mitral valve annuloplasty and chordal...
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Mitral valve annuloplasty and chordal cutting The effects on interventricular flow of the infarcted heart
L.A. Teeuwen
Student: Faculty mentor: Direct mentor: GIPS-M mentor: Dhr. L.A. Teeuwen dr. M.E. Erasmus Prof. J.H. Gorman Prof. W.J. van Son Student Number: Institution: The Perelman School of Medicine, University of Pennsylvania S1832905 Department: The Gorman Cardiovascular Research Group
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List of Abbreviations
IMR - Ischemic mitral regurgitation
CAD - Coronary artery disease
MI - Mitral insufficiency
MR - Mitral regurgitation
LV - Left ventricle
PM - Papillary muscle
PCI - Percutaneus revascularisation
CABG - Coronary artery by-pass graft
MVP - Mitral valve plasty/repair
MRI - Magnetic resonance imaging
ABP - Arterial blood pressure
PCPW - Pulmonary wedge pressure
CVP - Central venous pressure
CO - Cardiac output
ESV - End systolic volume
EDV - End diastolic volume
SV - Stroke volume
EF - Ejection fraction
CHF - Congestive heart failure
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Summary Introduction Ischemic mitral regurgitation (IMR) is the leakage of the mitral valve which is a common complication of coronary artery disease, this is caused by ventricular remodelling. The ventricular remodelling causes the shape of the valve to deform and forces the papillary muscles with chordae tenineae out of place. The pull of the chordae tendineae on the leaflets becomes disruptive: chordal tethering. Most cases are treated with a repair by placement of a ring around the mitral valve forcing the circumference back into its original shape. This technique has great short-term results but regurgitation reoccurs in up to 80% of the cases in 5 years. 4D-flow MRI is a method of evaluating flow dynamics of the left ventricle in-vivo. A healthy ventricle is characterized by the formation of vortices. In previous studies by this institute it was shown that the implantation of under-sized rings, which is common practice in the treatment of IMR, causes significant changes in intra-ventricular flow in healthy animals. The influence of a repair for IMR on the internal ventricular blood flow patterns of the infarcted heart are unknown. Chordal cutting, a technique where the most tethered chordeae are cut, is believed to improve leaflet mobility and coaptation, this could potentially enhance the durability of the repair. Investigating the flow-patterns in hearts treated by these methods could help in developing better and longer lasting repair techniques. Material and Methods Over the course of a year 25 dorset sheep were subject to a series of three subsequent procedures. First an infarct was induced in all animals by ligating a specific part of the circumflex artery. After the infarction has consolidated over the course of 8 to 16 weeks the animals received a pre-operative MRI. Two weeks after the MRI a 28 mm Physio ring was implanted in all animals. A chordal cutting procedure was done at random in half the animals. On the same day a post-operative MRI was performed. All animals were euthanized after completion of the procedures. During the three procedures hemodynamic and echographic data was collected. MRI data was processed in order to assess 4D flow images of the left ventricle pre and post operatively. Data was analysed statistically with students T-test and Chi-square test. Results Nine out of 25 animals survived yielding good results. Most animals died because of the induced MI or surgical complications. Hemodynamic data showed an overall decrease in cardiac function. Blood-flow patterns observed pre and post operatively were incoherent. Almost all animals in the pre-operative phase showed vortices close to the mitral valve and a column of flow proceeding towards the apex. The disbanding of the column into vortices was found in half the cases. The other half of the cases the column disbanded without forming vortices. These two distinct flow patterns were also observed post-operatively but held no relation with pre-operative flowpatterns, hemodynamic differences or chordal cutting. Discussion The flow patterns pre-and post-operatively were incoherent but showed components as seen in healthy animals in other studies. The implantation of normal sized rings did not have structural effects on the intra-ventricular flow. The effect of IMR seems to be at random but does not significantly disrupts flow components as seen in healthy subjects. Chordal cutting does not seem to have influence on the intra-ventricular flow as is observed. Undersized rings seem to have most influence on intra-ventricular flow. In general no factors were found to explain the differences in flow patterns. The size of the infarcted area has not been investigated in this study, this could be a factor worth investigating. Improvement of post-processing techniques could help in describing flows more adequately and determine effects of surgical procedures.
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Samenvatting Introductie Ischemische mitralis insufficientie (IMR) is een veel voorkomende complicatie bij myocardiale infarcering. Remodelering van de hartwand heeft als gevolg dat de vorm van de klep veranderd en ook de papillair spieren met daarbij de chordae tendineae uit het lood worden getrokken: chordal tethering. In de meeste gevallen wordt deze complicatie behandeld door het plaatsen van een ring rondom de klep, een zogenaamde annuloplasty. Dit forceerd de klep terug in zijn orginele vorm. De techniek heeft goede korte termijn resultaten, maar op de lange termijn kan het aantal recidief lekkages oplopen tot 80% in 5 jaar. 4D-flow MRI in een methode voor het evalueren van bloedstromen van de linker ventrikel in-vivo. Bloedstromen in een gezonde ventrikel worden gekarakteriseerd door het ontwikkelen van vortexen. In voorgaande onderzoeken door dit instituut is gebleken dat het inbrengen van extra kleine ringen, wat een gebruikelijke methode is in de kliniek, een significante verandering veroorzaakt in de bloedstroompatronen van de linker ventrikel in gezonde dieren. De invloed van een ringimplantatie op de ventriculaire bloedstroom patronen bij IMR is onbekend. Chordal cutting, het doornemen van de meest trekkende chordeae, is een opkomende techniek die mogelijk de mobilititeit en coaptatie van de klepbladen bevorderd. Deze techniek heeft de potentie om de duurzaamheid van de procedure te vergroten. Het onderzoeken van de bloedstroompatronen in harten die zijn behandeld met deze method kan ons inzicht vergroten en bijdragen aan de ontwikkeling van betere operatie technieken. Materiaal en Methode Over de loop van 1 jaar zijn 25 schapen onderworpen aan drie opeenvolgende procedures. Als eerste werd een infarct geinduceerd door een specific deel de arteria circumflex af te binden. Nadat de infarcering is geconsolideerd over de loop van 8 tot 16 weken kregen de dieren een pre-operatieve MRI. Twee weken hierna kregen de schapen een 28 mm Physio ring geimplanteerd. In de helft van de dieren werd ook een chordal cutting procedure uitgevoerd. Na de operatie ondergingen de dieren een MRI waarna ze werden geëuthenaseerd.Tijdens de procedures werd hemodynamische en echografische data verzameld. MRI data werd verwerkt om 4D-flow beelden van voor en na de operatie te kunnen evalueren. De data werd statistisch getoetst met T-test en Chi-square test. Resultaten Negen uit 25 dieren overleefden alle procederes een gaven representabele resultaten. De meeste dieren bezweken door complicaties van het geïnduceerde infarct of operatie. Hemodynamische gegevens lieten over de hele linie een terugloop in hartfunctie zien. De bloodstroompatronen zoals gezien in de pre- en postoperatieve fase waren inconsistent. Bijna alle dieren in de pre-operatieve fase lieten vortexen zien die dicht tegen de mitraalklep ontstonden, ook werd er een kolom van stroming gezien die richting de apex van het hart bewoog. Het uiteenvallen van de kolom in vortexen werd gevonden in de helft van de gevallen. In de andere helft viel de kolom uiteen zonder vortexen te vormen. Deze twee onderscheidende patronen werden ook gezien in de post-operatieve fase. Echter is heeft het ontstaan van deze patronen geen relatie met de pre-operatieve status, hemodynamische verschillen of chordal cutting. Discussie De bloedstroompatronen geobserveerd in de pre en post-operatieve fasen waren incoherent maar lieten componenten zien die aanwezig zijn in de bloedstroompatronen van een gezonde ventrikel. Het inbrengen van een ring van normale grootte had geen structurele effecten op de bloedstroom patronen. Het effect van IMR lijkt willekeurig te zijn maar lijkt de bloedstroom niet significant te verwarren. Chordal cutting lijkt ook geen invloed te hebben op de stromingspatronen. In het algemeen zijn er geen factoren gevonden die de veranderingen in bloedstroom patronen veranderen. Te kleine ringen lijken uiteindelijk de meeste invloed te hebben. Het bekijken van de infarct grootte hebben we niet bekeken en zou een factor zijn om nog te onderzoeken. Ook het verbeteren van de analyse technieken van 4D-flow zou kunnen helpen om de bloedstroom patronen adequater te beschrijven.
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Table of Content
Summary ................................................................................................................................ 3
Samenvatting ......................................................................................................................... 4
Introduction ........................................................................................................................... 6 1.1 Ischemic Mitral Regurgitation ......................................................................................................... 6 1.1.1 Prevalence, incidence, mortality and morbidity ........................................................................................... 6 1.1.2 Pathophysiology ............................................................................................................................................ 6 1.2 Chordal Cutting ................................................................................................................................ 7 1.3 Longterm Outcomes. ........................................................................................................................ 7 1.3.1 Repair Failure ............................................................................................................................................... 7 1.4 Intra-ventricular hemodynamics ...................................................................................................... 9 1.4.1 Flow in the Healthy Heart ............................................................................................................................ 9 1.4.2 Flow in heart failure and myocardial infarction .......................................................................... 10 1.4.3 Behaviour of Flow with Annuloplasty and Chordal Cutting ...................................................... 10 1.5 Posing the Question ....................................................................................................................... 11 1.6 Aims of the research ...................................................................................................................... 11
Material & Methodes ............................................................................................................ 12 2.1 Study Design .................................................................................................................................. 12 2.2 Animal model ................................................................................................................................. 12 2.3 Experimental Procedures ............................................................................................................... 12 2.3.1 Procedure Overview ................................................................................................................................... 12 2.3.2 General Pre- and Post-Operative Procedures ............................................................................................ 12 2.3.3 Procedure 1: Surgery for myocardial infarction induction ........................................................................ 13 2.3.4 Procedure 2: 4D flow MRI Acquisition ...................................................................................................... 13 2.3.5 Procedure 3: Annuloplasty with or without chordal cutting ...................................................................... 13 2.4 Assessment of left ventricular function ......................................................................................... 14 2.5 Processing of MRI data .................................................................................................................. 14 2.5.1 Analysis of Ventricular Flow including 4D MRI ........................................................................................ 14 2.5.2 Pre-processing of MRI data ........................................................................................................................ 15 2.5.3 Post-processing: 4D MRI ............................................................................................................................ 16 2.6 Statistical Analysis ......................................................................................................................... 16 Results .................................................................................................................................. 17 3.1.1 Procedural Outcome .................................................................................................................... 17 3.1.2 Left Ventricular Function ............................................................................................................ 18 3.2 Left Ventricular Flow Dynamics ................................................................................................... 18 3.2.1 Flow Dynamics in the Infarcted Heart ....................................................................................................... 18 3.2.1 Flow Dynamics in the Repaired Heart .................................................................................................... 20 3.3 The influence of Chordal Cutting .................................................................................................. 21
Discussion ............................................................................................................................. 22 4.1 Key Findings .................................................................................................................................. 22 4.1.1 changes in ventricular function ................................................................................................................... 22 4.2 Pre-operative results ....................................................................................................................... 22 4.2.1 Myocardial infarction and Vortices ............................................................................................................ 22 4.3 Post-operative results ..................................................................................................................... 23 4.3.1 Annuloplasty and Vortices .......................................................................................................................... 23 4.3.2 Purpose of vortex formation ....................................................................................................................... 23 4.3.3 Chordal Cutting .......................................................................................................................................... 24 4.3.4 Hemodynamic flow and Chordal cutting .................................................................................................... 24 4.2 Limitations and future recommendations ...................................................................................... 24 Conclusion ............................................................................................................................ 25
Acknowledgements ............................................................................................................... 26
References ............................................................................................................................ 27
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Introduction 1.1 Ischemic Mitral Regurgitation
1.1.1 Prevalence, incidence, mortality and morbidity Ischemic Mitral Regurgitation (IMR) is a common complication related to coronary artery disease(CAD) and myocardial infarction (MI). (1) Up to 19% of patients with symptomatic CAD are found to have IMR during cardiac catherization and 29-62% among patients with myocardial infarction.(1-8)Of all cases involving IMR 6 -17% have severe mitral regurgitation (MR). (5,9,10) MI as a result of IMR has a twice as high mortality in comparison to MI in general. (11,12) The mitral regurgitation can cause heart failure and the increased left atrial pressure could lead to atrial fibrillation and pulmonary oedema. (11) This makes IMR a dangerous and clinically relevant complication of myocardial ischemia.
1.1.2 Pathophysiology When there is a decrease in oxygen supply toward the myocardium, ischemia and necrosis causes dysfunction and remodelling of the left ventricle (LV). (13) This consequently affects the support system of the mitral valve, which is closely entwined with the left ventricle, leading to malcoaptation and tethering of the leaflets. The first hypothesis was that the papillary muscles had to be involved in the ischemic area(14) This theory known as “papillary muscle dysfunction syndrome” was later disproved in an animal model where MI area is restricted to the PM and/or its close surrounding did not cause MR. (13) The subvalvular system, which consists of papillary muscles (PM) and chordae tendineae, works as a parachute. It prevents prolapse of the mitral valve under the high pressures during mid-systole and aids in opening the valve, when the ventricle dilates during diastole. The system is highly depended upon the function of the entire ventricle. This brings us to the now accepted theory as to why MI can cause MR. There are two mechanisms that ultimately lead to IMR. Firstly, due to MI a substantial LV area can become dysfunctional, hence the movement of the LV in general is altered, impaired or otherwise deviates from normal contractile function. Secondly, in the acute phase of an MI wall thinning and local ventricular dilatation are a result of intermyocyte collagen degradation, this will also cause the papillary muscles to shift out of place. (15,16) The shift of papillary muscles puts tensile stress upon the chordae tendinea causing tethering. Chordal tethering plays a mayor role in the pathophysiology of IMR and is also a factor in the failure of treatment. (17) This ventricular remodelling added to a dysfunctional ventricle causes further restriction of leaflets and induces valve tethering in acute MI. (18,19) The remodelling also has an effect on the annulus; the surrounding tissue of the valve where the leaflets attach to the heart. It partly consists of myocardium and cartilage and has a specific saddle shape. The ventricular remodelling causes the annulus to enlarge and deform. When losing its natural saddle shape, effective coaptation will no longer be possible. IMR can also arise from chronic ischemia, either caused by CAD or progressed MI. In the acute stage of MI only the affected portion of the ventricle remodels. When the disease progresses into a more chronic state, similar to CAD, the entire ventricle shows hypertrophy. The normal cone shaped LV becomes more cylindrical. (19) This has the same negative effects on the annulus and subvalvular system.
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1.1.3 Surgical treatment IMR is characterized by regurgitation with intact mitral valve leaflets but a disturbed chordal anchoring and tensioning in the infarcted myocardium. One could argue that (partly) resolving the ischemic damage will cause reverse remodelling and therefore lifting the IMR. This is true for highly selective patient groups where a percutaneous revascularisation (PCI) within 4 hours of the onset of MI can reverse the disease greatly. (20-22) IMR treated with PCI or coronary artery by-pass graft (CABG) in later stages or of a more chronic nature did not have favourable outcomes. (23) Studies showed that 40% to 60% of patients had persistent MR after CABG. (20,24,25) A reduced mid-term survival of residual MR after CABG was also found. (20) Isolated CABG is therefore not a viable treatment for IMR. (19) According to the guideline of the American Heart Association a mitral valve repair (MVP) in combination with a CABG is the preferred treatment of mild to moderate IMR. (26) A repair aims to relieve the tethering forces upon the valve and restore the annular geometry. In 97% of cases this is primarily achieved by annuloplasty: The placement of a ring on the atrial side of the mitral annulus. (27) This ring can be flexible or rigid, and primarily consists of a titanium core with a polyester cover that serves as a base for stitching. By freezing the annulus in the shape it has during systole, a more optimal coaptation can be achieved. In addition to the annuloplasty the surgeon can do specific repairs on the subvalvular system like shortening or reattachment of chordea tendinea.
1.2 Chordal Cutting The current most common therapy for IMR: reduction annuloplasty introduced by Bolling et al(28) as a known persistence of leaflet tethering. (29) It’s well recognized that this persistence of leaflet tethering is responsible for recurrent MR after restrictive annuloplasty. (30-33) Chordal Cutting, first proposed by Messas et al (34), is a treatment option that targets the subvalvular system by cutting specifically the basal chordea tendinea mostly in addition to annuloplasty. The basal chordea tendinea are defined as the first category of three based on their insertion on the mitral valve. (35)
1. Basal: Chordae who are attached to the base of the leaflet and or annulus 2. Intermediar: Chordae who are attached to the ventricular side of the leaflet 3. Marginal: Chordae who are attached to the margin of the leaflet.
The principle is based on the observation that the marginal chordae, which are positioned at the tip of the leaflet, predominantly prevent prolapse whereas the basal chordae serve the overall shape of the leaflet during systole and are more affected by ventricular remodelling. (34) Tethering by basal chordae causes the anterior leaflet to be pulled toward the aorta as a result of decreasing the mobility and causing malcoaptation of the leaflet. By cutting a minimal number of basal chordae mobility and coaptation can be restored without compromising the LV function.(36,37) Chordal Cutting among other subvalvular treatments is becoming a viable option during annuloplasty. (38).
1.3 Longterm Outcomes.
1.3.1 Repair Failure In two reviews assessing the functionality and outcomes of several treatment methods of IMR, Magne et al (9) describes the onset of recurrent mitral regurgitation after mitral valve repair. (19) Within 6 months of operation the prevalence of 2+ MR is already 15 – 25 % and will increase within 5 years towards possibly 70% (figure 1). A more recent study among a group of 251 patients with chronic ischemic mitral regurgitation conducted by Acker et al (39) found that repaired valves had 30% higher tendency of regurgitation in comparison to mitral valve replacement Another interesting
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finding is the lack of reverse remodelling in the cases with recurrence compared to cases without recurrent regurgitation. Recurrent mitral regurgitation after annuloplasty is primarily due to progressive ventricular remodelling, a lack of reversed remodelling, (19,39,40) or the ring design itself. Assessment of the mean annular shape in healthy patients have shown that the septo-lateral distance, which is the diameter between the aorta and posterior parts of the annulus, is greater in comparison to the generic ring prosthetics. (41) The implanted ring has a tendency to move toward the aorta pulling the posterior leaflet more towards the anterior also causing tethering and therefore regurgitation. The effects of recurrent MR on survival are unclear. LV function is the main prognostic determinant on long-term survival after MVP. (19) 2+ MR or higher is significant enough to cause extra workload to the LV, possible having a negative effect on the LV function. Acker et al (27) did a follow-up until one year and found no adverse effect of that kind. However, another study with a follow-up of 3 years found a reduced event free survival in patients with recurrent regurgitation. Considering that the 5-year survival among repair patients with chronic ischemic mitral regurgitation after repair is 58%. The effects of MR may therefor become clinicaly significant after a longer period of time.
Figure 1. Incidence of postoperative ≥2+ mitral regurgitation reported in the literature as a function of time after MVP. Julien Magne et al: Ischemic regurgition: a complex multifaceted disease (9)
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1.4 Intra-ventricular hemodynamics
1.4.1 Flow in the Healthy Heart The flow in the left ventricle has always been thoroughly investigated by different means. It started out with in-vitro visualisations, which first recognized the presence of vortices forming in the diastolic flow of the left ventricle. (42,43) With the progression of technology; colour Doppler mapping and later 4D flow Magnetic Resonance Imaging (MRI) it became possible to visualize the internal blood flow of the heart in greater detail. Yet the understanding of the behaviour of the blood flow in the LV has been very limited.(44-46) The blood flow within the ventricle can be divided into three components, each with different starting points and destinations within the cardiac cycle. (47,48) (figure 2) During diastole the flow from the atrium is split into two: 1) direct flow and 2) retained flow. The direct flow converts into 2 counter-rotating vortices residing close to the heart base, in some studies also referred to as a vortex ring. (47,49,50) The direct flow will be ejected into the aorta during the subsequent systole. The retained flow arises from between the two vortices moving directly towards the apex, where it will stay for the remainder of the heart cycle. During the following heart cycle, a part of the retained flow will be ejected. As a result, it takes two heart-cycles for the retained flow to get from the atrium into the systemic circulation, hence the name: delayed ejection volume. The third component is the residual volume; it is the volume that permanently resides in the ventricle. There is an exchange between the residual volume and delayed ejection volume, making the residual volume a dynamic component that can be addressed in times of need. The residual volume has a direct effect on the direct flow; it is hypothesized that the direct flow collides with the residual flow causing the vortex ring that remain close to the base of the heart, making a quick departure possible. (48) Therefore, the intra-ventricular flows are not only shaped by the anatomical structures of the heart, but also by the hemo-dynamics itself. One could say that these vortices are simply there; observations without any effect and therefore do not serve any particular purpose. Carlhall and Bolger (51,52) suggest something differently: Because vortices have a tendency to remain close to the heart base and have a circular direction toward the aorta means that the direct flow in the healthy heart only needs a change of direction in order to end up in the aorta . The amount of energy that needs to be put in is smaller. This efficiency is beneficial for cardiac function. In heart failure the implications of losing this efficiency are most clear. The formation of vortices close to the mitral valve has been observed in previous studies (42,43,45,49). It has been demonstrated that formation of vortex rings is more efficient when It comes to fluid transport than a straight flow, giving weight tot the notion that vortex formation is an important means of ventricular efficiency.
Diastole Systole
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1.4.2 Flow in heart failure and myocardial infarction In systolic heart failure end-diastolic and end-systolic volume are increased and cardiac-output decreased; the ventricle has become dilated and less functional, due to damage of the myocardium or overloading. This anatomical change is mirrored in the flow data, where the vortical flow structures of the exchanging volumes have been compromised. (48) The residual flow increases constraining the exchange in volumes that enter the ventricle. In addition, this residual volume is less available for recruitment into the exchanging components. The vortices, once part of the direct flow, are now bigger, slower and are directed away from the outflow tract. There is no longer a kinetic benefit to be gained from these vortices. This large quantity of retained flow must be redirected and reaccelerated. It is observed that there is a difference in the relationship between direct and retained flow when it comes to severe and compensated heart failure. The direct flow is estimated to comprise more than one third of end-diastolic volume in the healthy human heart, this decreases when heart failure progresses. (52) In mild or compensated heart failure there is a balance between direct and retained flow. (48)In decompensated heartfailure the retained flow is greater than the direct flow. (48) These findings suggest that the intra-ventricular flow can be used as an assessment or predictor for the long or short-term, of cardiac function.
1.4.3 Behaviour of Flow with Annuloplasty and Chordal Cutting A prior study was conducted among eight sheep by this institute analysing the influence of restricted annuloplasty on ventricular flow (53). The results showed that the blood flow is redirected after annuloplasty. The inflow jet is more directed towards the septum and in addition results in alteration or elimination of the observed vortex ring. These findings were contradictory to the expectation that the influence would be minimal because the subvalvular apparatus remained untouched in the procedure. This elimination is most probably caused by the smaller ring sizes used in this study. (54) In spite of the deterioration of vortices, the LV function in the subjects remained the same. Future work is needed to quantify energy efficiency or draw any conclusions on long-term effects. In vitro studies have suggested that abnormal vortex formation is correlated with poor cardiac function.
Figure 2. Schematic representation of the left ventricle and its components of flow through the heart cycle. 1: direct flow. 2: indirect flow during first heart cycle. 3: indirect flow during subsequent heart cycle. 4: residual flow. Note that the indirect flow and residual flow exchange volume constantly.
End-systole
Early-diastole Mid-diastole
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(49,50) Despite the absence of quantifiable evidence, the influence of annuloplasty on ventricular flow must not to be underestimated. Especially when the consequences on the long-term are unknown. Further investigation to address the effects of disease, like myocardial infarction, on ventricular flow is necessary. The altered wall morphology and function and tethering added to an annuloplasty could all contribute to alterations in ventricular flow. Chordal cutting added to these factors could have a significant effect on the intra ventriculair bloodflow patterns. The subvalvular apparatus is intwined with the ventricle and contributes to its ventricle. We therefore expect notable effects from subvalvular procedures like chordal cutting.
1.5 Posing the Question The main question was the influence of the annuloplasty and chordal cutting on the flow patterns and function of the left ventricle. This study is a continuation of earlier work by this institute on annuloplasty and ventricular flow in healthy animals. A quantitative assessment has been made on the intraventricular flow by using 4D flow MRI data; which makes it possible for us to assess whether the vortices described in previous studies are present after MI and a repair. Does chordal cutting alter intraventricular flow? Does it impair or improve LV function? Is it possible to draw conclusions on the long-term effects of chordal cutting?
1.6 Aims of the research The purpose of this study is to do a qualitative assessment with 4D flow MRI of the influence IMR and the surgical intervention on intra ventricular flow of the LV.
1. To determine the effect of myocardial infarction on the intra-ventricular blood flow. 2. To determine the effect of ring-implantation on sick heart. 3. Investigate if hemodynamic measurements can explain differences in hemodynamic flow. 4. Investigate the effect chordal cutting might have on intra-ventricular blood flow.
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Material & Methodes
2.1 Study Design This study is a qualitative cross-sectional observation.
2.2 Animal model The animal used in this study is the Dorset sheep. Sheep have been widely used as a model for cardiovascular research, especially for testing intra-cardiac devices (55,56). Hemodynamic parameters like heart rate, systemic and intracardiac pressures approximate that of human values (57). This model is also suitable for the purpose of this study. First, the anatomy of the mitral valve is the same on the key elements: annular geometry, amount of leaflets and orientation of the subvalvular system (anteriolateral and posteriomedial papillary muscle groups). Second, the lack of a collateral coronary network, which is similar to the human anatomy, makes creating myocardial infarction by ligation possible (58).Finally, the lab’s extensive experience in comparable circumstances shows that sheep can be easily handled and to produce representable data(Gorman studies).
2.3 Experimental Procedures
2.3.1 Procedure Overview Twenty five animals underwent three procedures in a period of 10 to 16 weeks:1) surgery for myocardial infarction induction, 2) preparation after 8-12 week follow-up for 4D flow MRI and 3) annuloplasty, with or without chordal cutting, all following the same peri-operative protocol. Chordal cutting in addition to a ring device was randomized. The used protocol is in accordance with National Institutes of Health’s “Guide for the Care and Use of Laboratory Animals”. During every stage of every procedure hemodynamic data like, arterial blood pressure (ABP), pulmonary wedge pressure (PCWP), central venous pressure (CVP) and cardiac output (CO) were monitored and collected via catheter probes. During open thorax procedures imaging of the mitral valve were acquired with echocardiogram for image processing. MRI data was collected on the second procedure and straight after ring implantation on the third procedure. A complete overview of procedures and the respective data collected at that time can be seen in table 1.
2.3.2 General Pre- and Post-Operative Procedures Venous access, needed for infusion of fluids, drugs, monitoring of blood pressure and to obtain blood samples, was gained with a venous-catheter, which was introduced via percutaneous puncture of the jugular vein. The animal was sedated, weighed and transported to the operating room and intubated. During the procedure anaesthesia was maintained with isoflorane. After completion of the procedure the animal was weaned from isoflorane and ventilated with 100% oxygen until spontaneous breathing was achieved. Analgesia was maintained with fentanyl, flunixin and buprenorphine. The animal was transported to a cage in the recovery room and extubated after
Table 1. overview of procedures and acquired data
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gaining adequate muscle tone. The following hours the vital signs, general demeanour and evidence of pain of the animal were closely observed.
2.3.3 Procedure 1: Surgery for myocardial infarction induction After preparation an incision was made on the 4th intercostal space. The thoracic cavity was exposed after careful dissection of subcutaneous tissues and muscle layers. After opening the pericardium an echocardiogram was made. The coronary anatomy was inspected to determine the appropriate artery to ligate in order to cause an infarction in the posterolateral left ventricular wall. Ligation was achieved with non-absorbable sutures. The epicardial echocardiogram is repeated and the animal was closely monitored to ensure the animal was stable for closure. When needed, small implantable epicardial pacing leads were secured to the atrial appendage.
2.3.4 Procedure 2: 4D flow MRI Acquisition After an 8-12 weeks consolidation period following the induction of myocardial infarction the first MRI was performed. The second MRI was performed straight after ring implantation. The animals were brought into the OR in preparation for the MRI. During the entire procedure the animal was under general anaesthesia. Procedure of acquisition did not differ between the two scans. Images were acquired using a 3T MRI system (Tim Trio; Siemens Healthcare; Erlangen, Germany). The scanner was equipped with a 40mT/m gradient coil and 18 channel RF receiver array. Cardiac gating was performed using a pressure transducer. Cardiac gating is a manner of synchronising the heart cycle with the scanning process in order to acquire stable images of the heart. An external ventilator enabled breath-holding procedures and allowed us to perform respiratory gating. A 2D retrospectively gated balanced steady-state free-precession acquisition was used to obtain 2, 3, and 4 chamber and short axis views. Parameters were as follows: TE=1.2 ms, TR = 2.4 ms, matrix = 192 x 156, Field of View = 260-340 x 260-340 mm2, Band Width = 1185 Hz/pixel, segments = 7, temporal resolution = 20 ms, cardiac phases = 30, slice thickness = 4 mm and no gap between slices. 4D flow was acquired with a dual respiratory and cardiac prospectively-gated cine phase-contrast MRI sequence. The following parameters were used: temporal resolution = 20.8 ms, spatial resolution = 2 x 2 x 2 mm3, flip angle = 8°, field of view = 320 mm x 320 mm, pixel bandwidth 460 Hz/pixel. Velocity aliasing during diastole was minimized by adjusting the velocity encoding sensitivity during diastole for each animal.
2.3.5 Procedure 3: Annuloplasty with or without chordal cutting 2 – 4 weeks after the first MRI, the animals were taken back to the operating room. After the standard preparation procedures the thorax was reopened. An echocardiogram was performed. The animals underwent cardiopulmonary bypass and cardiac arrest was evoked with cardioplegia. The mitral valve was exposed through a left atriotomy. The device insertion of a 28 mm Physio Ring (Carpentier-Edward™) was done with 2-0 Ti-Cron® sutures. Animals that were randomly selected also received a chordal cutting. The animal was re-warmed after closure of the atriotomy and a second echocardiogram was performed. The chest was closed after the surgical team established that the animal was stable and had an acceptable cardiac function. Then, the animal was transported to the MRI under general anaesthesia. Finally, the animal was taken back to the OR after completion of the scan and terminated. The heart was excised for inspection and used for histologic research in other projects.
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2.4 Assessment of left ventricular function The end-systolic (ESV) and end diastolic volume (EDV) were computed by contour tracing the endocardial border of the LV in short axis MRI images in QMass (Medis; Netherlands). Papillary muscles were included in the volume. The biggest and smallest volume of the LV within the cardiac cycle were selected to represent the end-systolic and en diastolic phase. Stroke volume (SV) was calculated from subtracting ESV from EDV. Ejection fraction (EF) was calculated by dividing SV by the EDV x 100%.
2.5 Processing of MRI data
2.5.1 Analysis of Ventricular Flow including 4D MRI The mathematical analysis of flow can be seen as particle(s) moving through space. The analysis works with velocity vectors: a point in space that describes the heading and speed of a particle. The MRI measures a velocity field within a 3D region of interest. In figure 3A the velocity field is represented in a two dimensional manner. From this vector field streamlines can be derived. Streamlines are curves that are everywhere tangent to the local instantaneous velocity field. A streamline represents the direction of flow at a given instant fixed in time and can differ each instant in time, as is represented in figure 3B. In mathematical terms: the vector has to be equal to the integrated curve of the streamline. When you add the factor of time you will produce path lines. Path lines are the trajectories followed by a fluid particle marked in the flow at specific location and started at a specific time. In figure 3C you can see that when you add the factor of time to the velocity vectors and streamlines you can follow particles that have started from a specific place through time. With the velocity field measurements acquired from MRI and post-processing methods we can determine the path lines of the flow within the left ventricle during the heart cycle.
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2.5.2 Pre-processing of MRI data MRI data has been processed with noise-cancelation software (supertool ®). By adding filters the excess imaging noise that mostly resides in air-filled cavities are removed, leaving the relevant vector fields within the circulatory system as untouched as possible. Filters were added, left out or adjusted for the best results (figure 3). The files were exported into Ensight compatible files.
Figure 3. A schematic representation of (A)Velocity fields and streamline derived from velocity fields with equation describing the relationship between streamline and velocity field vector. (B)Velocity fields and streamline as they are different at each instant in time (C) Schematic representation of pathlines derived from velocity fields and streamlines as shown in B
A B
Figure 3. A: raw 4Dflow MRI data with excess noise. B: 4Dflow MRI data after addition of noise filters note the absence of noise in air filled cavities.
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2.5.3 Post-processing: 4D MRI Ensight (Ensight, CEI, Apex, NC) is a software package capable of performing fluid dynamics analysis. The program makes it possible to produce a visual representation of interventricular flow in a wide variety of digital media. Apart from qualitative, quantitative analysis can also be performed by the software. Atrial ventricular flow is calculated and exported into the dataset. The MRI data is loaded within a cuboid volume containing a 3D representation of the entire left ventricle and atrium during all cardiac phases. The user will be able to navigate around and zoom in and out into the 3D representation of the data and can also navigate through time. Planes parallel to the cuboid faces can be added within the volume to show either magnitude or velocity MRI images within a specific time point of the cardiac cycle. Magnitude MRI images show anatomy and velocity MRI images show particle velocities in a colour scale. The planes can be shifted within the cuboid, this allowed us to go through the images in a manner similar to MRI diagnostic imaging programs. By using velocity colour scales and changing the time point to early diastole the inflow jet of the left ventricle became clearly visible. Another plane which gives a cranial/caudal short-axis view was moved toward the location of the vena contracta of the inflow. A plane was placed in the cuboid on the same location. By using the short and long axis views on the carnial/caudal plane and the added plane was manipulated until it enveloped the vena contracta of the outflow jet as tightly and as close to the mitral valve as possible. A visual representation of the process steps are in a figure in the appendix. The plane was selected to produce path lines from its origin and the orifice of the cross-section of the vena contracta was calculated. This allows tracing of every particle that passes through this plane during the cardiac cycle and its motion path line plotted in space. By adding the velocity colour scale to the traced paths, the speed of the individual particles became visible. The tracing can be animated which gives a visual representation of diastolic inflow. For better results the speed and length of the trace animations can be adjusted accordingly. Ensight enabled us to make media files, we mostly produced MPEG4 movies and JPEG image series. All images or videos were shot from a long-axis 3 chamber point of view. This ensured that the image contains the LV, LA, mitral valve, LV outflow tract and Aorta. Evidently all these structures participate in guiding the flow from lung to central circulation. Within the frame a colour scale was added which expresses the speed of flow in cm/s. One JPEG image series contained 1 cardiac cycle. 3 Images from early diastole, mid-diastole and early systole were selected for qualitative assessment.
2.6 Statistical Analysis Quantitative data was processed using Microsoft Office Excel 2013. Statististical analysis was done with SPSS version 21 (SPP, Inc., Chicago, IL) Measurements are reported as mean with standard deviation. Differences between post-MI and post-repair flow parameters were assessed with a paired Student’s t-test or Wilcoxon Signed Rank test depending on distribution. Nominal Endpoints were analysed with Chi-Square test. For all tests P<0.05 was considered statistically significant.
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Results
3.1.1 Procedural Outcome In a one-year period 25 animals were processed (figure 4)(mean weight = 60.8 ± 20.8 kg). Nine out of the 25 animals survived the entire process, yielding satisfying results. With one animal it was not possible to acquire MRI data because of stability issues during scanning. Seven animals died during ring implantation, the cause of death was mostly an arrhythmia or tissue tear. Seven animals died shortly after MI induction, mostly because of Congestive Heart Failure (CHF). Two animals died because of reasons unrelated to the study procedures. The acquired data per animal may vary. In total we acquired 18 first MRI’s and nine post-operative MRI’s. Echo data in every animal was collected during every open thorax procedure, however only data from nine animals was available. Due to lack of time, only the echoes of animals that survived all procedures have been processed and are therefor useable in this study.
Figure 4: Overview of survival during experimental procedures.
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3.1.2 Left Ventricular Function
Hemodynamic data derived from MRI data shows the overall cardiac function before and after implantation of the annuloplasty ring. All parameters were distributed normally. There was a decrease in all parameters except for Heart Rate, which shows a significant increase. Of the decreasing parameters EDV and SV were significant. Although a decreasing trend is visible it is not as significant as the decrease in ESV, EF and CO.
3.2 Left Ventricular Flow Dynamics
3.2.1 Flow Dynamics in the Infarcted Heart A total of 18 flow patterns have been analysed in the post-myocardial phase. All images were analysed from a three-chamber long axis view. The Mean peak flow is 330.0 cm/s (± 46,01) and the mean surface of the vena contracta 902.82 mm2 (±127,81) The transmitral blood flow in all cases is characterized by vortices forming close to the heart base in early systole. Although not always apparent or coherent they are observable in all but one sheep. These high velocity vortices have a tendency to form two clusters behind the anterior and posterior MV leaflets. They tend to have a same size and are counter rotating. In most cases (15 out of 18) these vortices have disappeared before the beginning of the systolic phase. In some animals (n=2) the vortices migrate towards the apex during diastole. Between the two vortices a big mass of fluid, roughly consisting of 2/3 of the observable inflow, is ejected directly toward the apex. This column can behave in two manors. Either the column converts into 1 or more vortices that last throughout the diastolic phase. Or the column moves towards the apex, where it unwinds in incoherent flow. Nine animals showed apical vortices and six showed no vortices formed. Three animals did not show a clear column moving towards the apex. A third aspect observed was the participation of the vortices in the outflow towards the aorta during systole. Ten cases showed clear participation. This flow was recruited from the apical vortices (n=6) and basal vortices (n=4). None of the cases showed participation from both basal and apical vortices. In six cases all vortices had unwound before the beginning of systole and could therefore not directly contribute to the outflow and in two cases no outflow has been observed at all.
Table 2: Hemodynamic data compared pre and post-operatively. Significant p value = 0.05
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Figure 5. Pre-Operative long-axis three chamber MRI views of ventricular 4D flow during early diastole (A) mid-diastole (B) and early systole (C). Top: Basal vortices with column of flow ejected towards apex forming a pical vortices. Bottom: basal vortices, column ejects towards apex without dispanding into vortices
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3.2.1 Flow Dynamics in the Repaired Heart The vena contracta is significantly smaller 499,81 mm2 (±192,87) and the flow has decreased with 141,05 cm/s (±55,70). In general the flow dynamics after annuloplasty showed the same characteristics and individual differences. The formation of basal vortices is present in all but one case. They are formed more coherently into two counter-rotating vortices close to the mitral leaflets compared to infarcted hearts without annuloplasty. There is no difference between pre and post-operative populations if it comes to the formation of apical vortices (p=0,761). The apical vortices in post-operative animals do, however have a tendency to merge with the basal vortices forming a helical pattern spreading throughout the posterior wall of the left ventricle. The helical tendency has been observed in pre-operative animals but was again much less apparent. In other observations like column forming, conservation and participation of vortices in the outflow no difference in occurrence between pre and post-operative animals has been found.
A
A B C
B C
Figure 6. Post-operative long-axis three chamber MRI views of ventricular 4D flow during early diastole (A) mid-diastole (B) and early systole (C). Top: Basal vortices with column of flow ejected towards apex forming apical vortices. Bottom: basal vortices, column ejects towards apex without disbanding into vortices
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3.3 The influence of Chordal Cutting Of the animals operated (n=9) five received a cutting procedure of the basal chordae. Hemodynamically only the end diastolic volume (100,32 ml ±6,68) and cardiac output measured over the catheter are significantly higher than in animals where no chordal cutting has been done. There is no correlation between chordal cutting and the observation of apical flow in post-operative animals (p=0,764). Overall there is no correlation between chordal cutting and the observation of flow patterns.
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Discussion We did a qualitative study on interventricular blood flow patterns under the pathological circumstances of a myocardial infarction with ischemic regurgitation in sheep pre and post repair. A focus of the study was the influence of chordal cutting.
4.1 Key Findings
4.1.1 changes in ventricular function In earlier research baseline MRI’s of healthy sheep with the same weight distribution showed much smaller EDV and ESV. This difference is in accordance with the expected LV remodelling causing an increase in volume and decrease in effective function. Comparing the ventricular function of healthy animals there is a much larger ventricular volume and output in the infarcted animal. The increased ventricular volumes are as expected because the remodelling in regurgitation causes dilatation. Measurements like EF, SV and CO are derived from a subtraction of EDV and ESV. This method prevents us from knowing where the output is heading. When the mitral valve regurgitates part of the ejection volume as derived from LV-volume measurements is going back into the right atrium creating “ineffective” cardiac output. Furthermore the regurgitation causes a decrease in afterload which increases output measurements even further In this context the pre- and post-operative left ventricular function as derived from MRI data shows a remarkable reduction in EDV in combination with stroke volume and, although not significant, cardiac output. The significant reduction in SV post-operatively can be explained by the elimination of backflow. The reduction in EF and CO can in part also be explained by this, but one also have to take in account the increased effort the LV has to make in order to produce CO.The decrease in EDV is also found in similar studies and could be explained by reverse remodelling of the left ventricle after lifting the mitral regurgitation. (59-61) The overall conclusion that can be derived from this data is that the annuloplasty is successful in lifting the MR.
4.2 Pre-operative results
4.2.1 Myocardial infarction and Vortices The healthy sheep heart shows blood flow patterns characterized by the formation of two vortices close to the mitral valve and a central column of fluid that directs toward the apex. (53) In this study the flow clearly separates in different components moving towards different parts of the LV. We observed the vortices close to the mitral valve as basal vortices in all animals. Although there was a tendency to form two counter rotating vortex clusters, it lacked overall consistency among the animals. The behaviour of the fluid column lacked consistency as well. The fluid column did behave in two distinguished ways; either converting in to vortices or unwinding in incoherent flow, but an explanation as to why was not found. In the context of flow components of which some clearly participate in the outflow and some don’t. As described in other studies, it was expected that the basal vortices are the direct flow component and the apical vortices are indirect flow. (47,48) When we observed participation in the out flow,which was not always the case, we saw either participation of the apical or the basal vortices. Direct flow should remain closer to the heart base while indirect flow moves towards the apex. In the infarcted heart it seemed that the direction of the direct and indirect flow is variable. In conclusion the flow patterns in the infarcted heart are recognizable but lack structure as seen in the healthy heart.
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4.3 Post-operative results
4.3.1 Annuloplasty and Vortices Witschey et al (53) showed that the influence of restrictive annuloplasty on interventricular flow patterns is significant. Causing little to moderate stenosis and a deterioration of vortices depending on the size of the annuloplasty rings. At first it was not expected that the annuloplasty would have any effects on flow patterns worth mentioning, because the subvalvular apparatus was left alone in these experiments. Our experiment used only 28 mm rings, which is close to physiological size. Overall the flow patterns did not change in our experiment between pre and post-operative scans. Any changes that occurred were not consistent among the entire group and no factors could be linked to explain it. The effect of normal size annuloplasty on intra ventricular flow patterns, as observed in this study, is therefor minimal. Even chordal cutting, which can be considered a subvalvular procedure did not seem to have any observable effect. From these findings compared to those of Witschey we can conclude that size of annuloplasty rings matters most in intra ventricular flow patterns. Although the components of healthy flow patterns are observed pre- and post-operatively, we can’t draw any conclusions on whether these flow patterns are to be defined as normal. In our study with under sizing the vortices are eliminated all together, this is not the case in normal sized rings and therefor not the case in this study in which normal size rings were used. The size of the outflow tract of the mitral valve seems to have the biggest impact on vortex formation, the impact of IMR or myocardial infarction seems to be smaller.
4.3.2 Purpose of vortex formation The formation of vortices close to the mitral valve has been observed in previous studies (42,43,45,49). It has been demonstrated that formation of vortex rings is more efficient when It comes to fluid transport than a straight flow, giving weight tot the notion that vortex formation is an important means of ventricular efficiency. Kim et al (45) dismisses this hypothesis with the argument that the calculated energy storage within the vortices observed is insignificant compared with the total stroke work of the left ventricular output. They also found that most of the energy of the vortices was lost before systole. This was partly observed in our study where vortices in some cases had unwound long before systole had begun. The purpose of vortices in the context of energy preservation therefore remains a topic of discussion. Looking at our data the absence or presence of vortices does not seem to make a difference if it comes to ventricular function on the short term. The repair mostly influences the ventricular function and the repair does not seem to have a coherent effect on vortex formation. Carlhall et al(48) described the exchanging components of diastolic flow (direct and retained) to be more constrained to a smaller space. Another study showed that in acute myocardial infarction the distance travelled by the inflow was significantly shorter. (62) This shortening is explained by dyskinesia or akinesia of the ventricular wall. The flow as observed in hearts with congestive heart failure shows the same pattern. (48) The residual flow as volume is increased in the failing heart keeping the direct and indirect flow away from the apex. Allthough not observed objectively, the tendency to remain close to the heart base has also been seen in some of our animals. Gharib’s theorem on vortex formation states that vortices need time to form. (49) This vortex formation time is influenced by EDV, EF and diameter of the mitral valve. The EDV defines the space needed to form the vortices, it does not take the possible contraining effect of the residual flow in to account. In light of these studies and our findings it seems plausible that the vortex formation of the exchanging volumes in the dialostolic flow is disturbed by the smaller space the have to form in, leading to the incoherent vortex formation as seen in our observations.
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4.3.3 Chordal Cutting When chordal cutting was applied, the EDV and CO were significantly higher than non-cut animals. In a comparable study, investigating the effects of chordal cutting in sheep and pigs, showed a decrease in EDV which was not significant (34). The same results were shown in a study among patients(38). A different study did show increase in LV volume (63). Da Col et al related the discrepancy between the latest 2 studies to the chronic and acute setting of the IMR, the acute setting showed EDV increase (64). The explanation given was that the acute affected myocardium was more subject to remodelling because there is still healthy tissue that can react to the changes. Our study can be considered a chronic setting because of the 8 – 12 week consolidation period after MI induction. As a result, the theory of Da Col cannot explain the EDV increase. The EDV increase could be a direct effect of the chordal cutting. Even though studies showed that the ventricular/valvular structure is preserved with current chordal cutting techniques, the structural integrity could be affected by the surgery. Long-term effects of chordal cutting show that EDV increases by 28% but still significantly less than in patients with ring annuloplasty alone. (65) The increased EDV in our study could be a short-term effect that resolves over time.
4.3.4 Hemodynamic flow and Chordal cutting Hemodynamically there have been no differences observed in flow patterns when it came to chordal cutting. When looking at the observed flow patterns in our study in the context of the described three components of left ventricular flow (Direct, Indirect and Residual) we can conclude that flow was notably altered by chordal cutting. This is contradictory to our expectations that there would be a notable difference. A main concern with chordal cutting is the maintainance of chordal continuity and its role in LV function. The minimal effect the chordal cutting has on the intraventricular flow can be explained by the small amount of chordea that are cut. The main goal of chordal cutting is prevention of recurrent MI by relieve of tethering of the mitral leaflets. Compared to controls chordal cutting does reduce recurrent mi and shows equal postoperative outcomes (66). No worsening of LV function showed, which could indicate that the chordal continuity is not compromised. The lack of influence of chordal cutting on intra ventricular flow is a
4.2 Limitations and future recommendations Because of the limited stress we can put on the animals, it was not possible to also include a baseline MRI in the protocol. Therefore the observations on healthy intra-cardiac flow have been based on other animals which limits our understanding of the transition from physiological flow to pathological flow. The flow made visible is only inflow from the mitral valve. The emitting plane is placed on the outflow tract of the mitral valve. Blood that already resides in the heart at the time of early diastole is thereby not visible. It is therefore difficult to make statements about the residual and indirect flow. A good future recommendation would be to improve post-processing methods so that residual flow and indirect flow can be fully included into the study. The size of the myocardial infarction is a factor that has not been investigated by this study. Because ventricular wall hypertrophy and dysfunction of wall motion are important factors in IMR, it could also have effects on intra-ventricular blood flow.
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Conclusion We looked at intra-ventricular blood flow patterns in sheep with induced myocardial infarction and ischemic mitral regurgitation who underwent an annuloplasty of the mitral valve. In addition we looked at the influence of chordal cutting on these bloodflow patterns. Compared to healthy blood flow patterns in healthy animals the blood flow in the sick ventricle has the same components. The residual flow seems to have increased There is not much difference in blood flow patterns between pre- and post-operative animals suggesting that normal sized rings do not have significant effects on the intra ventricular blood flow. Chordal Cutting, although a procedure affecting the subvalvular system, also showed to be little to no influence on the blood flow patterns. These results are in coherence with other studies showing that chordal cutting has little to no effect on ventricular function.
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Acknowledgements First and foremost I want to thank Prof. Joseph H. Gorman III and Prof. Robert C. Gorman for inviting me to their lab and giving me the chance to work in an extraordinary environment with extraordinary people. It has always been a dream to live and work in the United States in the field of medicine that I love. It cannot be said enough that I’ve been offered chances a lot of my fellow students would be jealous off. Being this closely involved in large animal studies, is not something you will be offered every day. I want to thank Dr Walter Witschey for introducing me into the complex world of MRI and 4D flow analysis. Without his guidance this internship would not have been possible. Joyce Han for showing me how to operate the software. Christen Dillard, Daniele Brown, Javier Gentile, Madeline Vind, Sabrina Leventhal and Jerry Zsido were the beating heart of the lab. They are the living proof that you can’t get anything done without a team that works as one. A special thanks goes out to Eric Lai for his attempts to teach me how to process echo data, and debating our on going research endlessly in the moments that we passed each other in the office. Every word in this thesis has been thoroughly checked for grammar and spelling errors by Maaike Buitelaar and Nada Ouf. I am grateful for the watching eyes of dr. M.E. Erasmus and dr. W. Bouma, who followed my progress closely from Groningen. I would also like to thank dhr. J.R. Huizenga and Valerie Sica for helping me with the tricky logistics of getting me on that plane.
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