis

This thesis describes a number of research projects that focus on the sometimes complex background of investigational techniques and accompanying interpretation of hemodynamic measurements. Besides the separate projects that aimed to answer specific research questions that arose from clinical practice, the overall goal was to establish the role of the medical engineer in stimulating, initiating, and executing clinical experimental research using hemodynamical measurements in the cardiovascular system. The projects have been performed at the department of Biomedical Engineering of the Eindhoven University of Technology and at the departments of cardiology, cardiothoracic surgery, and vascular surgery of the Catharina Hospital in Eindhoven, which is one of the largest cardiovascular centers in Europe. Because hemodynamic measurements in several pathologic conditions are the main focus in each chapter a general introduction in degenerative diseases of the cardiovascular system is first given inchapter 2.

Chapter 3 describes a study performed at the department of cardiology in which the hemodynamic characteristics of two different types of coronary stents were compared at implantation and at six-month follow-up. So far, only anatomic data had been available for comparison of these stents.

In cooperation with the department of cardiothoracic surgery, the study described in chapter 4 was performed to answer the question whether the orientation of a mechanical heart valve prosthesis could influence coronary physiology both in resting conditions and during exercise.

Being able to measure absolute coronary blood flow, has been a holy grail in cardiology for more than 40 years. Measuring absolute coronary blood flow as well as coronary pressure simultaneously would mean a great step forward in understanding coronary physiology. In chapter 5 the validation of a such technique based on thermodilution is described, which was developed at the department of Biomedical Engineering of the Eindhoven University of Technology. The technique was validated in-vivoin dogs in the Central Animal Laboratory of the University of Maastricht and soon thereafter tested and applied in the catheterisation laboratory of the Catharina Hospital Eindhoven. The animal study is described inchapter 6 and the human study is described inchapter 7.

In chapter 8 a research project is described to estimate global bio-mechanical properties of the wall of the aorta in-vivo in patients with an abdominal aortic aneurysm. Simultaneous aneurysmal volume and intra-vascular blood pressure measurements were carried out. This study was achieved in close collaboration with the departments of vascular surgery and radiology.

A general discussion is presented inchapter 9 and the role of the medical engineer is a large heart center is discussed.

(15)

(16)

Degenerative diseases of the

cardiovascular system

Despite the ability of the human body to adapt to pathologic conditions of the cardiovascular system to a certain extent, catheter based or surgical intervention might eventually be inevitable. The decision to intervene is often based on anatomic assessment and not on hemodynamic measures to determine the severity of the disease. A basic overview of different degenerative processes and their hemodynamic consequences throughout the cardiovascular system is outlined in this chapter.

The most important degenerative process in the human circulation is atherosclero-sis, affecting both large and small arteries and the microvasculature. Atherosclerosis has various manifestations throughout the vascular system. It is generally believed that atherosclerosis plays an important role in the initiation and the progression of atherosclerotic plaques. Despite the fact that the first signs of atherosclerosis are observed in adolescents, the disease is usually slowly progressing and symptoms typically occur a few decades later.

2.1 Coronary artery disease

When atherosclerosis affects the coronary arteries, atherosclerotic plaques cause local or diffuse narrowings throughout the coronary arteries. As a result of these narrowings coronary blood flow can become impaired, which consequently leads to myocardial ischemia.

2.1.1 Pathophysiology

Myocardial ischemia is the result of an imbalance between the oxygen demand and the oxygen supply to the heart muscle. The coronary arteries supply the heart with oxygen and nutrients and arise just above the aortic valve (figure 2.1). The epicardial arteries (∅ 2.5-4 mm) branche into smaller arteries and arterioles to eventually form

(17)

a network of capillaries. Vessels with a diameter >0.4 mm, are defined as conductive vessels or conduit vessels (Pijls and DeBruyne, 2000, chapter 2). Vessel with a diameter between 100 and 400 µm are called pre-arterioles, whereas vessels <100µm are called arterioles. Together these vessels form the resistive vessels (Chilian et al., 1989). The branching continues until thin walled capillaries are formed that perfuse the myocardium(∅ 5 µm). Here the actual exchange of oxygen, nutrients, and waste products takes place.

In a normal coronary system the conductive vessels offer negligible resistance to blood flow compared to the microcirculation (vessels <200µm). The resistance of the coronary circulation, here defined as the mean pressure difference over the myocardium divided by the mean myocardial flow, is mainly regulated by the vascular tone of the arterioles. Therefore coronary blood flow is primarily determined by variations in resistance of these vessels. Depending on the demand of oxygen, values of blood flow can increase by a factor 5 during exercise compared to resting (baseline) conditions in healthy humans. This regulatory mechanism can also compensate for resistances caused by a stenosis in the epicardial vessels. The compensation in arteriolar resistance will, however, be at the cost of maximal achievable flow. This explains why, especially during exercise, patients might experience chest pain as the result of myocardial ischemia.

2.1.2 Anatomic assessment of the coronary circulation

Usually, patients with typical chest pain eventually undergo a cardiac catheterisation. During cardiac catheterisation a guiding catheter is introduced through which contrast dye is injected to visualize the lumen of the coronary artery using X-ray fluoroscopy. These two-dimensional projections of the coronary arteries are assessed visually or by semi-automatic edge detection algorithms like quantitative coronary angiography (Reiber et al., 1985). Regardless of the technique used, stenosis severity can be misjudged for many reasons as is shown in figure 2.2.

Even when a more accurate impression of the anatomic severity is obtained invasively, i.e. by intra-vascular ultrasound (IVUS), still no physiologic information is obtained. The functional severity of a stenosis is further influenced by the extent of the myocardial perfusion area, the presence of collateral flow, and the resistance of the microvascular bed. Non of these factors can be taken into account by anatomic analysis of the stenosis itself (Gould et al., 1990).

2.1.3 Physiologic assessment of the coronary circulation

Several indices have been proposed to assess coronary artery disease in a physiologic way. An index that describes the vasodilatory reserve of the coronary circulation is the coronary flow reserve or CFR. CFR is defined as the mean hyperemic coronary blood flow divided by the mean coronary resting blood flow (Gould et al., 1990).

CF R = Qhyp Qrest

(18)

Figure 2.1: The right coronary artery (RCA), arising from the right coronary cusp, runs through the atrioventricular groove towards the backside of the heart. The RCA gives rise to several branches that perfuse the right ventricle, the inferior part of the the interventricular septum, and, in the majority of the cases, part of the posterolateral side of the left ventricular wall as well. The left coronary artery (LCA) arises from the left coronary cusp and usually bifurcates into the circumflex artery (Cx) and the left anterior descending artery (LAD). The LAD gives rise to several branches that supply the superior part of the interventricular septum, and the anterior side of the left ventricular wall. The Cx supplies the lateral side of the left ventricular wall (Zipes et al., 2005, chapter 18).(Medical Illustrations copyright c 1997-2008 Nucleus Medical Art,Inc. All Rights Reserved. www.nucleusinc.com)

(19)

Figure 2.2: Different projections of schematically drawn coronary stenoses may lead to misjudgement of the true anatomic severity. The black area within the circle represents the intact lumen of the artery. On the left the anatomically severely narrowed coronary artery appears almost normal in the different projections. On the right the coronary artery appears to be severely narrowed in one projection whereas in the other projection the artery look normal. No information of the functional importance of an epicardial coronary stenosis is obtained in this way (adapted from (Aarnoudse, 2006))

CFR is influenced by both the epicardial and the microvascular condition of the coronary system, but does not distinguish between an increased epicardial resistance or a microvascular flow impairment. Moreover, CFR is dependent on age, heart rate, arterial blood pressure, and has a wide range of normal values.

Fractional flow reserve, or FFR, is an index that describes the hyperemic flow in the presence of a stenosis (QS

hyp) relatively to the hyperemic flow in the case that the

coronary artery would be completely normal (QN

hyp). By definition the prerequisite

for the determination of FFR is that hyperemia is present. In this case the myocardial resistance (R) is minimal and constant resulting in averaged maximal blood flow during the heart cycle. Consequently it can be derived that the ratio of QS

hyp and

QN

hypcan be described by a ratio of mean pressures. When central venous pressure is

assumed to be small (Pv<< Pd), FFR can be determined as the mean pressure distal

in the coronary artery (Pd) divided by the mean aortic pressure (Pa) both measured at

maximum hyperemia, equation 2.2. Besides the fact that FFR has a uniform normal value of 1 for every coronary artery and every person, it is largely independent on arterial pressure, heart rate, or the status of the microcirculation.

F F R = Q S hyp QN hyp = (Pd− Pv)/R (Pa− Pv)/R ≈ Pd Pa (2.2)

Other concepts than CFR and FFR are necessary to describe the specific status of the microcirculation. For a physiologic description of the microcirculation, mean microvascular resistance has been defined as the mean perfusion pressure divided by the mean myocardial flow. However, it has not been possible to determine

(20)

(mean) absolute coronary or myocardial blood flow during catheterisation so far. Therefore an index of microcirculatory resistance, or IMR, has been proposed by Fearon et al.(2003) and Aarnoudse et al. (2004b). Instead of absolute values of mean blood flow, a derivative of flow is used: the mean transit time, Tmn, determined using

thermodilution. The mean transit time is inversely proportional to the blood flow and is related to the time a bolus of cold saline needs to travel down the coronary artery when injected into the ostium of the coronary artery.

It would, however, be a great step forward in the understanding of coronary physiology, to be able to measure mean absolute coronary blood flow in selective coronary arteries and consequently absolute values of mean microvascular resistance. In chapter 5 a method based on continuous infusion thermodilution is proposed to determine absolute coronary blood flow. Besides the in-vitro study described in chapter 5, the method will be validated and applied in-vivo in both animals and humans as well (chapter 6 and 7).

2.1.4 Treatment

When the presence of coronary artery disease has been confirmed, either by anatomic assessment or by physiologic measurements, the proper therapy should be applied. Usually the therapy is focussed on revascularisation of the coronary artery to restore coronary blood flow. One possibility of revascularisation is percutaneous coronary intervention (PCI). In PCI a guide wire is advanced into the coronary artery distal to the location of the stenosis. Next, a balloon catheter, either with or without a stent, is advanced over the guide wire until the location of the stenosis. The balloon is inflated and the atherosclerotic plaque is pushed aside in order to expand the coronary lumen. A stent is used to prevent elastic recoil of the vessel wall.

It has been shown in clinical trials that stent placement results in a decreased restenosis rate after six months (20%) compared to balloon angioplasty alone (30%)(Erbel et al., 1998). However, in-stent restenosis might occur after stent placement, largely caused by neointima formation. Drug eluting stents (DES) have been introduced with the prospect of reducing the restenosis rate. DES are coated with a polymer that slowly releases a drug which inhibits cell growth, and hence, neointima formation. However, only anatomic follow-up data related to these stents were available so far, mostly obtained from intravascular ultrasound (IVUS) and quantitative coronary angiography (QCA) (Morice et al., 2002; Moses et al., 2003). As has been pointed out above, the functional severity of a (re-)stenosis does not necessarily have to correspond to the anatomic severity of a stenosis. For that purpose the aim ofchapter 3 was to perform hemodynamic measurements in DES stents both immediately after implantation and at follow-up to better understand the physiologic behavior of these new type of stents and compare this to bare metal stents.

(21)

Figure 2.3: The aortic valve. The aortic valve is located between the left ventricle and the aorta. Normally is consists of three cusps from two of which the coronary arteries arise. As a result of fusion of the commissures turbulent flow through the valve traumatizes the leaflets which eventually might lead to bacterial endocarditis. When the valve becomes severely obstructed, aortic valve replacement (AVR) might be performed. (Medical Illustrations copyright c 1999-2008 Nucleus Medical Art,Inc. All Rights Reserved. www.nucleusinc.com)

2.2 Valvular disease. The aortic valve

The aortic valve is situated between the left ventricle and the aorta. It consists of three cusps, formed by leaflets, and the aortic annulus. The cusps together with the sinuses of Valsalva form a space from which the coronary arteries emerge. There are three cusps: the right coronary cusp, from which the right coronary artery emerges, the left coronary cusp, from which the left coronary artery emerges, and the non-coronary cusp (figure 2.3).

In the case of an aortic stenosis an outflow obstruction is gradually developing. Depending on the etiology of the degeneration of the valve the outflow obstruction is the result of fusion of the commissures or stiffer properties of the leaflets due to calcification and degeneration. The pathophysiological cause of the diseased valve can be classified as acquired or congenital. From this classification acquired age-related degeneration of the aortic valve is the most common cause for aortic stenosis. Risk factors for degenerative aortic stenosis are often similar to those of vascular

(22)

Table 2.1: Severity of aortic valve stenoses by valve area and mean gradient. Severity AVA [cm2_] _{Mean gradient [mmHg]}

Mild >1.5 <25

Moderate 1-1.5 25-50

Severere <1.0 >50

AVA, aortic valve area

atherosclerosis namely diabetes, hypertension, hypercholesterolemia, and smoking, but might occur without such risk factors (Peltier et al., 2003).

Regardless of the etiology of the aortic valve stenosis, the left ventricle experiences a pressure overload due to the valvular obstruction. Since the development of the aortic stenosis is a gradual process it allows adaptation of the left ventricle. Normal cardiac output is maintained by left ventricular hypertrophy, which may sustain large trans-valvular pressure gradients for many years without reduction in left ventricular systolic function or development of symptoms. Once symptoms occur, however, prognosis is poor if the aortic stenosis remains untreated. Angina pectoris, syncope, and dyspnea in exercise are the typical symptoms of a severe aortic stenosis.

2.2.1 Clinical assessment

Doppler-echocardiography has become the most important clinical technique to determine the severity of an aortic stenosis. Moreover, it is the technique of choice for follow-up of patients because of its non-invasive character. Besides the possibility to distinguish bicuspid and tricuspid valves, trans-thoracic echocardiography is used in detecting thickened and calcified leaflets as well (figure 2.4). When the aortic stenosis is detected, the left ventricular function as well as the degree of hypertrophy can be determined.

Doppler-echocardiography is essential in determining the aortic stenosis severity. Functional severity of the aortic stenosis is based on trans-valvular pressure gradients and the aortic valve area. Using the Bernoulli equation in combination with Doppler-derived velocity measurements through the aortic valve and the left ventricular outflow tract (LVOT), trans-valvular pressure gradients can be reliably estimated (figure 2.4).

The aortic valve area can be measured on an anatomic cross-sectional view of the aortic valve but is more reliably estimated using the continuity equation. To calculate the aortic valve area the values for the blood flow velocities in the LVOT and through the aortic valve also as well as the dimensions of the LVOT should be determined. Classification of aortic stenosis severity is shown in table 2.1.

2.2.2 Treatment

Aortic valve replacement (AVR) is the treatment of choice in adults with an aortic stenosis. The decision to replace the aortic valve with an prosthetic valve is mostly symptom driven. However, in asymptomatic patients with severe aortic stenosis or

(23)

Figure 2.4: Example of echocardiography of an aortic stenosis. Top panel: Two dimensional parasternal long axis view of the heart. Left- and right ventricular cavity (LV and RV) as well as the left atrium (LA) and the aorta (Ao) can clearly be distinguished. A clear bright echo at the location of the aortic valve (AoV) indicates a calcified valve. Moreover, the interventricular septum (IVS) and the posterior left ventricular wall (PW) are thickened indicating that the aortic valve might cause an outflow obstruction. Bottom panel: Doppler measurements of the blood flow velocity through the aortic valve. An estimate of a mean pressure gradient of 70 mmHg and a peak gradient of more than 100 mmHg confirms a severe aortic stenosis.

(24)

progressive left ventricular dysfunction, AVR is also indicated.

Since the 1960s valvular prostheses have been commercially available. Nowadays mono-leaflet tilting disk and bi-leaflet valves are most commonly used. The durability of most mechanical valves is excellent. The disadvantage of mechanical valves is the increased risk of thromboembolic complications and consequently require long-term anticoagulation therapy. Biological valve prostheses on the other hand do not require long-term anticoagulation therapy but have limited durability.

Regardless of the type of prosthesis, the pressure gradient over the valve is reduced significantly after AVR. The reduced pressure gradient over the valve has a favorable effect on coronary flow (Camici and Crea, 2007; Hildick-Smith and Shapiro, 2000). It has been suggested that the orientation of placement of mechanical valves also influences coronary blood flow (Bakhtiary et al., 2006; Kleine et al., 2002c). In chapter 4 the influence of the orientation of mechanical valve prostheses on coronary perfusion is investigated.

2.3 Peripheral vascular disease. The Abdominal Aortic

Aneurysm

An abdominal aortic aneurysm (AAA) is a permanent dilatation of the abdominal aorta. By definition an abdominal aortic diameter >3 cm is considered to be an AAA. Nature and cause of the development of an AAA are unclear, however, smoking, hypertension, and age are strongly associated with aneurysms of the aorta.

The risk of developing an AAA is 4 to 9% in the male population over 65 years of age whereas the risk is 5 to 10 times as low in the female population of the same age (Zipes et al., 2005, chap 53). The paramount concern of AAAs is the risk of rupture. Eventually 1 in every 3 aneurysms will ultimately rupture (Darling et al., 1977) resulting in sudden death in 75% to 90% of the cases (Fleming et al., 2005).

2.3.1 Anatomic assessment. The diameter criterium

It has been shown that the risk of rupture strongly correlates with maximal diameter of an AAA (Glimaker et al., 1991). For AAAs smaller than 4.0 cm the risk of rupture is 0.3% per year which increases to 1.5% per year for AAAs with a diameter between 4.0 and 4.9 cm. Aneurysms of 5.0 to 5.9 cm have an annual risk of rupture of 6.5% (Brown and Powell, 1999). The risk of rupture for AAAs of 6.0 cm and larger increases sharply although this risk cannot be estimated accurately.

Because of the strong correlation with rupture, the maximal diameter is used in clinical practice for risk stratification. Generally a diameter of 5.5 cm and larger is considered an indication for surgery or endovascular repair. For clinical follow-up, ultrasonography is a practical and inexpensive method to determined maximal aneurysmal diameter. This method is, however, insufficient for planning operative repair. Computed tomography (CT) or magnetic resonance imaging (MRI) are generally used for this purpose. Both techniques permit 3D reconstruction of the

(25)

Figure 2.5: An example of an infra-renal abdominal aortic aneurysm (AAA). An AAA is a permanent dilatation of the abdominal aorta >3 cm. The normal abdominal aortic diameter ranges from 2 to 2.5 cm. (Medical Illustrations copyright c 1999-2008 Nucleus Medical Art,Inc. All Rights Reserved. www.nucleusinc.com)

entire aneurysm and have higher accuracy in determining the maximal diameter compared to ultrasonography.

2.3.2 Physiologic assessment. Hemodynamic measurements

Despite the small risk, aneurysms below accepted cut-off values do rupture and vice versa, many AAAs larger than the cut-off value of 5.5 cm will not rupture within the patient’s life time (Conway et al., 2001; Powell and Brown, 2001). In an effort to develop methods to better predict the risk of rupture, biomechanical parameters have been investigated.

Finite element wall stress analysis has shown to better correlate with rupture than maximal diameter alone (Fillinger et al., 2003). Such a stress analysis requires an accurate geometric description of the aneurysm, usually obtained by CT or MRI. Additionally, wall properties are needed to perform patient specific stress analysis. Values for these mechanical properties are often based upon tensile test of excised aneurysmal material.

Efforts have been made to determine values for wall properties in-vivo. Moreover, it has been shown that distensibility of the aneurysm was increased in patients who experience rupture (Wilson et al., 2003). To calculate the distensibility of an AAA both the current hemodynamic load as well as the accompanying volume change are required and should be determined simultaneously. In chapter 8 a study is performed to estimate biomechanical properties of aneurysms larger than 5.5 cm by simultaneously measured pressure and volume measurements.

(26)

Hemodynamic evaluation of

coronary stents

Coronary stenoses resulting from atherosclerosis, reduce maximal achievable coronary blood flow through the artery involved. Percutaneous coronary intervention using drug eluting stents or bare metal stents positively influences coronary physiology on the short term. Superior anatomic results are found for drug-eluting stents when compared to bare metal stents. Long term hemodynamic effects, however, are not available for drug eluting stents in comparison to bare metal stents. In this study we investigated physiologic parameters of coronary stents at implantation and at 6-month follow-up in the drug-eluting sirolimus stent and its bare metal counterpart implanted in pairs within the same patient. Twenty patients, accepted for percutaneous coronary intervention (PCI) of at least two coronary arteries with comparable vessel- and stenosis characteristics, received at random one sirolimus-eluting stent and one bare metal stent. Hemodynamic measurements were performed just after stent implantation and at 6-month follow-up. The physiologic characteristics of the drug-eluting sirolimus stents were superior to those of the equivalent bare metal stent.

Published in: M. van ’t Veer, N.H.J. Pijls, W. Aarnoudse, J.J. Koolen, and F.N. van de Vosse. Evaluation of the hemodynamic characteristics of drug-eluting stents at implantation and at follow-up. European Heart Journal, 27:1811-1817, 2006.

(27)

3.1 Introduction

Drug-eluting stents have been introduced with the prospect of reducing restenosis rate after percutaneous coronary intervention (PCI). However, only anatomic data related to follow-up of these stents are available so far, mostly obtained from intravascular ultrasound (IVUS) and quantitative coronary angiography (QCA) (Morice et al., 2002; Moses et al., 2003). It has been shown repeatedly that the physiologic parameters fractional flow reserve (FFR) and hyperemic trans-stent gradient (HTG) better reflect the physiologic status of a coronary segment or stenosis both in native coronary arteries and after stenting (Pijls et al., 1996, 2002b; Lopez-Palop et al., 2004). Moreover, it has been shown that there exists a relation between the wall shear stress (WSS) and the neointimal thickness (Wentzel et al., 2001; Gijsen et al., 2003). Therefore the aim of this study was to investigate FFR, HTG, and WSS at implantation and at 6-month follow-up in the sirolimus stent (CypherTM_{, Cordis, Johnson &}

Johnson, Miami, Florida) and in its bare metal counterpart (Bx VELOCITYTM_),

randomly implanted in pairs in two comparable arteries with comparable stenoses within the same patient.

3.2 Methods

3.2.1 Study population

Twenty consecutive patients with stable angina pectoris were selected. They were accepted for elective PCI of at least two coronary arteries with a comparable reference diameter and comparable stenosis characteristics. In none of the patients previous myocardial infarction had occurred in the myocardial regions supplied by the respective arteries. The reference diameter of both arteries should vary less than 0.5 mm and the length of the stenosis should not differ more than 50%. Patients with very tortuous vessels, severe obstructive pulmonary disease, as well as patients with a contraindication for aspirin or clopidogrel were excluded. There were no further exclusion criteria.

All patients were selected from the population referred to our hospital for elective PCI of 2-vessel disease (figure 3.1). Among a total of 228 referred for elective 2-vessel PCI, 20 patients fulfilled the criteria of having comparable stenoses with comparable length, severity, and reference diameter.

Immediately before the procedure, the placement of the sirolimus and the bare metal stent (BMS) in the two stenoses was determined by computer-coded randomization. The study was approved by the institutional review board of the Catharina Hospital and written informed consent was obtained from all patients prior to the study. It should be noted that at the time the study was performed, in our country, drug-eluting stents were not available for routine patients, except in studies.

(28)

Figure 3.1: Patient flow chart. Twenty consecutive patients fulfilling the study inclusion criteria were selected from the total population of patients undergoing PCI referred to our hospital in the period June 1st_{till December 3}rd_{, 2003}

(29)

3.2.2 Interventional protocol

All procedures were performed by the femoral approach with 6F guiding catheters. Patients were pre-treated with aspirin and clopidogrel. Prior to the procedure 5000 IU of heparin was administered. After intracoronary administration of 200 µg nitroglycerine, coronary angiography was performed. Next, a sensor-tipped pressure guide-wire (PressureWire 4, Radi Medical Systems, Uppsala, Sweden) was used as routine guide wire in all of the procedures and pressure measurements were performed by this wire as described below. After successful stent implantation and repeated measurement of coronary pressures, this pressure wire was replaced by a Doppler flow wire (FloWire, Jomed, Ulestraten, The Netherlands) for velocity measurements and WSS calculations as described below. Post-interventional phar-macologic treatment included aspirin and clopidogrel as routine in our center. All invasive measurements were repeated after 6 months with the same sequence and methodology of all physiologic measurements.

3.2.3 Hemodynamic analysis

After adequate calibrating and positioning the pressure sensor in the distal part of the coronary artery, hyperemia was induced by intravenous infusion of adenosine through the femoral vein (140 µg/(kg · min) ) as described before (Pijls et al., 1996; Pijls, 2004). After steady state maximum hyperemia had been achieved, FFR was determined as the ratio of distal coronary pressure (Pd) and aortic pressure (Pa).

FFR expresses maximal achievable blood flow in the presence of a stenosis as a ratio of normal maximal blood flow in the hypothetic case that the coronary artery would be completely normal (Pijls et al., 1996; Pijls, 2004). Adenosine was stopped and the stent was placed. Thereafter adenosine was started again and post-stent FFR was measured. Subsequently, during sustained hyperemia, the wire was slowly pulled back under fluoroscopic guidance and a pull-back recording was made (Pijls et al., 2002b; Pijls, 2004). Hyperemic trans-stent gradient (HTG) was calculated as the pressure just proximal to the stent (Pprox) minus the pressure just distal to the

stent (Pdist), both determined at maximum coronary hyperemia. Also the trans-stent

pressure ratio (TPR) was calculated as the ratio of Pdist and Pproxduring maximum

coronary hyperemia. Next, adenosine was stopped and the pressure wire was exchanged for a Doppler flow wire and average peak velocity (APV) was measured at the entrance and the exit of the stent and within the body of the stent at rest. An approximation of WSS (τ ) at the different positions was calculated assuming a Poiseuille flow yielding:

τ = 8ηv

d (3.1)

where η is the dynamic viscosity of whole blood, v represents the average cross-sectional velocity at the particular location, and d the corresponding diameter obtained from the QCA analysis (indicated in figure 3.2). Prior to the initial intervention and prior to the follow-up procedure, a venous blood sample was taken

(30)

Figure 3.2: Definition of the hemodynamic parameters in this coronary artery study. Pa, Pd, Pprox, and Pdistrepresent aortic pressure, distal pressure, pressure just proximal

and just distal to the stent, respectively, all measured during maximal hyperemia. FFR represents the fractional flow reserve, HTG the hyperemic stent gradient, and TPR the trans-stent pressure ratio. WSS indicates the approximate wall shear stress in the stent calculated using equation 3.1. The diameter of the stented vessel is indicated with ’d’.

before the administration of heparin for the determination of blood viscosity as described elsewhere (Matrai et al., 1987). Because of the assumption of a parabolic Poiseuille flow in a circular straight tube the average velocity was taken half of the measured APV (Buchi and Jenni, 1998). The definitions of the several hemodynamic indices are clarified in figure 3.2. Our method is fundamentally the same as used by Wentzel et al. and Gijsen et al. However we do not use a finite element model to calculate local wall shear stresses. Our equation is the analytic solution of the Navier-Stokes equations, under the assumptions of an incompressible steady laminar Newtonian flow through a straight tube.

3.2.4 Angiographic analysis

Angiograms were made after nitroglycerine administration in at least two orthogonal projections and QCA was performed and analyzed as described before (Reiber et al., 1985). Reference diameter, percentage diameter stenosis, and minimal luminal diameter (MLD) were calculated offline (QCA-CMS 4.0, MEDIS medical imaging systems, Leiden, Netherlands) both before and immediately after the procedure, and at six-month follow-up period. Late lumen loss was defined as the difference between the post-procedural MLD and the follow-up MLD at six months as described earlier (Morice et al., 2002; Moses et al., 2003). The diameters of the artery at the entrance of the stent, within the stent, and at the exit of the stent were measured in the two projections, averaged, and then used for the WSS calculations at those positions.

(31)

3.2.5 Statistical analysis

The number of twenty patients was arbitrary but based on the consideration that if a relevant difference between the stents would be present with respect to the hemodynamic indices, this should be demonstrable in this group. Because of the extensive invasive study protocol, it was considered inappropriate to include a larger group of patients.

The design of the study introduces two sources of repeated measures that we considered for the analysis. First, measurements were performed immediately after placing the stents and repeated at follow-up. We calculated the difference between parameters for these time points and compared them across the stent groups. Second, two different stent types were compared within each patient. Therefore, we used the Wilcoxon signed-rank test for paired observations. All tests were performed two-sided. A P-value of <0.05 was considered significant.

In performing statistical tests, no corrections were made with regard to the Type I error as the primary outcome of this study was the difference between FFR from immediately after stenting to follow-up. Further tests may be considered as indicative for the difference in the results between the stents. Statistical software package SAS (Version 8.2, SAS Institute, Cary, NC, USA) was used for the statistical analysis.

3.3 Results

3.3.1 Baseline characteristics and procedural results

All twenty patients eligible for the study consented to participate. Twenty sirolimus stents and twenty BMSs were implanted in pairs in twenty patients. Four patients received an additional stent due to a residual significant pressure gradient elsewhere in the vessel (n=3) or a dissection (n=1). These additional 4 stents were also drug-eluting stents. No procedural complications occurred. Patient characteristics are presented in table 3.1. Baseline angiographic and hemodynamic characteristics as well as stent characteristics are presented in table 3.2. No significant differences were present at baseline between the two groups.

3.3.2 Clinical follow-up at 6 months

There where no deaths among these twenty patients after six-month follow-up. Two cases of sub-acute stent-thrombosis occurred: one in a sirolimus and one in a bare metal stent. These events occurred within the same patient and were possibly provoked by removal of the sheath several hours after the intervention, accompanied by bradycardia and a vasovagal reaction. Both stents were successfully re-opened by re-intervention. The CK-MB level rose to 677 U/l in this patient.

At six months, four re-interventions were necessary based upon an ischemic FFR: two cases of in-stent restenosis and the other two cases because of restenosis just proximal to the stent. All re-interventions were related to the BMS and were all treated by placing a drug-eluting stent within or overlapping the former stent.

(32)

Table 3.1: Patient characteristics Patients 20 Male/female 16/4 Age, years 59.1±10.5 Risk factors Smoking 9 Diabetes 3 Hypertension 9 Family history 15 Cholesterol, mmol/l 5.46±0.85 HDL, mmol/l 1.28±0.29 Medication Aspirin 20 Clopidogrel 19 GP2B3A inhibitors 11 Bta-blockers 16 Statins 16 ACE-inhibitors 6

HDL: High Density Lipids

Table 3.2: Baseline angiographic and pressure data before stent implantation and stent characteristics Sirolimus BMS P-value (n=20) (n=20) Angiographic parameters Lesion length, mm 14.9±5.3 14.8±4.2 0.99 Vessel RCA/Cx/LAD 8/5/7 8/5/7

-Lesion type (A/B1/B2/C) 6/5/8/1 7/5/6/2

-Reference diameter, mm 2.8±0.4 2.8±0.5 0.94 MLD, mm 1.2±0.4 1.2±0.3 0.54 Diameter stenosis, % 57±12 57±13 0.95 Pressure variable FFR 0.61±0.20 0.61±0.16 0.98 Stent characteristics Diameter, mm 2.9±0.3 2.9±0.3 0.58 Length, mm 17.8±5.7 16.5±3.7 0.46

Inflation pressure, atm 14.7±1.5 14.6±1.7 0.81

(33)

3.3.3 Angiographic follow-up at 6 months

Immediately after intervention, the angiographic characteristics of both groups were similar. However, after six months they differed significantly with respect to the MLD, the percentage diameter stenosis, and the late lumen loss in favor of the sirolimus stent (table 3.3). The MLD of the sirolimus stent versus the BMS was 2.3±0.4 versus 1.7±0.4 mm (p=0.041), the percentage diameter stenosis was 14±9 versus 36±15% (p=0.022), and the late luminal loss was 0.1±0.3 versus 0.6±0.5 mm (p=0.047), respectively.

3.3.4 Hemodynamic follow-up and WSS at 6 months

No significant differences were seen immediately after intervention between the two groups with respect to the hemodynamic data and WSS (table 3.3). However, at six-month follow-up, both FFR and HTG of the sirolimus group differed significantly from the bare metal group. FFR was 0.91±0.05 versus 0.83±0.10 (p=0.028) and HTG was 1.2±1.2 versus 7.5±8.1 mmHg (p=0.026) in favor of the sirolimus-stent. Also the TPR differed significantly: 0.99±0.01 in the sirolimus group versus 0.91±0.09 in the bare metal group (p=0.029) (table 3.3).

The normal reference value of WSS in a coronary artery at rest is 1.5-2 Pa (Ku, 1997). There was no significant difference in wall shear stress for any of the positions at baseline between the groups. The within stent values at six months differed significantly between the two groups (p=0.009). The values of WSS at the entrance and exit of the stent did not differ significantly at six months (table 3.3). Values for the WSS at different positions are presented in figure 3.3.

3.4 Discussion

This study shows that drug-eluting sirolimus stents have a better and a more physio-logic hemodynamic performance at six-month follow-up than the corresponding bare metal stents. Moreover, at follow-up the sirolimus stent maintained normal values of WSS in contrast to the bare metal stent, where high values of WSS were found within the stent.

It has been shown previously that calculating local WSS in stents is useful in identifying specific locations at risk for restenosis (Wentzel et al., 2001; Gijsen et al., 2003). In those studies, WSS was calculated with a higher spatial resolution compared to our study where only global approximate values of WSS were obtained. Nevertheless our values are in the physiologic range of 1.5-2 Pa along the stented segment in both vessels just after stenting, the normal resting value for coronary arteries in a wide range of species (Ku, 1997). In contrast to the BMS, the sirolimus stent maintained this normal WSS after six months. The high values of WSS found in the BMS after six months reflect the decreased MLD and consequently the higher percentage diameter-stenosis. These findings are in concordance with previous angiographic studies (Morice et al., 2002; Moses et al., 2003). As WSS also accounts

(34)

Table 3.3: QCA data and physiologic parameters immediately after stent implantation and at 6-month follow-up

Sirolimus BMS P-value

(n=20) (n=20)

Angiographic parameters MLD, mm

Immediately after PCI 2.4±0.3 2.3±0.4 0.23

6-month follow-up 2.3±0.4 1.7±0.4 0.023

Change at follow-up -0.1±0.3 -0.6±0.5 0.041

Diameter stenosis,%

Immediately after PCI 14±10 19±11 0.05

6-month follow-up 14±9 36±15 <0.001

Change at follow-up -1±12 15±21 0.022

Late loss, mm 0.1±0.3 0.6±0.5 0.047

Coronary pressure parameters FFR

6-month follow-up 0.91±0.05 0.83±0.10 0.027

Change at follow-up 0.01±0.05 -0.05±0.10 0.028

HTG

6-month follow-up 1.2±1.2 7.6±8.1 <0.001

Change at follow-up -1.2±2.0 4.1±8.7 0.026

TPR

6-month follow-up 0.99±0.01 0.91±0.09 0.002

Change at follow-up 0.01±0.02 -0.05±0.10 0.029

WSS (normal value: 1.5-2 Pa) Entrance of stent

6-month follow-up 1.8±0.8 2.4±1.4 0.24

Within stent

6-month follow-up 1.6±0.7 3.9±3.1 0.003

Exit of stent

6-month follow-up 1.7±0.9 1.9±1.1 0.34

Change at follow-up -0.1±0.6 -0.2±0.8 0.7

MLD = minimal luminal diameter, PCI = percutaneous coronary intervention, FFR = fractional flow reserve, HTG = hyperemic trans-stent gradient, TPR = trans-stent pressure ratio, WSS = wall shear stress

(35)

Figure 3.3: Approximate WSS values at three positions immediately after implantation and at 6-month follow-up for the sirolimus stent (top) and the bare metal stent (bottom). The locations marked with ’prox’ and ’dist’ indicated the position just proximal and just distal to the stent, respectively.

(36)

for the average cross-sectional velocity and viscosity, it is a better indicator for the local hemodynamics within the stent than the anatomy-derived parameters alone.

Despite extensive studies on FFR and pressure gradients across bare metal stents immediately after implantation and at follow-up (Pijls et al., 2002b; Hanekamp et al., 1999), little was known so far about those physiologic and hemodynamic characteristics of drug-eluting stents over time. The FFR and HTG we found in both groups show that after six months approximately half of the total pressure gradient present in the vessel stented with the BMS was due to gradient across the stent, in contrast to the vessel stented with the sirolimus stent where this gradient across the stent itself was very small (7.5±8.1 mmHg in the BMS versus 1.2±1.2 mmHg in the sirolimus stent respectively, p=0.026).

A recurring hyperemic gradient of 5-10 mmHg after six months in BMS, due to intimal hyperplasia, has been described earlier (Pijls et al., 2002b; Hanekamp et al., 1999). The present study shows that for sirolimus stents this phenomenon is much less severe. For both groups the pressure loss along the remaining non-stented part of the coronary artery was identical, indicating that the arteries in both groups were diseased to a similar degree with a diffuse hyperemic pressure decline of approximately 10 mmHg.

In patients with multiple but distant abnormalities within one coronary artery and a significantly decreased FFR (<0,75-0.80), in the past it was not recommended to stent spots or segments with a hyperemic gradient of <10 mmHg because, as mentioned above, despite optimal deployment a hyperemic gradient of 5-10 mmHg was present again after six months in the majority of the bare metal stents (Hanekamp et al., 1999). For sirolimus stents our study shows that the average HTG after 6 months is significantly smaller, i.e. 1-2 mmHg. Therefore a practical implication of this study for interventional cardiology is that in such diseased arteries with multiple non-adjacent lesions, whether or not superimposed on diffuse disease or separated by side branches and each in itself not hemodynamically significant but in series responsible for inducible ischemia, the possibility for successful interventional treatment by several stents is significantly improved. The beneficial effect of bare metal stents in those stenoses with gradient less than 10 mmHg was often disappointing in the past due to the recurring gradient of approximately 5-10 mmHg after 6 months. Having established now that across DES only minor gradients are present at follow-up, interventional treatment in such patients has become more rationale. It should be emphasized that stenting on a purely anatomic basis in these patients makes little sense if FFR of all lesions together is >0.80 (Pijls et al., 2007).

Finally, because both the sirolimus stent and the BMS were implanted in pairs in stenoses with comparable characteristics within the same patient, the biological environment and risk factors were identical as much as possible and the possibilities that the differences observed were due to other factors than the stent itself was minimized as much as possible.

(37)

3.4.1 Limitations

Calculation of WSS in this study was based upon QCA, APV, and viscosity, limited to the entrance, exit, and body of the stent. These calculations are influenced by the inaccuracy in APV which has been described before (Buchi and Jenni, 1998). To have obtained accurate geometrical information and consequently accurate numerical shear stress data, IVUS would have been necessary. However, because this would have further prolonged the time of these extensive procedures, we chose for WSS calculations by equation 3.1 at the entrance, body, and exit of the stent only, as explicated in section 3.2.3.

Although we did not specifically investigated inter and intra observer variability, we assumed that this would be limited, because WSS is calculated directly from viscosity, flow velocity, and QCA, all of which have a small inter and intra observer variability (Matrai et al., 1987; Buchi and Jenni, 1998; Reiber et al., 1985). With respect to the limited number of stenoses (2 × 20), it should be noted that it was not the intention of this study to demonstrate any difference in restenosis- or adverse event rate, but to acquire better understanding of the physiologic behavior of sirolimus stents compared to the BMS, which was clearly achieved in this study (table 3.3).

3.5 Conclusions

At six-month follow-up the sirolimus stent was superior compared to its bare metal counterpart not only with respect to angiographic but also to physiologic characteristics. Fractional flow reserve was significantly higher and the hyperemic trans-stent gradient significantly lower for the sirolimus stent. Furthermore, in contrast to the bare metal stent, the sirolimus stent maintained a normal wall shear stress within the stented segment.

Acknowledgements

This study was supported by a grant of Cordis, a Johnson & Johnson Company and by grant 04-03 of the foundation ’Stichting Vrienden van het Hart’, Eindhoven the Netherlands. The authors are indebted to the nursing staff of the catheterisation laboratory of the Catharina Hospital in Eindhoven for their dedicated assistance in the invasive procedures.

(38)

Editorial:

Hemodynamic findings after drug-eluting

stenting: expected, provocative, or challenging?

This editorial by Fernando Alfonso refers to ’Evaluation of the hemodynamic characteris-tics of drug-eluting stents at implantation and at follow-up’ (van’t Veer et al., 2006)

Published in: European Heart Journal 2006;27:1764-1766, printed with permission of the European Heart Journal, Oxford University Press

In this article van’t Veer et al. present a comprehensive and detailed study comparing the hemodynamic characteristics of drug-eluting stents (DES) with those obtained by conventional bare metal stents (BMS). After DES, long-term physiologic parameters including fractional flow reserve (FFR), hyperaemic gradient, and wall shear stress (WSS) were superior to those found in equivalent BMS implanted in the same patients (van’t Veer et al., 2006). Although these findings are of major interest, most of the new information provided could be perceived as well expected considering the large body of evidence demonstrating the superb late results after DES implantation. Nevertheless, as will be highlighted in this editorial, some study findings and their implications are rather provocative. Furthermore, on the basis of their results, these investigators from the Catharina Hospital (Eindhoven)(van’t Veer et al., 2006) dare to challenge some widely accepted strategies in the management of patients with diffuse coronary artery disease (CAD).

Coronary physiology after DES

Previous land-mark studies from the same group have unequivocally established the superiority of FFR over conventional angiography to assess the functional severity of coronary stenosis (Pijls et al., 1996). Even intravascular ultrasound (IVUS), able to provide a thorough anatomic coronary assessment, can only be used as a surrogate of lesion physiology (Alfonso et al., 2003). Large-scale serial morphological studies have consistently demonstrated the unique ability of DES to prevent restenosis and to inhibit neointimal proliferation. However, functional studies after DES implantation using direct hemodynamic assessment are scarce (Gijsen et al., 2003; Carter et al., 2005). The elegant study of van’t Veer et al. assessing FFR, stent-induced gradients, Doppler-derived intracoronary velocities, and WSS, fills the gap in our understanding of DES influence on coronary physiology. The study design, randomly allocating in pairs DES and BMS in well-selected matched lesions of patients with two-vessel disease, circumvents the potential confounding influence of systemic and anatomic factors on outcome measures. This sound methodology enables to obtain meaningful hemodynamic information from a relatively small patient cohort, which, in turn, is critical when relatively sophisticated diagnostic procedures are performed during coronary interventions (Alfonso et al., 2003). Likewise, excluding unstable lesions, infarct-related vessels, and selecting the intravenous approach to administer adenosine minimizes potential pitfalls in physiologic measurements.

(39)

A previous study demonstrated that FFR immediately after BMS was able to predict long-term clinical outcome (Pijls et al., 2002b). Intuitively, it is difficult to anticipate a similar application for this parameter after DES, considering their low restenosis rate. Likewise, DES thrombosis is exceedingly rare (although occurred in one patient of the present series).

Therefore, the routine assessment of hemodynamic factors is not justified. However, from an academic stand point, the excellent long-term hemodynamic findings obtained after DES are re-assuring.

WSS in atherogenesis and neointimal proliferation

Atherogenesis

WSS is the tangential drag (frictional) force produced by flowing blood on the endothelial surface. WSS is probably the most important local factor influencing atherogenesis (Stone et al., 2003; Irace et al., 2004). It has been suggested that atherosclerosis predominantly develops at segments with low WSS. Low WSS induces endothelial dysfunction, inflammation, and smooth muscle cell proliferation. Atherosclerosis frequently has an eccentric distribution and preferentially occurs in the proximal coronary segments, at bifurcations, and in the inner curve of the artery. Typically, all these locations have low WSS. In particular, at the hips of the bifurcation (walls opposite to the flow divider), low WSS values are systematically detected. According to the HagenPoiseuilles law, WSS is inversely proportional to the cube of the radius explaining its dramatic relation with the lumen size. Although some investigators have hypothesized that a threshold level of WSS is required to affect atherogenesis, the boundary between atheroprotective and atherogenic effects remains as yet undefined (Irace et al., 2004). Moreover, the contribution of WSS to atherogenesis appears clear in low-risk individuals, but its effects might be masked in high-risk subjects or in mature lesions (Irace et al., 2004). For precise local WSS calculations, the non-linear, incompressible fluid, three-dimensional NavierStokes equations (governing the conservation of mass, energy, and momentum) need to be solved. This form of detailed virtual analysis (computational fluid dynamics) is now reasonably practical using specialized programs for the discretization of flow using finite-element methods (Stone et al., 2003; Irace et al., 2004; Wentzel et al., 2001; Carlier et al., 2003; Sanmartin et al., 2006). A mesh is generated and adequate boundary conditions are defined. Local WSS is a sophisticated parameter that may be calculated only after a comprehensive anatomical and physiologic assessment. This requires a true three-dimensional anatomic reconstruction of the vessel in relation to the distribution of intravascular velocity profiles. In previous studies, biplane angiography combined with IVUS was used for accurate volumetric lumen reconstruction (Stone et al., 2003; Irace et al., 2004; Wentzel et al., 2001; Carlier et al., 2003; Sanmartin et al., 2006). Alternatively, WSS may also be measured using a global analysis at different coronary segments, as in the study of van’t Veer et al.. This provides a valid approximation to WSS at selected vessel positions highly attractive in the clinical setting.

(40)

Neointimal proliferation

Neointimal thickness distribution after BMS is related to local factors including extent of vascular injury, inflammation, and WSS. Neointimal tissue tends to proliferate in areas with low WSS, whereas the stent remains free of cell proliferation in areas with high WSS (Wentzel et al., 2001; Carlier et al., 2003). Of interest, stent design and deployment techniques influence WSS. Experimentally, increasing WSS using a flow divider within BMS, has been accompanied by local reductions in neointimal hyperplasia, inflammation, and wall injury (Carlier et al., 2003). Although evidence suggests that WSS influences neointima proliferation after BMS, its exact role remains controversial (Stone et al., 2003).

Preliminary data of WSS after DES are particularly intriguing. In the study of Gijsen et al. biplane angiography and IVUS were used to determine volumetric lumen geometry 6 months after DES. Flow velocities were directly recorded within the stent, and WSS was obtained from computational fluid dynamics. A significant inverse relation was found between WSS and DES neointimal thickness. More recently, Carter et al. conducted serial analysis of segmental WSS after oversized BMS and DES implantation in a porcine model. Relatively low WSS was induced after deployment with both stents. However, at 30 days, IVUS-derived lumen areas were larger and normalized WSS was lower after DES. A negative correlation was found between WSS immediately after BMS and the subsequent neointimal formation. Unexpectedly, post-DES WSS had a positive correlation with the neointimal proliferation. The study of van’t Veer et al. demonstrated that WSS at follow-up is higher in patients treated with BMS than in those treated with DES. Although such findings might be expected because of the poorer angiographic results of the former group, this concept deserves further attention. In particular, the ability of DES to inhibit neointimal proliferation critically depends on their initial pharmacologic action. Later on, when the drug effect has vanished, an excellent hemodynamic profile, with physiologic WSS patterns, may further prevent cell proliferation. However, in this study, the mean in-stent WSS after DES was 1.9±0.8 Pa but only 1.6±0.7 Pa at follow-up. Therefore, at least in some patients, relatively low late WSS values were found. Whether low WSS 6 months after DES could promote a delayed neointimal response remains speculative. Conversely, one may also suggest that a negative feedback control loop may occur after BMS. In this scenario, cell proliferation and the resulting lumen narrowing significantly increase WSS which, at least on theoretical grounds, might prevent further neointimal growth. The potential contribution of high WSS to reduce the extent of late neointimal obstruction is also largely speculative. In the present study, however, the potential long-term implications of the hemodynmic parameters seen immediately after stenting were not analysed.

To the best of our knowledge, the attractive methodology used in this study has not been previously validated in human coronary arteries; therefore, reproducibility data might have been of interest. In contrast, the correlation of these measurements with those found using the classical approach to determine local WSS warrants further studies. Finally, most WSS analyses currently neglect flow pulsatility, coronary motion, and wall distensibility. Eventually, the challenge remains to develop a robust