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MITRAL REGURGITATION IN LEFT VENTRICULAR ASSIST DEVICE (LVAD) PATIENTS _______________ A Thesis Presented to the Faculty of San Diego State University _______________ In Partial Fulfillment of the Requirements for the Degree Master of Science in Bioengineering _______________ by Bradford G. Fisher Fall 2010 iii Copyright © 2010 by Bradford G. Fisher All Rights Reserved iv DEDICATION This thesis is dedicated to my loving parents, Diane Branman and Dale Fisher. v Such is the audacity of man, that he hath learned to counterfeit nature, yea, and is so bold as to challenge her in her work. ―Pliny the Elder vi ABSTRACT OF THE THESIS Mitral Regurgitation in Left Ventricular Assist Device (LVAD) Patients by Bradford G. Fisher Masters of Science in Bioengineering San Diego State University, 2010 The heart pumps blood around the body. Its most important component is the left ventricle (LV) because it pumps freshly oxygenated blood out to the entire body. Heart failure is when a diseased heart cannot provide the body with enough blood flow. One treatment option for heart failure is the Left Ventricular Assist Device (LVAD). It is an implantable mechanical pump that augments the LV function and ensures adequate blood flow to the body. One example is the Thoratec HeartMate II, a new and popular LVAD model. The mitral valve prevents blood from flowing backward from the left ventricle to the left atria. Mitral regurgitation, a common problem in heart failure patients, is when the valve does not function normally and blood does flow backwards across it. In this investigation the SDSU Cardiac Simulator was used to examine mitral regurgitation in LVAD patients with a closed aortic valve. Mitral regurgitation was found in simulations with an incompetent mitral valve, but not in simulations with a normal mitral valve. Surgical mitral valve repair should be considered in these patients to prevent mitral regurgitation and its detrimental effects.. vii TABLE OF CONTENTS PAGE ABSTRACT ............................................................................................................................. vi LIST OF TABLES ................................................................................................................... ix LIST OF FIGURES ...................................................................................................................x ACKNOWLEDGEMENTS ................................................................................................... xiv CHAPTER 1 BACKGROUND ...........................................................................................................1 1.1 Heart Physiology ................................................................................................2 1.2 The Cardiac Cycle..............................................................................................4 1.3 Heart Failure ......................................................................................................6 1.3.1 Causes .......................................................................................................6 1.3.2 Symptoms .................................................................................................7 1.3.3 Incidence, Mortality, and Economic Impact .............................................7 1.4 Left Ventricular Assist Device (LVAD) ............................................................9 1.4.1 Pulsatile Pumps .........................................................................................9 1.4.2 Continuous Flow Pumps .........................................................................10 1.4.3 Outpatient Management and Medical Therapy.......................................10 1.5 HeartMate II .....................................................................................................11 1.5.1 Pump Function ........................................................................................13 1.5.2 Vital Peripheral Components ..................................................................14 1.5.3 Clinical Studies .......................................................................................15 1.6 Mitral Valve .....................................................................................................16 1.6.1 Mitral Valve Disease...............................................................................20 1.6.2 Mitral Valve Repair ................................................................................22 1.7 Reverse Remodeling ........................................................................................24 1.8 Aortic Valve Closure .......................................................................................25 2 MATERIALS AND METHODS .................................................................................27 2.1 Specific Cardiac Simulator Setup for this Experiment ....................................29 viii 2.2 Cardiac Simulator Control ...............................................................................31 2.3 Data Acquisition and Sensors ..........................................................................32 2.4 Experimental Design ........................................................................................32 3 RESULTS AND DISCUSSION ..................................................................................35 3.1 Study 1 .............................................................................................................35 3.1.1 Pressure and Flow Waveforms ...............................................................36 3.1.2 Variable Relationships ............................................................................37 3.1.3 Conclusions .............................................................................................41 3.2 Study 2 .............................................................................................................41 3.2.1 Initial Examination of different Mitral Conditions .................................42 3.2.2 Relationships between Independent and Dependent Variables ..............44 3.2.3 Mitral Incompetence, Regurgitation, and TVP .......................................55 3.2.4 Effects of Mitral Condition and Cardiac Function on Flow ...................57 3.2.5 Conclusion ..............................................................................................59 4 SUMMARY AND CONCLUSION ............................................................................61 4.1 Background ......................................................................................................61 4.2 Materials and Methods .....................................................................................62 4.3 Results and Discussion ....................................................................................63 4.4 Conclusion .......................................................................................................65 REFERENCES ........................................................................................................................67 APPENDIX A STUDY 2 DATA .........................................................................................................70 B PRESSURE COUPLING BETWEEN AORTA AND LEFT VENTRICLE ..............74 ix LIST OF TABLES PAGE Table 1.1. List of Abbreviations ................................................................................................3 Table 1.2. The Cardiac Pump Cycle ..........................................................................................4 Table 1.3. The ACC/AHA and NYHA Classifications for Heart Failure Severity ...................6 Table 1.4. Conditions that Commonly Contribute to Heart Failure ..........................................7 Table 1.5. Age adjusted HF Incidence Rate per 1,000 Person Years ........................................8 Table 1.6. Classes of Therapy for LVADs ..............................................................................10 Table 1.7. Continuous Flow LVADs and the Therapy for which they are Federally Approved......................................................................................................................11 Table 1.8. The Layers of Valve Tissue: Fibrosa, Spongiosa, and Atrialis/Ventricularis ........19 Table 2.1. Experimental Design: all Combinations of the below Variables Tested ...............34 Table 3.1. Variables for a Normal Patient without an LVAD Compared to Target Values from Previous Trials ........................................................................................36 Table. 3.2. Results from Study 1; Normal MV (a) and Absent MV (b) ..................................40 Table 3.3. Previous Study Comparison; Zamarripa Enriquez-Almaguer and Samaroo ..........54 Table 4.1. Summary of Study 2 Variable Relationships ..........................................................64 Table A.1. Study 2 Data part 1 ................................................................................................71 Table A.2. Study 2 Data part 2 ................................................................................................72 Table A.3. Study 2 Data part 3 ................................................................................................73 Table B.1. Amplitude of LVP and AoP under several Flow Conditions and the Percentage Difference between them...........................................................................76 x LIST OF FIGURES PAGE Figure 1.1. A frontal cross-section of a human heart displaying the four chambers, the four valves, and the connecting vasculature. Source: Sylvia S. Mader, Understanding Human Anatomy and Physiology 5th ed.: The McGraw−Hill Companies, 2004............................................................................................................1 Figure 1.2. The path of blood as it flows through the heart. Source: Arthur C. Guyton and John E. Hall, Textbook of Medical Physiology 11th ed. China: Elsevier Inc., 2006. ......................................................................................................................3 Figure 1.3. The pressure, volume, and flow with respect to cardiac pump cycle. Source: Despopoulos and Stefan Silbernagl, Color Atlas of Physiology 5th ed., Suzyon O’Neal Wandrey, Ed. New York: Thieme, 2003. ......................................5 Figure 1.4. Incidence of HF by age and gender. Source: Robert J. Adams et al., "Heart Disease and Stroke Statistics 2010 Update. A Report From the American Heart Association," Circulation Feb 2010; 121: e46 - e215., vol. E, no. 121, pp. 46-215, Feb 2010. ......................................................................................8 Figure 1.5. Position of implanted HM II and percutaneous line connected to exterior System Controller. Holstered rechargeable battery packs connected for mobile use. Source: HeartMate II® Left Ventricular Assist System Clinical Operation and Patient Management. (2010) Thoratec Corporation. [Online]. http://www.thoratec.com/ ............................................................................................12 Figure 1.6. Cross-section of HM II pump. Source: HeartMate II® Left Ventricular Assist System Clinical Operation and Patient Management. (2010) Thoratec Corporation. [Online]. http://www.thoratec.com/........................................................12 Figure 1.7. The LV pressure is coupled to LVAD flow. Source: HeartMate II® Left Ventricular Assist System Clinical Operation and Patient Management. (2010) Thoratec Corporation. [Online]. http://www.thoratec.com/ ........................................13 Figure 1.8. Vital peripheral HM II system components: (a) System Controller, (b) System Monitor, (c) Rechargeable battery packs, (d) Power Base Unit (PBU), and (e) Emergency Power Pack (EPP). Source: HeartMate II® Left Ventricular Assist System Clinical Operation and Patient Management. (2010) Thoratec Corporation. [Online]. http://www.thoratec.com/ ........................................15 Figure 1.9. Basic anatomy and components of the MV. Source: David H. Adams. (2010, June) Mitral Valve Repair Center at The Mount Sinai Hospital. [Online]. http://www.mitralvalverepair.org/ ................................................................17 Figure 1.10. Saddle shape of the MV annulus relative to leaflet structure. The highest point is between markers 4 and 5 on the side of the anterior leaflet with a xi smaller peak near marker 10 on the side of the posterior leaflet. Source: Chad E. Eckert et al., "In Vivo Dynamic Deformation of the Mitral Valve Annulus," Annals of Biomedical Engineering, vol. 37, no. 9, pp. 1757-1771, 2009. ...................18 Figure 1.11. Mitral valve leaflets: (a) top view of leaflets during coaptation with labeled axes, (b) diagram of excised leaflet tissue laid flat also with labeled axes, (c) and detailed top view of leaflets during coaptation. Source: Karen May-Newman and Frank C. P. Yin, "Biaxial mechanical behavior of excised porcine mitral valve leaflets," American Journal of Physiology, vol. H, pp. 1319-1327, 1995. Source: David H. Adams. (2010, June) Mitral Valve Repair Center at The Mount Sinai Hospital. [Online]. http://www.mitralvalverepair.org/ ...............................................................................18 Figure 1.12. Primary and secondary chordae tendinae with their leaflet insertions. Source: David H. Adams. (2010, June) Mitral Valve Repair Center at The Mount Sinai Hospital. [Online]. http://www.mitralvalverepair.org/ ...........................21 Figure 1.13. Mitral regurgitation due to papillary muscle displacement from LV dilation. Source: David H. Adams. (2010, June) Mitral Valve Repair Center at The Mount Sinai Hospital. [Online]. http://www.mitralvalverepair.org/ ................22 Figure 1.14. Leaflet resectioning technique used to repair partial anterior leaflet prolapsed. Source: David H. Adams. (2010, June) Mitral Valve Repair Center at The Mount Sinai Hospital. [Online]. http://www.mitralvalverepair.org/ ................23 Figure 1.15. Leaflet resectioning technique used to repair posterior leaflet prolapsed. Source: David H. Adams. (2010, June) Mitral Valve Repair Center at The Mount Sinai Hospital. [Online]. http://www.mitralvalverepair.org/ ...........................23 Figure 1.16. Decrease in heart size from reverse remodeling following LVAD implantation. Source: Stefan Klotz, A.H. Jan Danserb, and Daniel Burkhoff, "Impact of left ventricular assist device (LVAD) support on the cardiac reverse remodeling process," Progress in Biophysics and Molecular Biology, no. 97, pp. 479-496, 2008. ...........................................................................................24 Figure 1.17. Top view of an open and closed aortic valve. Source: E. Gregory Thompson and George Philippides. (2010, June) UCSD Health Library. [Online]. http://myhealth.ucsd.edu/library/healthguide/enus/support/topic.asp?hwid=zm2794 ............................................................................25 Figure 2.1. SDSU Cardiac Simulator; Fully assembled simulator with mock circulatory loop on top and stepper motor on the bottom (a), Left Ventricular Chamber (LVC) lid and attached Left Atrial Chamber (LAC) (b), Left Ventricular Chamber (c), Mock Aorta (d), Compliance Chamber 2 (e), Compliance Chamber 1 (f), Vascular Resistance Clamp (g). ......................................28 Figure 2.2. Picture of circulatory mock loop (excluding compliance chambers) setup for this study with critical components labeled (a) and diagram of the same with sensors and mitral valve labeled (b). ...................................................................30 xii Figure 2.3. Model left ventricle with attached LVAD connector; side view (a) and top view (b). Thoratec Heart Mate II LVAD; pump (c) and pump with percutaneous line (d). ...................................................................................................31 Figure 2.4. Mitral valve conditions: Normal valve displaying undamaged leaflet (a), Damage 1 with 1.39mm2 of leaflet removed (b and c), Damage 2 with 11.17mm2 of leaflet removed (d), Damage 3 allowing 78.5mm2 of regurgitation (e), and Damage 4 allowing 253.59mm2 of regurgitation (f) ................33 Figure 3.1. LVP (mmHg) and Flow (L/min) for Normal Patient without an LVAD. .............36 Figure 3.2. LVP (mmHg) and Flow (L/min) for hemodynamic conditions with a Normal MV and Medium Cardiac Function (a), Absent MV with Medium Cardiac Function (b), Normal MV with Off Cardiac Function (c), and Absent MV with Off Cardiac Function (d). .............................................................................38 Figure 3.3. Dependent variables compared to VAD Speed (krpm) and grouped by Cardiac Function (Off and Medium) and Mitral Condition (Normal and Absent); the dependent variables are LVP (mmHg) (a), Mitral TVP (mmHg) (b), Flow (L/min) (c), AoP (mmHg) (d), and Aortic TVP (mmHg) (e). .....................39 Figure 3.4. LVP (mmHg) compared to Mitral Condition for different hemodynamic conditions. ....................................................................................................................43 Figure 3.5. Flow (L/min) compared to Mitral Condition for different flow conditions. ........45 Figure 3.6. Summary of VAD Speed influence on Flow (at Low Cardiac Function and Normal AoP); Flow waveform grouped by VAD Speed for a Normal MV (a) and an Incompetent MV (b), Flow vs VAD Speed for a Normal MV (c) and an Incompetent MV (d), table of VAD Speed vs Flow for a Normal MV and an Incompetent MV (e). ....................................................................................................46 Figure 3.7. Summary of VAD Speed influence on LVP (at Low CF and Normal AoP); LVP waveform grouped by VAD Speed for a Normal MV (a) and an Incompetent MV (b), LVP vs VAD Speed for a Normal MV (c) and an Incompetent MV (d), table of VAD Speed vs LVP for a Normal and Incompetent MV (e). ....................................................................................................47 Figure 3.8. Summary of Cardiac Function influence on Flow (at VAD Speed 9.0 and Normal AoP); Flow waveform grouped by Cardiac Function for a Normal MV (a) and an Incompetent MV (b), Flow vs Cardiac Function for a Normal MV (c) and an Incompetent MV (d), table of VAD Speed vs Flow for a Normal MV and an Incompetent MV (e). ...................................................................48 Figure 3.9. Summary of Cardiac Function influence on LVP (at VAD Speed 9.0 and Normal AoP); LVP waveform grouped by CF for a Normal MV (a) and an Incompetent MV (b), LVP vs CF for a Normal MV (c) and an Incompetent MV (d), table of LVP vs Flow for a Normal MV and an Incompetent MV (e). .........50 Figure 3.10. Summary of AoP influence on Flow (at VAD Speed 9.0 and Low Cardiac Function); Flow waveform grouped by AoP for a Normal MV (a) and an Incompetent MV (b), Flow vs AoP for a Normal MV (c) and an xiii Incompetent MV (d), table of AoP vs Flow for a Normal MV and an Incompetent MV (e). ....................................................................................................51 Figure 3.11. Summary of AoP influence on LVP (at VAD Speed 9.0 and Low Cardiac Function); LVP waveform grouped by AoP for a Normal MV (a) and an Incompetent MV (b), LVP vs AoP for a Normal MV (c) and an Incompetent MV (d), table of LVP vs AoP for a Normal MV and an Incompetent MV (e). ....................................................................................................52 Figure 3.12. Comparison of Mitral TVP with a Normal MV and an Incompetent MV; least pulsatile flow condition with Normal AoP (a), most pulsatile flow condition with Normal AoP (b), average flow condition with Normal AoP (c), and average flow condition with Hypertensive AoP (d). This set of graphs shows Mitral TVP with respect to time. The top line on each graph represents the waveform with a Normal MV. The bottom line represents the same flow conditions with an Incompetent MV. The white area shows the difference in Mitral TVP for a Normal and Incompetent MV with all other variables held the same. Graphs (a) and (b) compare the least and most pulsatile flow conditions at the same AoP, while graphs (c) and (d) compare Normal and Hypertensive AoPs with the same pulsatile condition. ................................................56 Figure 3.13. Area (mmHg*seconds) of positive Mitral TVP per cardiac cycle for Normal and Incompetent MVs; visual display of variable graphed below (a), the area (mmHg*seconds) of positive Mitral TVP by flow condition for a Normal MV, an Incompetent MV, and their disparity (b). ..........................................58 Figure 3.14. Difference in Flow (L/min) between Off and Medium Cardiac Function for a Normal and Incompetent MV. .............................................................................60 Figure B.1. Comparison of LVP and AoP waveforms for different flow conditions. Low pulsatility refers to Low Cardiac Function and High VAD Speed (10.5 krpm). High pulsatility refers to Medium Cardiac Function and Low VAD Speed (7.5 krpm). .........................................................................................................75 xiv ACKNOWLEDGEMENTS I wish to express my sincere gratitude to Dr. Karen May-Newman for her guidance and help throughout my thesis and graduate school experience. I am indebted to Dr. Roberta Gottlieb and Dr. Khaled Morsi who have been kind enough to serve on my defense committee. My fellow students Inna Bergal, Phanthiwa Posuwattanakul, Annamarie Mendoza, Murrad Kazalbash, Amanda Pascoe, Luz Enriquez-Almaguer, Fernando Olea, and Gail Samaroo provided unmeasured help and companionship during my time at SDSU. I extend a deep appreciation to the editing expertise provided by Robert Branman and Stuart Portnoy. My sister Blaire’s encouragement was uplifting and invaluable. Finally, I must thank my parents for the foundation of support and direction they have provided throughout my life. 1 CHAPTER 1 BACKGROUND The heart is the central component of the vertebrate cardiovascular system (Figure 1.1 [1]). Its purpose is to pump blood from the lungs to the body and back again in a closed system. Blood is carried away from the heart in arteries and arterioles, and returned to the heart in venules and veins. Blood transport is vital to bring oxygen and nutrients to the body’s tissues, as well as to remove carbon dioxide and waste chemicals [1]. semilunar valves (aortic right and pulmonary left) Figure 1.1. A frontal cross-section of a human heart displaying the four chambers, the four valves, and the connecting vasculature. Source: S. S. Mader, "The Cardiovascular System," in Understanding Human Anatomy and Physiology 5th ed.: The McGraw−Hill Companies, 2004, ch. 12. pp. 227. 2 1.1 HEART PHYSIOLOGY The heart’s function necessitates that it be centrally located in the body. It rests in the thoracic cavity immediately above the diaphragm. A human heart weighs approximately 300g, consisting primarily of muscle tissue. Muscle tissue’s contractile properties provide the pumping action of the heart. Heart wall contractions force blood out of a chamber and it flows back in when the heart wall relaxes. The heart wall is composed of three layers; an outer layer of connective tissue (epicardium), a middle layer of cardiac muscle (myocardium), and an inner layer of epithelial cells (endocardium) [2]. The heart has four chambers and four valves: two atrial chambers that fill with blood from the vascular system and pump it to the ventricles, two ventricles that fill with blood from the atria and pump it back out to the body, two atrio-ventricular valves between the atria and the ventricles, and two semilunar valves between the ventricles and the arteries they pump to [2]. The heart contains two of all the aforementioned structures because it is actually two pumps housed in one organ. The right side receives deoxygenated blood from the body’s tissues and pumps it to the lungs, while the left side receives oxygenated blood from the lungs and pumps it out to the body. The ventricle walls are much thicker than the atria walls because they need to pump blood much farther and against higher back pressure. Additionally the wall of the left ventricle (LV) is much thicker than that of the right ventricle for the same reason [2]. The path of blood flow is presented in Figure 1.2 and all abbreviations are listed in Table 1.1 [3]. The valve’s purpose is to ensure a one way flow of blood during cardiac pumping. When pressure on one side of the valve is higher, the valve is open and blood flows forward freely. However, when pressure on the other side is higher the valve closes preventing backflow. The opening and closing is a passive action caused by hemodynamic forces including pressure and flow. The atrio-ventricular valves on the right and left sides are called the tricuspid valve and bicuspid valve respectively, due to their differing structures. The right and left semilunar valves are called the pulmonary valve and aortic valve (AV) respectively, because of the arteries to which they lead. The bicuspid valve is also more commonly called the mitral valve (MV) as it will be referred to from here on [4]. 3 Figure 1.2. The path of blood as it flows through the heart. Source: A. C. Guyton and J. E. Hall, "Heart Muscle; The Heart as a Pump and Function of the Heart Valves," in Textbook of Medical Physiology 11th ed. China: Elsevier Inc., 2006, ch. 9, pp 104. Table 1.1. List of Abbreviations HF Heart Function LAC Left Atria Camber LVAD Left Ventricular Assist Device LVC Left Ventricle Chamber AV Aortic Valve CF Cardiac Function MV Mitral Valve LAP Left Atrial Pressure TVP Trans-valvular Pressure LVP Left Ventricular Pressure LA Left Atria AoP Aortic Pressure LV Left Ventricle krpm Thousands of revolution pre min HM II HeartMate II D1-D4 Damage 1 – Damage 4 Source: Arthur C. Guyton and John E. Hall, Textbook of Medical Physiology 11th ed. China: Elsevier Inc., 2006. 4 1.2 THE CARDIAC CYCLE The cardiac pump cycle has two main stages (Table 1.2 and Figure 1.3 [5]). One is ventricular contraction (systole) and the other is ventricular relaxation (diastole) [2]. During diastole the heart wall stretches and thins, then regains shape during systolic contraction [4]. Muscle contractions for the pump cycle are finely controlled by the heart’s internal nervous conduction system [2]. In a healthy individual the pump cycle works exactly as it is described in Table 1.2 and Figure 1.3. However, this is not the case for individuals suffering from cardiovascular disease and subsequent heart failure. Table 1.2. The Cardiac Pump Cycle Passive Ventricular Filling Under venous pressure blood moves into the atria, through the semilunar valves, and into the ventricles. Active Ventricular Filling (Atrial systole) The atria contract pushing more blood into the ventricles through the semilunar valves. Isovolumetric Contraction The ventricles begin to contract, which ends diastole and begins systole. The semilunar valves immediately close with ventricular contraction. Pressure in the ventricles increases until it is greater than the arterial pressure. Ventricular Ejection When the pressure in the ventricles exceeds the arterial pressure the semilunar valves open and blood is ejected out of the ventricles to the arteries. Pressure and flow continue to rise; then they peak and start to decrease. Isovolumetric Relaxation When the ventricular pressure drops below the arterial pressure the semilunar valves close. This is also the end of systole and the beginning of diastole. As the myocardium relaxes pressure in the ventricles continues to drop. When it drops below the venous/atrial pressure the semilunar valves open and the cycle begins again. Source: Agamemnon Despopoulos and Stefan Silbernagl, Color Atlas of Physiology 5th ed., Suzyon O’Neal Wandrey, Ed. New York: Thieme, 2003. 5 Figure 1.3. The pressure, volume, and flow with respect to cardiac pump cycle. Source: A. Despopoulos and S. Silbernagl, "Cardiovascular System" in Color Atlas of Physiology 5th ed., Suzyon O’Neal Wandrey, Ed. New York: Thieme, 2003, ch. 8, pp. 191. 6 1.3 HEART FAILURE Heart failure (HF) is when the heart is unable to provide the body with a sufficient volume of blood flow. Right heart failure is usually caused by high pulmonary pressure from left heart failure, which is significantly more common. The two forms of HF are preserved, which has a normal left ventricular ejection fraction (>40-50%) and reduced, which has an impaired ejection fraction (<35-45%). There are two formal classifications for HF severity. They are referred to by the names of the organizations that founded them, which are the American College of Cardiology / American Heart Association (ACC/AHA) and the New York Heart Association (NYHA) (Table 1.3) [6] [7]. Table 1.3. The ACC/AHA and NYHA Classifications for Heart Failure Severity Source: R. J. Adams, T. M. Brown, M. Carnethon, D. Lloyd-Jones, and G. Simone, "Heart Disease and Stroke Statistics 2010 Update. A Report From the American Heart Association," Ammer. Heart Assoc., vol. E, no. 121, pp. 46-215, Feb 2010. 1.3.1 Causes Although HF is often fatal, it is not in itself a cause of death, but is the final stage of a progressive cardiac disease. There are many conditions that can contribute or lead to HF (Table 1.4 [6]); but the most common culprits are hypertension, coronary heart disease, valvular disease, diabetes, and cardiomyopathy [6]. Cardiomyopathy itself is simply an abnormality in heart muscle form or function without a separate cause, such as hypertension or myocardial infarction [7]. Hypertension is the top contributing factor to HF, with coronary heart disease in a close second. Seventy-five percent of HF patients have a history of high 7 Table 1.4. Conditions that Commonly Contribute to Heart Failure Source: R. J. Adams, T. M. Brown, M. Carnethon, D. Lloyd-Jones, and G. Simone, "Heart Disease and Stroke Statistics 2010 Update. A Report From the American Heart Association," Ammer. Heart Assoc., vol. E, no. 121, pp. 46-215, Feb 2010. blood pressure and about 70% have a history of coronary heart disease [6] [7]. Also the lifetime risk of people with high blood pressure (>160/90mmHg) is twice that of people with low blood pressure (<140/90mmHg) [6]. 1.3.2 Symptoms The characteristic symptoms of HF are breathlessness, fatigue, and fluid retention. The shortness of breath is caused by pulmonary edema (increased pulmonary capillary pressure) while the fatigue is from multiple non-specific causes. These symptoms are difficult to diagnose, particularly in the elderly and obese, populations that are at high risk for HF. For this reason skilled physicians and objective test measurements are required to appropriately diagnose HF and asses heart function. Also, to improve treatment and understanding, an underlying cause for HF should always be sought [7]. 1.3.3 Incidence, Mortality, and Economic Impact HF is a huge problem for the aging populations of first world countries. In the United States the lifetime risk of HF for those over 40 is 20% [6]. The entire population has a HF incidence of about 2-3%. However, the incidence rises sharply with age and is 10-20% in people 70-80 years old [7]. HF is more common in African Americans than European Americans, as well as more common in males than females [6]. The differing incidence 8 between males and females is significant in younger populations, but converges towards old age (Table 1.5 and Figure 1.4) [7]. Table 1.5. Age adjusted HF Incidence Rate per 1,000 Person Years European Male 6.0 American Female 3.4 African Male 9.1 American Female 8.1 Source: K. Dickstein, A. Cohen-Solal, G. Filippatos, J. J. V. McMurray, P. Ponikowski, P. A. Poole-Wilson, A. Stromberg, D. J. Veldhuisen, D. Atar, A. W. Hoes, and A. Keren, "ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008," European Heart J., no. 29, pp. 2388-2442, 2008. Figure 1.4. Incidence of HF by age and gender. Source: R. J. Adams, T. M. Brown, M. Carnethon, D. Lloyd-Jones, and G. Simone, "Heart Disease and Stroke Statistics 2010 Update. A Report From the American Heart Association," Ammer. Heart Assoc., vol. E, no. 121, pp. 46-215, Feb 2010. HF also has a huge impact on the economy of healthcare. In 2007 alone there were nearly 3.5 million hospital visits for HF in the United States, and in 2010 39.2 billion was spent by Americans to treat HF [6]. HF is a very deadly condition; it is mentioned in nearly 300,000 American deaths per year, meaning it is mentioned in nearly one out of every eight deaths [6]. In death statistics HF 9 has mentions instead of being listed as the underlying cause because, as stated above it is the end condition of several cardiac diseases [7]. Most HF patients eventually perish from their condition; its one and five year mortality rates are 20% and 50% respectively [6] [7]. The quality of life (QOL) of HF patients is extremely compromised. A study in England ending in 1999 examined just this issue. It found HF patients had a QOL comparable to chronic bronchitis and worse than atrial fibrillation, angina, high blood pressure, and history of myocardial infarction. It also found that in addition to physical QOL, HF patients had significantly reduced mental health and social functioning. This study highlighted that HF affects every aspect of a person’s life, and not just mobility or exercise tolerance [8]. 1.4 LEFT VENTRICULAR ASSIST DEVICE (LVAD) A Left Ventricular Assist Device (LVAD) is a mechanical blood pump used as therapy for heart failure patients. LVAD pumps all have an inflow cannula connected to the apex of the LV and an outflow cannula connected to the ascending aorta. In short, they aid and replace the LV function to maintain sustainable levels of systemic perfusion [9]. LVADs are used for three classes of therapy: Bridge-to-Transplant, Bridge-to-Recovery, and Destination Therapy (Table 1.6) [9] [10]. The preferred treatment for congestive heart failure is a heart transplant, but due to their limited availability use of LVADs for destination therapy is on the rise [11]. 1.4.1 Pulsatile Pumps The two LVAD pump designs are pulsatile and continuous. Pulsatile pumps are comprised of a pumping chamber bounded by unidirectional valves and driven by either a pneumatic (air pressure) or electromagnetic (pusher plate) pump action. Pulsatile LVADs successfully mimic the cardiac cycle including systole, diastole, stroke volume, and blood ejection; although they are not phased to the heart contractions. They most commonly have a programmable beat rate, but a fixed stroke volume [9]. Although formerly the most popular type of LVAD they have significant drawbacks compared to continuous flow pumps [11]. Their large size prevents their use in small patients and makes their surgical implantation much more difficult, their need for external air venting means they need a large diameter percutaneous lead, the number of moving components makes them more prone to mechanical failure, and they are noisy reducing the patients QOL [10]. 10 Table 1.6. Classes of Therapy for LVADs Therapy Bridge-to-Transplant Bridge-to-Recovery Destination Therapy Circulatory support until patient can Description receive a heart transplant. The first and by far most common use of LVADs. Not available for patients over 65 because they Comments are not eligible for heart transplants. Circulatory Support until Circulatory support until patient’s heart recovers (days patient expires due to to weeks) and device can be either related or explanted. unrelated complications. Least used LVAD therapy Only the newest LVADs because the most common are FDA approved for types of heart failure are nonthis therapy. Available recoverable with current to all patients regardless medial techniques. Most of heart transplant eligibility. commonly used for postcardiotomy shock, acute inflammatory cardiomyopathies, and myocardial infarction. Source: S. R. Wilson, M. M. Givertz, G. C. Steward, and G. H. Mudge, "Ventricular Assist Devices: The Challenges of Outpatient Management," J. of the Amer. College of Cardiology, vol. 54, pp. 1647-1659, November 2009. Source: A. Loforte, A. Montalto, F. Ranocchi, G. Casali, G. Luzi, P. L. Della Monica, and F. Sbaraglia, "Long-Term Mechanical Support With the HeartMate II LVAS," Transplantation Proc., vol. 41, pp. 1357–1359, 2009. 1.4.2 Continuous Flow Pumps Currently there are many continuous flow LVADs going through clinical investigations, including the HeartMate II (Table 1.7) [9]. They propel blood through a central rotor powered by a miniaturized motor, with either a spinning impeller (axial flow) or by forcing blood along the axis of concentric cones (centrifugal flow). They are preferable to pulsatile pumps because they are smaller, more mechanically reliable, and have a better risk-tobenefit ratio [9]. 1.4.3 Outpatient Management and Medical Therapy Education and rehabilitation after surgical implantation are vital components of VAD patient therapy. The patient and their caregivers must be educated on how to monitor the device and perform routine maintenance prior to hospital discharge. Patient rehabilitation must begin prior to hospital discharge and be continued after. The most important part of rehabilitation is physical exercise as it is shown to improve QOL. Adoption of a healthy diet is also necessary because HF patients are prone to cachexia and hypoalbuminemia. 11 Table 1.7. Continuous Flow LVADs and the Therapy for which they are Federally Approved Company LVAD Name BTT Destination Therapy Thoratec Paracorporeal √ Thoratec VAD √ Novacore Implantable √ Thoratec LVAD √ Jarvic 2000 LVAD √ Thoratec HeartMate XVE √ Jarvic Heart √ HeartMate II √ √ √ √ Source: S. R. Wilson, M. M. Givertz, G. C. Steward, and G. H. Mudge, "Ventricular Assist Devices: The Challenges of Outpatient Management," J. of the Amer. College of Cardiology, vol. 54, pp. 1647-1659, November 2009. The outpatient medical therapy is often handled by a cardiology team, including doctors, nurses, and a VAD patient coordinator. As all blood contacting devices cause bloodtrauma and increase risk of thromboembolism, appropriate anticoagulation and antiplatelet therapy is vital. The anticoagulation therapy must balance the risk of a thromboembolic event against the probability of anticoagulation induced bleeding. The medical team must also monitor and aggressively fight high blood pressure to prevent thromboembolism as well as VAD dysfunction. Blood pressure in VAD patients is best taken by radial artery palpation instead of brachial artery auscultation because the VAD produces sound that contradicts auscultation. 1.5 HEARTMATE II The HeartMate II (Figures 1.5 and 1.6) is a continuous axial flow LVAD manufactured by Thoratec [12]. It is roughly cylindrical with a length of 7.0 cm, maximum diameter of 4.0 cm, and weight of 350 g [10]. It has only one moving part, a rotor which spins on patented ball-and-cup bearings and has vanes to propel blood. It is implanted either preperitoneally or intra-abdominally and is oriented parallel to the diaphragm. Blood contacting surfaces experiencing high shear have a smooth polished titanium surface (rotor, stator, pump chamber), 12 Figure 1.5. Position of implanted HM II and percutaneous line connected to exterior System Controller. Holstered rechargeable battery packs connected for mobile use. Source: HeartMate II® Left Ventricular Assist System Clinical Operation and Patient Management. (2010) Thoratec Corporation. [Online]. http://www.thoratec.com/ Figure 1.6. Cross-section of HM II pump. Source: HeartMate II® Left Ventricular Assist System Clinical Operation and Patient Management. (2010) Thoratec Corporation. [Online]. http://www.thoratec.com/ 13 while the other blood contacting surfaces have a thrombo-resistant textured surface (inlet cannula, inlet elbow, outlet elbow) [12]. 1.5.1 Pump Function Flow through the HM II is determined by the pump speed and the left ventricular pressure (LVP). The HM II operates at a fixed speed between 6,000 and 15,000 rpm, although most therapy only uses speeds from 8,000 to 10,000 rpm. As the LVP increases during heart contraction the pressure gradient across the pump is reduced which increases flow through the pump (Figure 1.7) [12]. The pulsatility index (PI) is one way of measuring heart function. The PI is calculated with Equation 1.1 PI = (Q_max - Q_min) / Q_avg (1.1) where PI is pulsatility index, Qmax is maximum flow, Qmin is minimum flow, and Qavg is average flow. The PI is positively correlated with heart contractility and negatively correlated with pump speed. Figure 1.7. The LV pressure is coupled to LVAD flow. Source: HeartMate II® Left Ventricular Assist System Clinical Operation and Patient Management. (2010) Thoratec Corporation. [Online]. http://www.thoratec.com/ 14 When the HM II is implanted first a satisfactory volume of blood flow and quality of treatment are established, then a number of baseline measurements are recorded (pump speed, pump power, flow, PI, and echocardiography readings). Subsequent changes in these values are closely monitored as they are more indicative of patient health than the values themselves. The flow through an implanted HM II is approximated from pump speed and power because it can’t be directly measured. Both gradual and sudden increases in pump power can indicate a thrombus in the pump chamber and require evaluation [12]. 1.5.2 Vital Peripheral Components Next to the pump itself the most important component of the HM II system is the System Controller (Figure 1.8a) [12]. The controller emits hazard alarms, records and stores operation data, and controls motor power and speed. The controller has two computer boards for redundancy and two power connection ports for both redundancy and to allow a change in the power source without any loss of function. The controller must always be connected to the HM II via the percutaneous line, which complicates bathing for the user. A HM II patient cannot swim or take a bath, and when showering they must use a plastic shower kit provided with the HM II. The controller should be disconnected for open heart defibrillation, but unlike other LVADs does not need to be disconnected for external defibrillation [12]. The Power Base Unit (PBU) is another vital component to the HM II (Figure 1.8d). Plugged into a standard wall outlet, it both recharges the HM II batteries (Figure 1.8c) used for portable operation and provides power for tethered operation. The PBU can charge up to 6 batteries at a time and charging may take up to 8 hours. Two batteries power the HM II for 3-5 hours. In case of residential power outage the PBU has an internal battery that will operate the HM II for approximately 30 minutes. The HM II system also includes an Emergency Power Pack (EPP) (Figure 1.8e) to deal with power outages. It is a single use power source that will power a HM II for approximately 12 hours [12]. The final key component to the HM II system is the System Monitor (Figure 1.8b). It connects to the PBU, through which it transmits information to and from the system controller. It is used to monitor and record pump performance and alarm conditions, as well as adjust system parameters to optimize therapy [12]. 15 a. c. b. d. e. Figure 1.8. Vital peripheral HM II system components: (a) System Controller, (b) System Monitor, (c) Rechargeable battery packs, (d) Power Base Unit (PBU), and (e) Emergency Power Pack (EPP). Source: HeartMate II® Left Ventricular Assist System Clinical Operation and Patient Management. (2010) Thoratec Corporation. [Online]. http://www.thoratec.com/ 1.5.3 Clinical Studies The first extensive clinical review of the HM II pump performance was published in 2009 and covered the first 281 patients to receive HM II therapy for at least 18 months. Survival was 82% at 6 months, 73% at 12 months, and 72% at 18 months after HM II implantation. This is much improved from the landmark REMATCH trial published in 2001, as it reported a one year survival of only 52% for all contemporary LVADs. In the HM II clinical review there were only seven device related deaths: two from a thrombosis lodged in the pump, one due to the inflow graft being twisted during implantation, one because the outflow elbow became disconnected, one severed percutaneous lead, and two power failures. Additionally there were no mechanical failures of the pump, and only two of 16 the percutaneous lead. To deal with the percutaneous lead failures, Thoratec has recently released an advisory detailing its proper handling and associated risks. The most common adverse events associated with the device are bleeding and stroke, which occurred mostly in the first 30 days after implantation. Further surgery was required for 59% of the patients and 72% of these were re-explorations to deal with bleeding complications [11]. The study included a functional assessment six months after HM II implantation. The fraction of patients able to perform a six minute walk increased from 13% to 89% and the average NYHA level decreased from 3.9 to 1.8. Based on a questionnaire, patients also had a significant improvement in quality of life. One caveat to these results: patients benefiting least from HM II therapy are given transplantation priority thus affecting survival rates [11]. Another less extensive study considered 18 patients. All 18 survived implantation, 13 had no significant complications in the first 30 days, and 12 were discharged with an NYHA class I. On the other hand, 5 patients died in the first 30 days after implantation and 6 needed re-thoracotomy to deal with internal bleeding [10]. 1.6 MITRAL VALVE The mitral or bicuspid valve (Figure 1.9) allows blood to flow from the LA to the LV, but prevents blood flow in the reverse direction [13]. It is a complicated structure, incorporating the following components: mitral annulus, leaflets, chordae tendinae, and papillary muscles. The annulus rests between the left atria (LA) and LV, and from it the leaflets extend into the LV chamber. The chordate tendinae arise from the free edge and ventricular surface of the leaflets, span the LV chamber, and attach to the papillary muscles. The papillary muscles themselves are small segments of cardiac muscle protruding from the basal LV wall. MV function requires the synergistic coordination of all these components along with LV contraction to maintain forward blood-flow [4] [14]. The MV annulus is a ring of collagenous tissue circling the mitral orifice between the LA and LV. In the past it was thought to be relatively flat and static, but recent research has revealed it to have three dimensional structure and dynamic motion with respect to the cardiac cycle [14]. The annulus contracts by about 30% during systole to improve coaptation, and dilates during diastole to aid ventricular filling [15]. Furthermore, during systole the mitral 17 Figure 1.9. Basic anatomy and components of the MV. Source: D. H. Adams. (2010, June) Mitral Valve Repair Center at The Mount Sinai Hospital. [Online]. http://www.mitralvalverepair.org/ annulus moves downward into the LV towards the apex of the heart and moves back upward towards the LA during diastole [16]. The three dimensional structure of the annulus is considered saddle shaped. The anterior and posterior leaflets extend from the raised sides of the saddle and the commissural regions are adjacent to the low sides of the saddle (Figure 1.10) [17]. Additionally the saddle height has been shown to increase during systole. The saddle shape and its height increase minimizes stress on the leaflets during coaptation [18] [19]. The MV leaflets (Figure 1.11) are actually one piece of tissue extending from the mitral annulus into the LV [13] [20]. This piece of tissue is divided into the posterior leaflet and the anterior leaflet. Although mitral leaflet structure is highly variable, the anterior leaflet is one large scallop and the posterior leaflet is usually three much smaller scallops (medial, central, and lateral) (Figure 1.11) [4]. 18 Figure 1.10. Saddle shape of the MV annulus relative to leaflet structure. The highest point is between markers 4 and 5 on the side of the anterior leaflet with a smaller peak near marker 10 on the side of the posterior leaflet. Source: C. E. Eckert, B. Zubiate, M. Vergnat, J. H. Gorman, III, R. C. Gorman, and M. S. Sacks, "In Vivo Dynamic Deformation of the Mitral Valve Annulus," Ann. of Biomedical Eng., vol. 37, no. 9, pp. 1757-1771, 2009. Figure 1.11. Mitral valve leaflets: (a) top view of leaflets during coaptation with labeled axes, (b) diagram of excised leaflet tissue laid flat also with labeled axes, (c) and detailed top view of leaflets during coaptation. Source: K. May-Newman and F. C. P. Yin, "Biaxial mechanical behavior of excised porcine mitral valve leaflets," Amer. J. of Physiology, vol. H, pp. 1319-1327, 1995. Source: D. H. Adams. (2010, June) Mitral Valve Repair Center at The Mount Sinai Hospital. [Online]. http://www.mitralvalverepair.org/ 19 When the valve is open the leaflets extend straight into the LV chamber. When the valve closes the leaflets arch upward and cover the orifice. The LV pressure pushes the free edges of the anterior and posterior leaflets together (coaptation) preventing blood from flowing back into the LA [15]. The region where coaptation occurs between the two leaflets is referred to as the commissure. The anterior leaflet is much larger than the posterior and during coaption it covers a majority of the mitral orifice [4]. The leaflet surface is about twice the mitral orifice [21]; this extra tissue serves two purposes. Some of the extra tissue provides surface area for coaptation with the opposing leaflet. The rest of the tissue balloons into the LA; force is distributed across this ballooning tissue, thus minimizing peak stress on the leaflets [18]. MV leaflet tissue is far from homogenous. It is broken up into three distinct zones based on distance from the annulus: basal, clear, and rough. The basal zone is adjacent to the mitral annulus, the rough zone is along the leaflet free edge, and the clear zone is in between. Both the basal and rough zone have a number of chordae tendinae insertions causing them to have a rough appearance and more heterogeneous microstructure. The clear zone is smooth with relatively homogenous microfiber organization. The mitral leaflet tissue is also organized in three layers: fibrosa, spongiosa, and ventricularis (Table 1.8) [4] [21]. Table 1.8. The Layers of Valve Tissue: Fibrosa, Spongiosa, and Atrialis/Ventricularis Layer Fibrosa Location Faces the LV Spongiosa Middle layer Composition High concentration of collagen, thickest layer Hi concentration of glycosaminoglycans (GAG) and proteoglycans (PG) Function Bears most of the load during coaptation Provides shear between outer support layers and diffuses gasses and nutrients Elastin allows for strain when valve is open Atrialis Faces the LA High concentration of (Ventricularis collagen and elastin, for Semilunar thinnest layer valves) Source: J. D. Bronzino, The Biomedical Engineering Handbook.: CRC Press, 1995. The mechanical behavior of mitral leaflets is principally determined by the rotation and uncrimping of collagen fibers. The elastic modulus of MV tissue is highly nonlinear due to its largely collagenous composition. In an unstressed state collagen is a crimped polymer. When 20 under tension collagen uncrimps and undergoes strain, but once fully uncrimped increasing tension does not result in more strain [22]. This is why small trans-valvular pressures produce a lot of strain in mitral leaflets, but with higher trans-valvular pressures the leaflets stiffen and undergo little further strain. Most of the collagen fibers are arrayed circumferentially as opposed to radially, causing preferential stiffening that limits circumferential strain. Most studies have examined the central portions of the leaflet which are more structurally homogenous, less is known about the leaflet edges which are more structurally complex [14] [20]. The papillary muscles and the chordae tendinae prevent the leaflets from moving too far into the LA and causing regurgitation (mitral prolapse). The two papillary muscles are differentiated based on the regions of the ventricular wall to which they attach (anterolateral and posteromedial). During ventricular contraction they contract approximately 4mm, pulling the chordae tendinae down toward the apex. The upper tips of the papillary muscles are called “bellies” at which the chordae tendinae emerge [4] [14]. The chordae tendinae are an array of thin strand-like structures that connect to the papillary muscles at their base and insert into the leaflets, annulus, and LV wall at their tips. The three classifications of chordae tendinae are primary, secondary, and basal (Figure 1.12) [13]. The primary chordae tendinae attach to the free edge of the leaflets, the secondary attach to the ventricular surface of the leaflets, and the basal attach to the annulus and LV wall. The chordae tendinae are principally tensile load-bearing structures and as such they have a high density collagen core surrounded by a sheath of mostly elastin [4] [14]. 1.6.1 Mitral Valve Disease The two common classes of MV malfunction are stenosis and incompetence/regurgitation. Stenosis occurs when LV filling is impaired by an obstruction to the valve orifice. Regurgitation however, occurs when the valve cannot close completely (malcoaptation) and there is a jet of backflow during systole. With a malfunctioning MV the heart must work harder to produce the same output. If a patient’s heart can’t compensate for the regurgitation then blood flow and systemic oxygenation are compromised [14]. Rheumatic fever is a leading cause of valvular disease in the third world, but is largely a thing of the past in the first world. In the United States diseases that directly affect the MV 21 Figure 1.12. Primary and secondary chordae tendinae with their leaflet insertions. Source: D. H. Adams. (2010, June) Mitral Valve Repair Center at The Mount Sinai Hospital. [Online]. http://www.mitralvalverepair.org/ today include myxomatous, endocarditis, Malfon’s syndrome, and Whipple’s disease. These all cause the development of pathologic mitral tissue which leads to malcoaptation and chordae tendinae rupture [23]. Currently the most common cause of mitral regurgitation is LV dilation (Figure 1.13) [13]. LV dilation is a common symptom of cardiovascular disease and heart failure. LV dilation causes mitral regurgitation is two ways; it results in mitral annulus dilation and it displaces the papillay muscles downward. The increased annulus size makes it more difficult for the leaflets to span across for coaptation and the displaced papillary muscles pull the free edge of the leaflet down preventing them from coapting during systole [15]. Of these two contributing factors, papillary muscle displacement has a stronger effect. Small papillary muscle displacements can result in regurgitation without annular dilation, but large dilations are necessary to cause regurgitation without any papillary muscle displacement. This type of mitral regurgitation is called functional mitral regurgitation because the MV components are not directly pathologic [15] [24]. 22 Figure 1.13. Mitral regurgitation due to papillary muscle displacement from LV dilation. Source: D. H. Adams. (2010, June) Mitral Valve Repair Center at The Mount Sinai Hospital. [Online]. http://www.mitralvalverepair.org/ 1.6.2 Mitral Valve Repair The treatment options for mitral regurgitation are mitral repair and mitral replacement. Mitral repair is preferred because it has superior survival rates and does not require anticoagulation therapy [25]. Mitral repair is fairly durable, although most patients experience a relapse of mitral regurgitation within 5 years. The three most common procedures used for mitral repair are annuloplasy, leaflet resectioning, and the Alfieri stitch [26]. Annuloplasty is when an artificial ring is sewn into the mitral annulus to maintain annulus shape, specifically preventing annular dilation. Annuloplasty rings can be rigid or flexible as well as flat or saddle-shaped. Flexible rings are supposed to deform dynamically similar to the native annulus, but their capacity for this function is questionable. Currently the most popular annuloplasty rings are rigid and saddle-shaped [17]. The Alfieri stitch (also known as edge-to-edge repair and dual orifice mitral repair) is sometimes performed along with annuloplasty when the latter is not sufficient to prevent mitral regurgitation on its own [24]. In this procedure the free edges of the posterior and anterior leaflets are sutured together at their midpoints. This simple procedure creates a dual orifice MV that accommodates sufficient forward blood flow and prevents regurgitation [26]. Leaflet resectioning is the mitral repair procedure most commonly used to treat mitral prolapse. There are several resectioning techniques used depending on the specific pathology 23 of the prolapsed valve (Figures 1.14 and 1.15) [13]. All involve the removal of some portion of valve leaflet and subsequent suturing of preserved sections. Annuloplasty is relatively durable, but suture lines in leaflets are sources of wear and degradation [14]. Figure 1.14. Leaflet resectioning technique used to repair partial anterior leaflet prolapsed. Source: D. H. Adams. (2010, June) Mitral Valve Repair Center at The Mount Sinai Hospital. [Online]. http://www.mitralvalverepair.org/ Figure 1.15. Leaflet resectioning technique used to repair posterior leaflet prolapsed. Source: D. H. Adams. (2010, June) Mitral Valve Repair Center at The Mount Sinai Hospital. [Online]. http://www.mitralvalverepair.org/ 24 1.7 REVERSE REMODELING Patients with chronic HF have elevated neurohormonal activation. These levels are initially beneficial to cardiac function, but if sustained for too long it leads to cellular damage and ventricular dilation. The sever LV dilation often associated with end-stage HF, was previously considered permanent tissue damage. This was disproven with the introduction of LVADs. After LVAD implantation patients have reduced LV chamber size, reduced LV free wall mass, improved myocardial contractile properties, and improved global pump function (Figure 1.16) [27]. This process of healing is called reverse remodeling. LVAD therapy benefits the LV directly by unloading it from the pressure and volume of its mechanical duties. The improved systemic and coronary artery perfusion from LVAD therapy also indirectly benefits the entire heart by normalizing neurohormone activation. When profound reverse remodeling of the heart was first discovered, it was hoped that many patients could be weaned from LVAD therapy without a heart transplant. However, subsequent studies in LVAD explanation led to rapid reoccurrence of HF in a majority of patients [27]. Figure 1.16. Decrease in heart size from reverse remodeling following LVAD implantation. Source: S. Klotz, A. H. J. Danserb, and D. Burkhoff, "Impact of left ventricular assist device (LVAD) support on the cardiac reverse remodeling process," Progress in Biophysics and Molecular Biology, no. 97, pp. 479-496, 2008. As noted earlier mitral regurgitation is commonly caused by LV dilation. A study looking at mitral regurgitation and LV dilation found MV regurgitant jet area to increase with increasing LV size. Additionally the MV regurgitant jet area was found to decrease along with LV size after initiation of LVAD therapy. The average jet area before implant was 10.6±2.4cm2 and after implantation fell to 4.2±0.9cm2 [28]. 25 1.8 AORTIC VALVE CLOSURE The AV (Figure 1.17) valve rests between the LV and aorta [29]. Its purpose is to allow blood to flow out of the LV towards the body during systole and prevent the reverse flow during diastole. Although its function is similar to that of the MV, its structure is quite different. The AV is composed of three symmetrical leaflets without any chordae tendinae or papillary muscles [30]. Figure 1.17. Top view of an open and closed aortic valve. Source: E. G. Thompson and G. Philippides. (2010, June) UCSD Health Library. [Online]. http://myhealth.ucsd.edu/library/healthguide/enus/support/topic.asp?hwid=zm2794 AV incompetence or the presence of an artificial AV has been considered a contradiction to LVAD therapy. Aortic regurgitation with an implanted LVAD causes central recirculation, where blood is propelled out of the LV by the LVAD only to flow back in through an incompetent AV. Recirculation increases LV pressure preventing recovery from HF, as well as increasing demands and mechanical wear on the LVAD pump. A prosthetic MV is also problematic because it increases the risk of thromboembolism [31]. To prevent recirculation and minimize risk of thromboembolism, the AV can be closed off when the LVAD is implanted. Different techniques of valve closure exist, but one successful technique is to sew a disk of pericardium to an annuloplasty or prosthetic valve ring and implant that ring in the AV annulus normally. An unpublished study headed by Dr. Robert Adamson showed that patients who underwent AV closure had a life expectancy no worse than LVAD patients who did not undergo AV closure (78% at 1 year and 53% at 3 years vs. 61% at 1 year and 45% at 3 years) [31]. One problem with LVAD therapy is that it can negatively impact the AV. An LVAD significantly relieves the LV of pressure. A weak heart with artificially low LV pressure may never contract strongly enough to open the AV. Prolonged valve closure can lead to 26 commissural fusion, when the commisure region of separate leaflets become permanently fused together. A recent study of AVs in continuous flow LVAD patients revealed commissural fusion in 8 of 9 patients. Although the mechanism of commissural fusion is not known, one prominent theory states that prolonged coaptation results in remodeling of valvular endothelial cells and local fibrosis [30]. LVAD patients with AV closure have a unique hemodynamic condition. Most LVAD patients can have series flow, when blood passes through the LV and then the LVAD without passing through the AV, or parallel flow, when blood exits the LV through the AV and LVAD simultaneously. In patients with a closed AV, however, only series flow is possible. Lack of a functioning AV makes these patients particularly vulnerable to problems with their MV, specifically regurgitation. As noted above moderate to severe mitral regurgitation is common in patients at the time of LVAD implantation. Reverse remodeling reduces the mitral regurgitation but persistent regurgitation is common [28]. Mitral regurgitation needs to be investigated in patients with this unique hemodynamic condition to fully understand the complications to which they are susceptible. 27 CHAPTER 2 MATERIALS AND METHODS The experimental apparatus used for this study is the SDSU Cardiac Simulator (Figure 2.1a). It is a circulatory mock loop that mimics the hemodynamics of the human LV, MV, AV, and aorta. It also mimics the pressure conditions, but not the flow conditions, of the left atria (LA). Because its LA component does not have dimensions similar to its analogous anatomic structure, as do the other components. The SDSU Cardiac Simulator also does not model the right side of the heart. It uses a stepper motor to create pressure and volume displacement simulating the pumping action of a human heart (Figure 2.1a). The circulatory mock loop system incorporates a left ventricle chamber (LVC), left atrial chamber (LAC), mock aorta, two compliance chambers, Tygon tubing (R-3603), and assorted plastic connectors. The system includes a location between the LAC and LVC for a prosthetic valve simulating the function of a MV. Also, between the LVC and mock aorta, the simulator contains another similar location for the placement of a prosthetic valve simulating the native AV. Fluid flows through the mock loop in the following order: LAC, MV, LVC, AV, mock aorta, compliance chamber 1, compliance chamber 2, and then returns to the LAC. The LAC, LVC, and mock aorta are in fixed relative positions, while the compliance chambers are connected via Tygon tubing and can be moved independently to a small degree. A 0.9% saline solution was used as an inexpensive, transparent, blood substitute in the mock loop.. The viscosity of water is approximately 25% that of blood, and this difference could lead to higher flow rates and lower pressures in the simulator compared to a human. Compliance chambers 1 and 2 (Figure 2.1e and 2.1f) form a Windkessel model to mimic the compliance of native arterial and venous blood vessels respectively. An adjustable metal clamp (Figure 2.1g) is fastened between the two compliance chambers to simulate the total vascular resistance. The compliance chambers contain approximately 2.1L (0.40L liquid and 1.7L air) and 8.8L (6.5L liquid and 2.3L air), respectively. In addition, the LVC contains approximately 0.5L of air to simulate the natural compliance of the left ventricle and its surrounding anatomic structure. 28 (d) (b) (e) (g) (a) (c) (f) Figure 2.1. SDSU Cardiac Simulator; Fully assembled simulator with mock circulatory loop on top and stepper motor on the bottom (a), Left Ventricular Chamber (LVC) lid and attached Left Atrial Chamber (LAC) (b), Left Ventricular Chamber (c), Mock Aorta (d), Compliance Chamber 2 (e), Compliance Chamber 1 (f), Vascular Resistance Clamp (g). The LVC (Figure 2.1c) is fixed to the center of the simulator and is made of 0.5in thick polycarbonate plates. Its shape is that of a rectangular prism with interior dimensions of 17x24x29cm (6.75x9.5x11.5in). The chamber is water filled (approximately 11.8L) when in use. The top is a removable lid (Figure 2.1b) allowing access to the interior of the chamber. The lid is fastened down with wing-nuts (0.24in ID) and has 5 openings. The LAC and mock 29 aorta are attached to two of these openings. The other three are used for various purposes depending on the nature of the experiment. Regardless of the experiment, all openings must be sealed from the atmosphere so a positive pressure can be maintained in the LVC. Another opening in the bottom of the LVC allows a connection to the piston of a stepper motor. When there are prosthetic valves in place to simulate the function of native mitral and AVs, and the stepper motor is turned on, the SDSU cardiac simulator replicates the functions of a normal human heart. The rising piston forces fluid out of the LVC and into the aorta, and the lowering piston pulls fluid back into the LVC from the LAC. The LAC (Figure 2.1b) is an acrylic cylinder 12.7cm in diameter and 14.6cm in height. The bottom connects to the LVC lid and an opening on the side allows liquid to enter from compliance chamber 2. The top of the LAC has no lid and is open to the atmosphere. When in use the LAC is filled with water and the pressure head simulates the pressure in a native human LA. Although the water level and corresponding pressure head fluctuate with simulated LV pumping, an average of 13cm (9.5mmHg) of water is maintained. The pumping action of the LA is not modeled by the SDSU cardiac simulator. The mock aorta (Figure 2.1b) is a piece of silicone tubing bent at right angle with the following dimensions: ID=32mm, OD=35.5mm, length=19cm and radius of curvature=9cm. This shape and material approximate the native human aorta. The bottom end is bonded to a hard plastic ring which allows it to be fastened to the lid of the LVC with two wing-nuts. The top end is connected to tubing which leads to compliance chamber 2. 2.1 SPECIFIC CARDIAC SIMULATOR SETUP FOR THIS EXPERIMENT For this study the SDSU cardiac simulator (Figure 2.2) was configured with both a model LV and a Thoratec HeartMate II LVAD (Figure 2.3). Both rest inside the LVC and are suspended from its lid (Figure 2.2). The model LV is a clear silicone bag in the approximate shape of a human LV. The flexible and elastic material is about 0.75mm thick. The resting volume of the ventricle bag is approximately 180cm3. Like an actual ventricle, the ventricle bag has two openings near the top. The larger one is connected to the LAC at the site of prosthetic MV fixation, and the smaller one connects to the mock aorta at the site of prosthetic AV fixation (4cm and 2.6cm in diameter respectively). Since an LVAD patient is being simulated in this study, the ventricle bag must have a third opening connected to an LVAD. 30 Mock Aorta LAC LV LVAD Pump LVC (b) Piston (a) Figure 2.2. Picture of circulatory mock loop (excluding compliance chambers) setup for this study with critical components labeled (a) and diagram of the same with sensors and mitral valve labeled (b). The apex of the ventricle bag is cut open and glued to a plastic connector leading to the HM II inlet, as shown in Figure 2.3c. The HM II, its system controller, and its power source were provided by Thoratec. The pump itself is identical to those used in clinical applications except there is a different texture on the interior blood contacting surfaces. This texture is designed to prevent blood trauma and does not affect the hemodynamic conditions being examined in this study. The HM II system controller is also the same as that used clinically, but the power source is a custom design for research use only. The critical dimensions and function of the HM II were discussed previously in the Chapter 1. The HM II outlet is connected to tubing that exits the LVC 31 (a) (b) (c) (d) Figure 2.3. Model left ventricle with attached LVAD connector; side view (a) and top view (b). Thoratec Heart Mate II LVAD; pump (c) and pump with percutaneous line (d). through one of the lid opening and reconnects to the mock aorta. The percutaneous power lead also exits the LVC through the lid and is connected to the HM II System Controller during use. In order to simulate a patient who has had their AV closed during LVAD implant surgery, a circular piece of plastic blocking all flow was placed in the location analogous to a native AV. In the MV location a Medtronic (Mosaic model) bioprosthetic aortic porcine valve was inserted. Bioprosthetic porcine valves are used because they are easier to acquire than human cadaver valves. Also, an AV is used because bioprosthetic MVs are not normally manufactured due to their complicated structure. 2.2 CARDIAC SIMULATOR CONTROL The simulator allows for active manipulation of three variables: vascular resistance, cardiac function (CF), and VAD speed. The metal clamp fastened between the two compliance chambers can be incrementally opened or closed, thereby adjusting the simulated vascular resistance (Figure 2.1g). The stepper motor, which simulates CF, is controlled with LabView on an attached computer. Finally, the HM II VAD speed is controlled with a computer attached to the HM II and a custom program provided by Thoratec. 32 2.3 DATA ACQUISITION AND SENSORS Data acquisition is performed with the National Instruments program BioBench (version 1.2) and a National Instruments signal conducting module (SC-2345) [32].The data acquisition system is connected to six sensors, four Hospira Transpac® disposable pressure transducers and two Transonic® flow probes. The pressure transducers are connected via thin hydraulic lines to the LAC, LVC, base of the mock aorta, and tubing between the HM II and mock aorta. The flow meters are attached to the tubing between the HM II and the mock aorta, and between the mock aorta and compliance chamber 1. This means the measurable variables are the left atrial pressure (LAP), left ventricular pressure (LVP), post-LVAD pressure, aortic pressure (AoP), LVAD flow, and aortic flow. 2.4 EXPERIMENTAL DESIGN Pressure and flow parameters are measured (at 200 Hz) under different hemodynamic conditions. The investigation included a preliminary study (Study 1) and a more extensive study (Study 2). Study 1 tested five LVAD speeds 7, 8, 9, 10, and 11 krpm. The typical clinical range for the HM II LVAD is 7.0-10.0 krmp, thus the experimental range provides information on the role of VAD speed somewhat beyond its usual clinical range. To simplify the experimental design, Study 2 used only three LVAD speeds (7.5, 9.0, and 10.5 krpm) instead of five. For both studies the cardiac function was simulated at three different levels; Off, Low, and Medium. For the Off condition the stepper motor was turned off. For the Low and Medium conditions the stepper motor provided a volumetric displacement of 32mL and 40mL approximately 68 times per minute. These three conditions simulate a heart with no function, severe heart dysfunction, and moderate heart dysfunction. In Study 1 only two MV conditions were tested, a Normal MV using a bioprosthetic valve, and an Absent MV in which the MV position was left empty. These two conditions simulate a normal healthy MV and a worst case scenario for mitral incompetence. The MV conditions were expanded in Study 2, in which a total of five MV conditions were tested in increasing order of mitral incompetence (Figure 2.4). As in Study 1 the first condition was a Normal MV using an intact Medtronic bioprosthetic valve. To model increasing mitral incompetence a series of four MV conditions 33 (b) (c) (e) (f) (a) (d) Figure 2.4. Mitral valve conditions: Normal valve displaying undamaged leaflet (a), Damage 1 with 1.39mm2 of leaflet removed (b and c), Damage 2 with 11.17mm2 of leaflet removed (d), Damage 3 allowing 78.5mm2 of regurgitation (e), and Damage 4 allowing 253.59mm2 of regurgitation (f) were created through increasingly large excisions made in the leaflet of the bioprosthetic valve. All the excisions were taken out of the tip of the same leaflet expanding on the previous excision site. The first and second excisions were V shaped and measured by the crosssectional area of leaflet tissue removed, while the third and fourth excisions were semicircular and measured by the cross-sectional area of regurgitation they allow. The first excision is 2mm long with a cross-sectional area of 1.39mm2 and the second is 4mm long with a crosssectional area of 11.17mm2. The third and fourth excisions allow a cross-sectional area of regurgitation of 78.5mm2 and 253.59mm2 respectively. Tests were run in between each excision of the valve and these MV conditions are referred to as Damage 1 though Damage 4 (D1-D4). Study 1 treated AoP as a dependent variable, leading to some AoP results that are physiologically unlikely in a human. Study 2 treated AoP as an independent variable with two categories, Normal and Hypertensive. The Normal AoP was set to 75mmHg and simulated a patient with normal/low blood pressure, while the Hypertensive AoP was 100mmHg and 34 simulated a patient with high blood pressure. All combinations of variables were tested for both studies, resulting in a total of 30 unique cardiac conditions simulated in Study 1 and 90 in Study 2 (Table 2.1). Table 2.1. Experimental Design: all Combinations of the below Variables Tested Variable LVAD Speed (krpm) Simulated Cardiac Function Mitral Valve Condition Aortic Pressure (mmHg) Conditions Tested Study 1 7, 8, 9, 10, 11 Off, Low, Medium Normal, Absent Study 2 7.5, 9.0, 10.5 Off, Low, Medium Normal, D1, D2, D3, D4 75, 100 35 CHAPTER 3 RESULTS AND DISCUSSION This chapter discusses the results of the preliminary first study and the more extensive second study. 3.1 STUDY 1 Study 1 differs from most previous studies employing the SDSU Cardiac Simulator in that the AV is closed. Having the AV sealed prevents parallel flow and ensures all flow through the LV and VAD is in series. Study 1 also introduces the Mitral Condition as an independent variable so the role of mitral incompetence and regurgitation in LVAD patients can be discerned. The independent variables in Study 1 are VAD Speed, Cardiac Function (CF), and Mitral Condition. The VAD Speeds used are 7, 8, 9, 10, and 11 krpm. The CF settings used are Off, Low, and Medium. The data from the Low CF, however, had to be discarded due to poor equipment performance. When the Cardiac Simulator was left on Low, the stepper motor would slowly migrate downward lowering the LVP and changing flow dynamics in the LV. The two Mitral Conditions tested were Normal MV and Absent MV. The Normal MV corresponds to a MV that closes completely and prevents all mitral regurgitation. The Absent MV corresponds to a completely incompetent MV that provides equal resistance to forward and backward flow. The simulated vascular resistance can also be considered an independent variable because it is kept the same throughout Study 1, although it is not measured. The dependent variables in Study 1 are Flow (L/min), LAP (mmHg), LVP (mmHg), AoP (mmHg), Mitral TVP (mmHg), and Aortic TVP (mmHg). The Trans-valvular pressure (TVP) is the pressure difference across a valve in the normal direction of flow. The Mitral TVP and Aortic TVP are calculated with equations 3.1 and 3.2 respectively. Mitral TVP = LVP – LAP (3.1) Aortic TVP = AoP – LVP (3.2) 36 3.1.1 Pressure and Flow Waveforms As described in the methods, Study 1 began with a simulation of a non-LVAD patient (Figure 3.1). The VAD was turned off and the VAD line was sealed, while the AV was left open with a normal bioprosthetic valve in place. Pressure and flow values were then successfully matched with target values from previous trials (Table 3.1). Figure 3.1. LVP (mmHg) and Flow (L/min) for Normal Patient without an LVAD. Table 3.1. Variables for a Normal Patient without an LVAD Compared to Target Values from Previous Trials Mitral LVP AoP Flow TVP Cardiac LAP Function mmHg mmHg mmHg L/min mmHg 7.72 17.38 43.18 2.64 9.52 Lo Simulated Non‐ Med LVAD Patient 7.14 25.54 64.57 3.28 18.40 na 14±13 45±13 1.7±.6 na Target Values from Lo Previous Trials Med na 23±32 63±17 2.5±3.5 na Aortic TVP mmHg 25.90 39.03 31±19 38±29 37 A cursory examination of LVP and Flow waveforms with different hemodynamic conditions is revealing. When the MV is Normal and CF is Medium, the LVP and Flow are highly pulsatile, similar to those seen when simulating a non-LVAD patient (Figure 3.2a and Figure 3.1). When the CF is Off there is no pressure or flow pulsatility with either Mitral Condition (Figure 3.2c and 3.2d). Since CF is the source of pulsatility, it is expected to be absent when CF is Off. When the MV is Absent and CF is Medium, there is very little LVP or Flow pulsatility (Figure 3.2b); the waveform resembles that of hemodynamic conditions with Off CF and a Normal MV (Figure 3.2c) more than Medium CF and a Normal MV (Figure 3.2a). These results tell us that a properly functioning MV is crucial to mimicking the heart’s normal hemodynamic conditions in an LVAD patient. 3.1.2 Variable Relationships The relationships between dependent and independent variables are presented and discussed here. The hemodynamic conditions that include Off CF with Normal MV, Off CF with Absent MV, and Medium CF with Absent MV all had the same LVP (5-7 mmHg), which did not vary with VAD Speed. The hemodynamic condition with Medium CF and Normal MV, however, had an LVP substantially higher at all VAD Speeds. The LVP also decreased linearly (34-21 mmHg) with increasing VAD Speed. This hemodynamic condition has a higher LVP due to the CF and MV working synergistically. During LV contraction the LVP increases because the MV prevents backflow and there is opposition to forward flow from simulated vascular resistance. Without either a working MV or CF, the LVP stays about the same as the LAP. The Navier-Stokes equation describes why pressure naturally drops with higher flow, but it is not clear why the pressure drop only happens with one hemodynamic condition (Figure 3.3a and Table 3.2). The Mitral TVP was about 5mmHg lower than the LVP for all hemodynamic conditions. This similarity arises because Mitral TVP is calculated from LVP and LAP (Equation 3.1), and LAP is comparatively stable throughout the study. Other than the 5mmHg displacement, Mitral TVP and LVP show the same relationships with changing independent variables (Figure 3.3b and Table 3.2). Average Flow was found to increase linearly with increasing VAD Speed for all hemodynamic conditions. From 7 to 11 krpm the flow increase was about 1.25 L/min (Figure 38 Figure 3.2. LVP (mmHg) and Flow (L/min) for hemodynamic conditions with a Normal MV and Medium Cardiac Function (a), Absent MV with Medium Cardiac Function (b), Normal MV with Off Cardiac Function (c), and Absent MV with Off Cardiac Function (d). 39 (a) (b) (c) (d) (e) Figure 3.3. Dependent variables compared to VAD Speed (krpm) and grouped by Cardiac Function (Off and Medium) and Mitral Condition (Normal and Absent); the dependent variables are LVP (mmHg) (a), Mitral TVP (mmHg) (b), Flow (L/min) (c), AoP (mmHg) (d), and Aortic TVP (mmHg) (e). 40 Table. 3.2. Results from Study 1; Normal MV (a) and Absent MV (b) Normal Mitral Valve LVAD LVP LAP AoP Cardiac Function (krpm) (mmHg) (mmHg) (mmHg) 7 6.02 6.83 44.03 8 6.31 6.43 56.55 9 6.04 6.33 70.74 Off 10 5.84 6.32 86.36 11 5.41 6.27 104.05 Off 34.19 6.57 17.49 7 28.08 6.12 64.48 8 26.04 6.09 76.82 Med 9 23.81 5.49 91.23 10 22.67 5.92 106.28 11 20.39 5.63 120.70 Flow Mitral TVP Aortic TVP (L/min) (mmHg) (mmHg) 2.05 ‐0.80 38.01 2.37 ‐0.12 50.24 2.68 ‐0.29 64.70 3.00 ‐0.48 80.52 3.32 ‐0.86 98.64 1.09 27.62 ‐16.70 2.49 21.96 36.40 2.78 19.95 50.79 3.06 18.32 67.42 3.36 16.75 83.61 3.58 14.75 100.32 (a) Absent Mitral Valve LVAD LVP LAP AoP Cardiac Function (krpm) (mmHg) (mmHg) (mmHg) 7 6.19 4.93 41.59 8 6.13 5.05 53.71 9 5.92 4.87 67.36 Off 10 6.05 4.72 82.88 11 5.86 4.44 101.56 Off 6.87 4.88 2.72 7 7.58 4.80 42.74 8 7.69 4.65 55.32 Med 9 6.80 4.53 69.32 10 6.74 4.45 84.99 11 6.54 4.48 102.16 Flow Mitral TVP Aortic TVP (L/min) (mmHg) (mmHg) 1.95 1.26 35.41 2.26 1.08 47.58 2.57 1.05 61.44 2.90 1.33 76.83 3.26 1.42 95.70 ‐0.09 1.99 ‐4.15 1.98 2.78 35.16 2.31 3.04 47.63 2.63 2.27 62.53 2.97 2.29 78.25 3.31 2.06 95.61 (b) 41 3.3c and Table 3.2). Flow was expected to increase with increasing VAD Speed as part of the HeartMate II’s design and function. The hemodynamic conditions that included Off CF with Normal MV, Off CF with Absent MV, and Medium CF with Absent MV all had similar flow rates at a given VAD Speed. The hemodynamic condition with Medium CF and Normal MV, however, had substantially higher flow at the same VAD Speed. At 7 krpm, flow was about 0.5 L/min greater, although at 11 krpm flow was only about 0.3 L/min greater. Flow is greater because CF is able to augment Flow when the MV is functioning. An Absent MV does not allow CF to augment Flow. Also, the role of CF in producing Flow decreases as VAD Speed increases. AoP and Flow are difficult to quantitatively compare because they are in different units, but they display the same pattern for all hemodynamic conditions. This relationship indicates that with a fixed resistance Flow and AoP are highly correlated (Figure 3.3d and Table 3.2). The Aortic TVP increased approximately linearly with increasing VAD Speed. As stated above Aortic TVP is calculated from AoP and LVP (Equation 3.2). Aortic TVP increases because AoP increases, while LVP remains relatively constant across the conditions in Study 1 (Figure 3.3d and Table 3.2). 3.1.3 Conclusions Study 1 established that without a functioning MV, CF does not affect average LVP or Flow. CF does, however, add some pulsatility to both LVP and Flow. It should be noted that the SDSU Cardiac Simulator does not model the LA as accurately as it models the LV, and does not model the right side of the heart at all. Pressure in the LAC is equalized by being open to the atmosphere. This mechanism mimics a normally functioning heart by providing the LVC with steady input pressure. Unfortunately, the simulator cannot model the pressure fluctuations that occur in patients with pathologic heart conditions. A more anatomic model may have shown CF augmenting flow to some degree, even with a completely incompetent MV. 3.2 STUDY 2 Study 2 expanded upon Study 1. Once again, parallel flow is when blood exits the LV through the AV and the LVAD simultaneously. Study 2 used a closed AV so blood only exits the LV through the LVAD, which is referred to as series flow. Study 2 sought to model an 42 increasing degree of mitral regurgitation with five, instead of two, Mitral Conditions. Finally, AoP was changed from a dependent to an independent variable in an effort to make the hemodynamic conditions more physiologically accurate. The independent variables in Study 2 are VAD Speed, CF, AoP, and Mitral Condition. The VAD Speeds used were 7.5, 9.0, and 10.5 krpm. The number of VAD Speeds was reduced from five to three to simplify the experimental procedure. The CFs used were Off, Low, and Medium. Data from the Low CF is acceptable because the stepper motor was only left on for short periods before being reset. This practice avoided the previous problem that occurred when the Low CF was left on for an extended period of time. The five Mitral Conditions were Normal, Damage 1, Damage 2, Damage 3, and Damage 4. The Mitral Conditions were designed to simulate an increasing degree of mitral incompetence from Damage 1 to Damage 4. Two AoPs are used and represent a patient with Normal arterial pressure (75mmHg) and Hypertensive arterial pressure (100mmHg). To obtain the desired AoP, the simulated vascular resistance was adjusted between different hemodynamic conditions, and so was not constant as in Study 1. The dependent variables are the same as in Study 1, except for AoP. 3.2.1 Initial Examination of different Mitral Conditions Upon initial examination, average LVP changes between Normal, D1, D2, and D3 were surprising and irregular (Figure 3.4). Although the variation is less than 5mmHg, its apparent irregularity is concerning. The variation occurs with all CFs including the Off CF. These results are surprising because it would not be expected that Mitral Condition would affect LVP when CF is Off. Indeed, in Study 1, Mitral Condition does not affect LVP without CF (Figure 3.2, 3.3, and Table 3.2). The Mitral Condition cannot be changed on the SDSU Cardiac Simulator without disassembly of the apparatus. This process is the assumed source of the unanticipated LVP variation. The need to disassemble and reassemble the apparatus in order to change an independent variable is a limitation to the simulator design. Even during experimentation it was realized that precisely the same hemodynamic conditions could not be achieved with Off CF (steady flow), despite considerable effort. Although the exact source of variation is not known it may be unavoidable changes in compliance inherent to the simulator dis/reassembly. 43 LVP vs Mitral Condition Figure 3.4. LVP (mmHg) compared to Mitral Condition for different hemodynamic conditions. In addition to the above-described unexpected variation, the data reflected a large drop in LVP between the D 3 and D 4 Mitral Conditions with Low and Medium CF, but not when CF is Off (Figure 3.4). This change is accepted because it is larger than the other changes, is supported by Study 1, and was expected based on the increased valve incompetence. An 44 incompetent MV allows backflow during contraction and lowers the average LVP by preventing it from maintaining pressures much higher than the LA. When CF is Off, the same LVP drop is not observed because it is caused by the interaction between MV and CF. The Flow also varies in an unexpected manner with changing Mitral Condition between Normal and Damage 3. In many instances the flow increases with a higher degree of mitral incompetence, even though increasing mitral incompetence is predicted to reduce flow (Figure 3.5). As discussed previously, it is assumed that simulator disassembly between Mitral Conditions is a likely cause of this variation. Another possible cause is the introduction of AoP as an independent variable. By varying the simulated vascular resistance to achieve the same AoP between hemodynamic conditions, the resistance was changed from a fixed variable to an unmeasured changing variable. The flow may be reacting to those unmeasured changes in resistance. Additionally in Study 1, AoP was directly linked to Flow (Figure 3.3c and 3.3d), by maintaining a constant AoP between different hemodynamic conditions. Maintaining such constancy may have masked changes in flow that would have otherwise been observed. The unexpected variation with changing Mitral Conditions complicates meaningful analysis of the data. Because of the difficulty in comparing Mitral Conditions, henceforth only the Normal and Damage 4 Mitral Conditions will be reported. This limitation allows a comparison between a Normal MV and an Incompetent MV, which is how the Normal and Damage 4 Mitral Conditions will be referred to from here on. 3.2.2 Relationships between Independent and Dependent Variables For this study pulsatility is the amplitude (max – min) of the respective waveform. Average Flow increases with increasing VAD Speed for both Normal and Incompetent MVs (Figure 3.6). Flow is expected to increase with increasing VAD Speed as part of an LVAD’s function and design. Flow pulsatility on the other hand decreases with increasing VAD Speed for both Mitral Conditions. The CF is responsible for all pulsatility in the system, so as VAD Speed and flow increase the relative role of CF and its resultant pulsatility decrease. Average LVP and pulsatility of LVP decrease with increasing VAD Speed for both Mitral Conditions (Figure 3.7). In a normal fluid-dynamic system, faster flow decreases pressure as described by the Hagen-Poiseuille equation. Although this equation is not typically applied to flexible or elastic structures, it still explains the relationship observed here. Just like 45 Flow vs Mitral Condition Figure 3.5. Flow (L/min) compared to Mitral Condition for different flow conditions. for flow pulsatility, LVP pulsatility decreases because the relative role of CF is reduced with increasing VAD Speed. Average Flow increases with increasing CF when a Normal MV is present, but does not result in any clear trend with an Incompetent MV (Figure 3.8). CF is supposed to induce forward flow as part of the cardiac simulator modeling a human heart. With an Incompetent 46 Normal Mitral Valve Incompetent Mitral Valve VAD Flow vs Time: Grouped by VAD Speed VAD Flow vs VAD Speed VAD Speed (krpm) 7.5 9.0 10.5 Avg. 1.35 3.02 5.32 Flow (L/min) for a Normal Mitral Valve Max. Min. Amp. 5.79 ‐1.03 6.82 7.03 1.03 6.00 8.32 3.89 4.44 Flow (L/min) for an Incompetent Mitral Valve Avg. Max. Min. Amp. 0.43 2.85 ‐0.66 3.51 2.53 4.89 1.46 3.43 5.99 7.67 4.98 2.69 (e) Figure 3.6. Summary of VAD Speed influence on Flow (at Low Cardiac Function and Normal AoP); Flow waveform grouped by VAD Speed for a Normal MV (a) and an Incompetent MV (b), Flow vs VAD Speed for a Normal MV (c) and an Incompetent MV (d), table of VAD Speed vs Flow for a Normal MV and an Incompetent MV (e). 47 Normal Mitral Valve Incompetent Mitral Valve LVP vs Time: Grouped by VAD Speed LVP vs VAD Speed VAD Speed (krpm) 7.5 9.0 10.5 LVP (mmHg) for a Normal Mitral Valve Avg. Max. Min. Amp. 21.38 80.90 ‐10.01 90.91 15.08 65.81 ‐17.19 83.00 8.29 54.74 ‐20.11 74.84 LVP (mmHg) for an Incompetent Mitral Valve Avg. Max. Min. Amp. 3.70 47.87 ‐19.90 67.78 0.76 41.71 ‐22.86 64.57 ‐3.01 34.07 ‐23.23 57.30 (e) Figure 3.7. Summary of VAD Speed influence on LVP (at Low CF and Normal AoP); LVP waveform grouped by VAD Speed for a Normal MV (a) and an Incompetent MV (b), LVP vs VAD Speed for a Normal MV (c) and an Incompetent MV (d), table of VAD Speed vs LVP for a Normal and Incompetent MV (e). 48 Normal Mitral Valve Incompetent Mitral Valve Flow vs Time: Grouped by Cardiac Function Flow vs Cardiac Function Cardiac Function Off Low Medium Avg. 2.19 3.02 3.70 Flow (L/min) for a Normal Mitral Valve Max. Min. Amp. 2.19 2.19 0.00 7.03 1.03 6.00 8.57 1.15 7.42 Flow (L/min) for an Incompetent Mitral Valve Avg. Max. Min. Amp. 2.80 2.80 2.80 0.00 2.53 4.89 1.46 3.43 3.29 6.86 1.65 5.20 (e) Figure 3.8. Summary of Cardiac Function influence on Flow (at VAD Speed 9.0 and Normal AoP); Flow waveform grouped by Cardiac Function for a Normal MV (a) and an Incompetent MV (b), Flow vs Cardiac Function for a Normal MV (c) and an Incompetent MV (d), table of VAD Speed vs Flow for a Normal MV and an Incompetent MV (e). 49 MV however, LV contraction can result in an equal amount of forward and backward flow. In this case, CF would not result in any augmentation to average forward flow. The average Flow with an Incompetent MV did decrease slightly (0.27 L/min) between Off CF and Low CF, as well as a small increase (0.66 L/min) between Low CF and Medium CF. These flow changes are small and may or may not be relevant. Flow pulsatility also increases with increasing CF for both Mitral Conditions (Figure 3.8). This is expected because CF is the source of pulsatility. LVP responds to changing CF in a manner similar to Flow. Average Flow increases with increasing CF when the MV is Normal, but there is no clear trend with the MV is Incompetent (Figure 3.9). During contraction the Normal MV closes preventing backflow. The resistance to forward flow from simulated vascular resistance combined with the lack of backflow raises the average LVP. An Incompetent MV, on the other hand, allows regurgitation during contraction that limits any pressure increase in the LV. Similar to Flow, average LVP decreases slightly (5.98mmHg) from Off CF to Low CF and increases slightly (4.13mmHg) from Low CF to Medium CF. The relevancy of these small changes is undetermined. As the source of pulsatility in the Cardiac Simulator, increasing CF increases LVP pulsatility for both Mitral Conditions as expected (Figure 3.9). Flow decreases with increasing AoP for both Mitral Conditions (Figure 3.10). In a cardiac system higher AoP is synonymous with higher afterload (pressure necessary to eject blood out of the LV). A higher AoP/afterload results in a lower flow if VAD Speed and CF are kept constant. Increasing AoP slightly increased flow pulsatility with a Normal MV, but slightly deceased pulsatility with an Incompetent MV (Figure 3.10). Average LVP and pulsatility of LVP increase with increasing AoP for both Mitral Conditions (Figure 3.11). The average LVP increases because the aorta and LV are connected by the VAD with no valves in between, so a higher AoP is directly transferred back to the LV. Due to lack of information, no hypothesis was formulated on how Flow and LVP pulsatility simultaneously interact with AoP and Mitral Condition, although they do appear to be more strongly influenced when the MV is Normal than when it is Incompetent. Average Flow decreases with the introduction of mitral incompetence for most hemodynamic conditions (Figure 3.6-3.11). As previously stated, an Incompetent MV allows regurgitation during systole resulting in a loss of net forward flow. The two exceptions are 50 Normal Mitral Valve Incompetent Mitral Valve LVP vs Time: Grouped by Cardiac Function LVP vs Cardiac Function Cardiac Function Off Low Medium LVP (mmHg) for a Normal Mitral Valve Avg. Max. Min. Amp. 8.44 8.44 8.44 0.00 15.08 65.81 ‐17.19 83.00 21.34 93.80 ‐19.38 113.18 LVP (mmHg) for a Incompetent Mitral Valve Avg. Max. Min. Amp. 6.74 6.74 6.74 0.00 0.76 41.71 ‐22.86 64.57 4.89 67.22 ‐29.64 96.86 (e) Figure 3.9. Summary of Cardiac Function influence on LVP (at VAD Speed 9.0 and Normal AoP); LVP waveform grouped by CF for a Normal MV (a) and an Incompetent MV (b), LVP vs CF for a Normal MV (c) and an Incompetent MV (d), table of LVP vs Flow for a Normal MV and an Incompetent MV (e). 51 Normal Mitral Valve Incompetent Mitral Valve Flow vs Time: Grouped by AoP Flow vs AoP VAD Flow (L/min) for a VAD Flow (L/min) for an Normal Mitral Valve Incompetent Mitral Valve Avg. Max. Min. Amp. Avg. Max. Min. Amp. Normal 3.02 7.03 1.03 6.00 2.53 4.89 1.46 3.43 Hypertensive 1.22 5.44 ‐0.97 6.40 0.69 2.87 ‐0.29 3.17 (e) Figure 3.10. Summary of AoP influence on Flow (at VAD Speed 9.0 and Low Cardiac Function); Flow waveform grouped by AoP for a Normal MV (a) and an Incompetent MV (b), Flow vs AoP for a Normal MV (c) and an Incompetent MV (d), table of AoP vs Flow for a Normal MV and an Incompetent MV (e). Aortic Pressure 52 Normal Mitral Valve Incompetent Mitral Valve LVP vs Time: Grouped by AoP LVP vs AoP Normal Hypertensive Aortic Pressure LVP (mmHg) for a Normal Mitral Valve Avg. Max. Min. Amp. 15.08 65.81 ‐17.19 83.00 21.98 80.90 ‐9.28 90.18 LVP (mmHg) for an Incompetent Mitral Valve Avg. Max. Min. Amp. 0.76 41.71 ‐22.87 64.57 3.48 46.03 ‐20.76 66.79 (e) Figure 3.11. Summary of AoP influence on LVP (at VAD Speed 9.0 and Low Cardiac Function); LVP waveform grouped by AoP for a Normal MV (a) and an Incompetent MV (b), LVP vs AoP for a Normal MV (c) and an Incompetent MV (d), table of LVP vs AoP for a Normal MV and an Incompetent MV (e). 53 steady state flow (Off CF, VAD Speed 9.0krpm, and Normal AoP) and High VAD Speed with Low CF (VAD Speed 10.5krom, Low CF, and Normal AoP) (Figure 3.8 and 3.6). When the CF is Off all flow is from the LVAD, which is continuous and steady. Without flow pulsatility, the MV plays no role in augmenting flow. Therefore, there is no reason to expect mitral incompetence to decrease Flow if there is no CF. Other than steady state flow, the MV is less efficacious in hemodynamic conditions with less pulsatility. The hemodynamic condition with the lowest pulsatility (other than zero) is also an exception to the Flow and Mitral Condition interaction. The increase in flow observed in both these cases may be due to lower resistance to forward flow because the Incompetent MV has less leaflet surface area, or changes in flow parameters caused by disassembly of the simulator between Mitral Conditions discussed above. Average LVP decreases with the introduction of mitral incompetence for all hemodynamic conditions. When the MV is Incompetent, the LV cannot achieve pressures as high as when the MV is Normal due to backward flow into the lower pressure LA, resulting in a lower average LVP. Interestingly, the hemodynamic conditions that increased in flow with mitral incompetence (zero and low pulsatility) do not also have an increase in LVP (Figure 3.63.11). For all hemodynamic conditions mitral incompetence decreases flow and LVP pulsatility. As mentioned earlier, mitral regurgitation prevents the formation of high LVP or its associated high flow rate, thus decreasing all pulsatility in the simulated cardiac system (Figure 3.6-3.11). All data for Study 2 is also presented in Appendix A. It is difficult to compare this study with those done using the SDSU Cardiac Simulator in the past due to a number of important differences. This study used a different VAD model and different VAD Speeds than previous studies. Also, unlike most of the previous experiments, the AV is closed preventing parallel flow. Additionally, AoP was treated as an independent variable in this study, while previous studies treated AoP as a dependent variable. Despite these discrepancies, by sorting through hemodynamic conditions and comparing those with similar pressures and flow rates, an overall similarity of function can be observed (Table 3.3) [32] [33] [34]. To review, for both Mitral Conditions, increasing VAD Speed increases flow, decreases LVP, and decreases all pulsatility. Increasing CF increases flow and LVP with a Normal MV, 54 Table 3.3. Previous Study Comparison; Zamarripa Enriquez-Almaguer and Samaroo Cardiac Function Off Off Low Low VAD Model VAD Speed Study Author AoP LVP Flow (krpm) (mmHg) (mmHg) (L/min) HeartMate II 9.0 Fisher 75.42 8.44 2.19 DeBakey 10.0 Zamarripa 80 10 2.6 HeartMate II 7.5 Fisher 75.21 21.38 1.35 DeBakey 7.5 Zamarripa 74 21 2.5 DeBakey 7.5 Enriquez‐Almaguer 71 27 2.03 Low HeartMate II 9.0 Fisher 74.51 15.08 3.02 Low DeBakey 10.0 Samaroo 77.9 1.4 3.4 Medium HeartMate II 7.5 Fisher 74.53 29.09 2.15 Medium DeBakey 7.5 Zamarripa 85 24 2.8 Medium DeBakey 7.5 Enriquez‐Almaguer 77 34 2.17 Medium DeBakey 7.6 Samaroo 67.7 19.7 2.9 Off HeartMate II 10.5 Fisher 100.09 8.53 2.53 Off DeBakey 10.0 Enriquez 93 17 2.43 Low HeartMate II 10.5 Fisher 99.07 14.65 3.15 Low DeBakey 10.0 Zamarripa 101 23 2.9 Low DeBakey 10.0 Enriquez‐Almaguer 101 25 2.5 Medium HeartMate II 9.0 Fisher 99.05 27.70 2.26 Medium DeBakey 10.0 Zamarripa 99 30 3.1 Medium DeBakey 10.0 Enriquez‐Almaguer 111 35 2.63 Medium HeartMate II 10.5 Fisher 99.73 19.81 3.86 Medium DeBakey 10.0 Samaroo 95.4 21.1 3.7 Source: Mario Alberto Zamarripa Garica, Characterization and Validation of an In-vitro Cardiac Simulator for Reproducing the Hemodynamics of LVAD Patients, 2006, Thesis from previous student using SDSU Cardiac Simulator. Source: Luz Enriquez-Almaguer, Biomechanics of Aortic Valve During LVAD Use, 2009, Thesis from previous student using SDSU Cardiac Simulator. Source: Gail Mijares Samaroo, Measurement of Fluid Mechanics in the Ventricle of a Simulated LVAD Patient, 2009, Thesis from previous student using SDSU Cardiac Simulator. 55 but does not notably change either Flow or LVP with an Incompetent MV. Increasing CF also increases pulsatility of flow and LVP with both Mitral Conditions. Increasing AoP decreases flow and increases LVP for both Mitral Conditions. Increasing AoP also increases both flow pulsatility and LVP pulsatility with a Normal MV, but has comparatively little effect when an the MV is Incompetent. Mitral incompetence causes lower flow and flow pulsatility, as well as lower LVP and LVP pulsatility. The pressure coupling between the Left Ventricle and the Aorta is covered in Appendix B. 3.2.3 Mitral Incompetence, Regurgitation, and TVP In this section Mitral TVP is examined in detail because it is the variable that provides the most information about Mitral Regurgitation. When Mitral TVP is negative the LVP is lower than the LAP, the MV is open, and fluid flows forward from the LA to the LV due to the pressure differential. However, when Mitral TVP is positive the LVP is higher than the LAP and the MV is closed. If the MV is healthy then there is no regurgitation, but if the MV is incompetent then mitral regurgitation allows backward flow of fluid from the LV to the LA due to the pressure differential. Mitral regurgitation will occur whenever there is an Incompetent MV present along with positive Mitral TVP. By comparing the waveforms of Mitral TVP with a Normal MV and an Incompetent MV, we can observe that Mitral TVP is consistently lower with an Incompetent MV. Although lower with an Incompetent MV throughout the cardiac cycle, the difference is most pronounced at the peak systolic pressure (Figure 3.12). Mitral Regurgitation cannot be directly measured with the Cardiac Simulator, but may be estimated from pressure variables. Given the same degree of mitral incompetence, a higher Mitral TVP will cause more regurgitation than a low Mitral TVP. Additionally, with a given level of incompetence, a longer duration of positive Mitral TVP will result in more regurgitation than a shorter duration of positive Mitral TVP. Positive duration and pressure can be combined into the area of positive Mitral TVP (mmHg*seconds) (Figure 3.13a). Given the above deduction, with the same degree of mitral incompetence mitral regurgitation would be proportional to the area (mmHg*seconds) of the positive Mitral TVP waveform, except for one problem: when regurgitation takes place Mitral TVP drops because fluid flows out of the LV and LVP therefore decreases. This drop in positive Mitral TVP, however, allows us to use 56 Mitral TVP (mmHg) Comparison of Mitral TVP Waveforms with Normal MV and Incompetent MV Least Pulsatile Flow Condition with Normal Aortic Pressure: Most Pulsatile Flow Condition with Normal Aortic Pressure: High VAD Speed (10.5krpm) and Low Cardiac Function Low VAD Speed (7.5krpm) and Medium Cardiac Function Normal MV Incompetent MV Mitral TVP (mmHg) (a) (b) Average Pulsatile Condition with Normal Aortic Pressure: Average Pulsatile Condition with Hypertensive Aortic Pressure: Medium VAD Speed (9.0krpm) and Low Cardiac Function Medium VAD Speed (9.0krpm) and Low Cardiac Function Normal MV Incompetent MV (c) (d) Figure 3.12. Comparison of Mitral TVP with a Normal MV and an Incompetent MV; least pulsatile flow condition with Normal AoP (a), most pulsatile flow condition with Normal AoP (b), average flow condition with Normal AoP (c), and average flow condition with Hypertensive AoP (d). This set of graphs shows Mitral TVP with respect to time. The top line on each graph represents the waveform with a Normal MV. The bottom line represents the same flow conditions with an Incompetent MV. The white area shows the difference in Mitral TVP for a Normal and Incompetent MV with all other variables held the same. Graphs (a) and (b) compare the least and most pulsatile flow conditions at the same AoP, while graphs (c) and (d) compare Normal and Hypertensive AoPs with the same pulsatile condition. 57 the difference in positive Mitral TVP between a Normal and Incompetent MV as a relative estimate for mitral regurgitation. The difference in area of positive Mitral TVP is clearly graphed for different hemodynamic conditions in Figure 3.13. Increasing VAD Speed causes a decrease in area of positive Mitral TVP. Therefore, higher VAD Speed reduces mitral regurgitation by lowering LVP and thereby also lowering Mitral TVP. Increasing CF causes a increase in the area of positive Mitral TVP. Additionally, higher CF increases mitral regurgitation by raising LVP and thereby also raising Mitral TVP. Increasing AoP causes an increase in area of positive Mitral TVP. Consequently, higher AoP also increases regurgitation by raising the LVP and thereby also raising the Mitral TVP. The results for two hemodynamic conditions (VAD Speed 7.5krpm, Hypertensive AoP, at both Low and Medium CF) are not reported because the desired AoP could not be achieved with the given VAD Speed and Cardiac Function. A thorough understanding of mitral regurgitation is important for LVAD patients because of its potential to harm their cardiovascular and overall health. Mitral regurgitation is a cause of LA dilation, pulmonary edema, and can lead to right heart failure. Unfortunately, mitral regurgitation is present in all simulated hemodynamic conditions except with Off CF. According to the information covered already, if degree of mitral incompetence is ignored, then mitral regurgitation is highest with a low VAD Speed, Low CF, and Hypertension. Also, mitral regurgitation is lowest with a high VAD Speed, Low CF, and Normal AoP. Consequently, if reverse remodeling improves an LVAD patient’s LV function, mitral regurgitation could also be increased. It must be noted that comparing the difference in Mitral TVP only allows for a relative estimate of mitral regurgitation between different hemodynamic conditions, not an estimate of absolute regurgitation. Mitral TVP and associated regurgitation is only affected by dependent variables influencing LVP because LAP is comparatively stable. If the LA were modeled more accurately with a closed chamber instead of one open to the atmosphere, then mitral regurgitation could also be modeled more accurately. 3.2.4 Effects of Mitral Condition and Cardiac Function on Flow Patients with both mitral incompetence and a closed AV have no valves associated with the LV to ensure forward flow of blood. One concern for these patients is that CF will not only 58 (a) (a) (b) Figure 3.13. Area (mmHg*seconds) of positive Mitral TVP per cardiac cycle for Normal and Incompetent MVs; visual display of variable graphed below (a), the area (mmHg*seconds) of positive Mitral TVP by flow condition for a Normal MV, an Incompetent MV, and their disparity (b). 59 fail to augment Flow as shown in Study 1, but will actively impair Flow. To determine if this is possible the difference in flow between Off CF and Medium CF was graphed (Figure 3.14). If the flow difference is positive then CF augments flow, and if it is negative then CF impairs flow. CF does augment Flow for all hemodynamic conditions except one (Incompetent MV, VAD Speed 9.0krpm, and Hypertensive AoP). This hemodynamic condition represents the lowest VAD Speed because a Hypertensive AoP (100mmHg) could not be achieved with VAD Speed 7.5 krpm and an Incompetent MV. Additionally, for all hemodynamic conditions, CF augments Flow less when mitral incompetence is introduced. This result is another indication of mitral regurgitation. Increasing CF may reduce net forward flow when hypertension is present and VAD Speed is low. An increase in CF causing a drop in flow, even if rarely, is a problem because it can form a positive feedback loop. A need for oxygen signals the heart to pump more, which lowers flow and reduces the supply of oxygenated blood. Less oxygen signals the heart to pump even more, exacerbating the problem still further. This occurrence would put undue strain on the LV and could prevent LV recovery or cause a reoccurrence of LV dilation. 3.2.5 Conclusion Neither mitral regurgitation, nor a drop in flow with increased CF, are likely to cause mortality or morbidity in an LVAD patient. As long as it functions without major complications, an LVAD will supply enough blood-flow to keep the patient alive. The danger is in causing damage to the cardiovascular system or allowing a relapse of cardiovascular dysfunction. CF decreasing flow could damage the LV, and mitral regurgitation has negative impacts on the LA, right heart, and lungs. This damage could impair QOL and prevent the eventual explanation of the LVAD. Difference in Flow (L/min) between Off and Medium Cardiac Function 60 Figure 3.14. Difference in Flow (L/min) between Off and Medium Cardiac Function for a Normal and Incompetent MV. 61 CHAPTER 4 SUMMARY AND CONCLUSION The heart is an organ which transports blood through the body, providing it with vital oxygen and nutrients [1]. It is composed of four chambers and four valves. The chambers contract to propel blood and the valves ensure unidirectional flow [4]. The most important portion of the heart is the left ventricle (LV) and its two valves, the mitral valve (MV) and aortic valve (AV). These components function together to pump freshly oxygenated blood to the entire body [2]. 4.1 BACKGROUND Heart Failure (HF) occurs when the heart cannot pump enough blood to maintain reasonable patient health [7]. It is not a disease itself, but is a symptom that can be caused by a number of cardiac diseases [6]. Hypertension and coronary heart disease are the most common factors contributing the HF [6] [7]. Hypertension actually doubles a person’s likelihood of developing HF. HF is an extensive health problem in the first world and causes nearly 300,000 deaths annually in the United States alone. Not only does HF affect health, but also the national economy. ; Over $39 billion was spent treating HF in 2009 [6]. One treatment option for HF is the Left Ventricular Assist Device (LVAD). The LVAD is an implantable mechanical pump that augments the LV function and ensures adequate blood flow to the body [9]. A heart transplant is generally superior to LVAD therapy. However, because of the limited availability of transplantable hearts, LVAD use has been increasing [11]. Although LVADs successfully maintain blood flow, they increase the risk of thromboembolism. They must also be plugged into either a rechargeable battery pack or a wall outlet at all times [9]. The HeartMate II (HM II) is new and successful LVAD model manufactured by Thoratec [10]. It houses a small electric motor that pumps blood by spinning a rotary turbine at 8-10 krpm. It has a percutanious (through the skin) line that is always connected to a system controller. The controller in turn either connects to a battery pack or a stationary power unit [12]. The HM II compares favorably to the ground-breaking REMATCH trial of 2001. The 62 REMATCH trial found a one year survival of 52% for contemporary LVADs, but the HM II demonstrated a 72% survival at one year. The MV controls blood flow between the LA and LV. Its function incorporates LV contraction with the mitral annulus, leaflets, chordate tendinae, and papillary muscles. The two types of MV disease are stenosis and incompetence/regurgitation. Stenosis is when forward flow through the valve is impeded, and regurgitation is when reverse flow is not completely prevented [4] [14]. Mitral regurgitation can cause LA dilation, pulmonary edema, and stress to the right heart. HF commonly leads to LV dilation, which itself causes mitral regurgitation [24]. A diseased MV can be treated with either surgical replacement or repair. Repair is preferable because it avoids the need for anticoagulation therapy, and it is fairly durable [25] [26]. The LV dilation caused by HF was once thought to be permanent tissue damage. In fact, with LVAD therapy, HF-caused LV dilation is largely reversible (reverse remodeling). Unfortunately, LVAD removal often causes a rapid reoccurrence of HF and LV dilation. Although the reverse remodeling seen during LVAD therapy reduces mitral incompetence, it is not usually sufficient to prevent LV dilation entirely [27]. The AV controls blood flow between the LV and the aorta. Aortic incompetence has been considered a contraindication to LVAD therapy because it would result in central blood recirculation. An artificial AV also complicates LVAD therapy because it increases the risk of a thromboembolism. Both these issues can be obviated without any deleterious effects by surgically closing the AV during LVAD implantation [31]. Closing the AV creates a hemodynamic condition different from other LVAD patients in which flow between the LV and LVAD can only happen in series, and not in parallel. Without an AV, these patients are more vulnerable to mitral regurgitation. This investigation sought to determine the presence and severity of mitral regurgitation in LVAD patients with a surgically closed AV. 4.2 MATERIALS AND METHODS Experiments were performed with the SDSU Cardiac Simulator, which is a circulatory mock loop that mimics the hemodynamics of a human LV, MV, AV, and aorta. The Simulator used a stepper motor to simulate cardiac contractile function. A 0.9% saline solution was used as a fluid analogous to blood. In conditions where prosthetic valves are in place to simulate the 63 function of native mitral and AVs, the SDSU cardiac simulator functions as a normal human heart. When the piston rises fluid is forced out of the LVC and into the aorta, and when the piston lowers fluid is pulled into the LVC from the LAC. To reproduce the hemodynamics of an LVAD patient the simulator was configured with a model LV and a HM II LVAD. The model LV is a silicone bag in the shape of a human LV. It has three openings which are connected to the LAC, mock aorta, and LVAD. The LVAD inlet is connected to the LV bag and the outlet is connected to the mock aorta. A Medtronic bioprosthetic porcine valve is used for the MV, but no AV is used. To simulate a closed AV a plastic disk blocking all flow is used in place of the AV. Pressure and flow are measured under different hemodynamic conditions with pressure sensors and flow probes. The recorded variables include LAP, LVP, AoP, and Flow. Study 1 used several VAD Speeds and Cardiac Functions with a Normal and Absent MV. Study 2 used more mitral conditions to simulate a range of increasing mitral incompetence. It also introduced AoP as an independent variable to model patients with both Normal and Hypertensive blood pressure. 4.3 RESULTS AND DISCUSSION In the preliminary Study 1, the Low CF data could not be used due to hardware malfunction. First a non-LVAD patient was modeled (AV open and VAD line clamped shut) and hemodynamic values were successfully matched to previous studies. Next an LVAD patient was modeled with varying hemodynamic conditions. All the hemodynamic conditions had an LVP of 5-7mmHg regardless of VAD Speed, except with a Normal MV and Medium CF. This last hemodynamic condition had a much higher LVP because the MV and CF worked together to increase LVP. Without either an MV or CF the LVP stays about the same as LAP. Additionally, the Mitral TVP is about 5mmHg lower than LVP at all times because it is calculated with equation 3.1 and LAP is relatively stable. Flow increased with increasing VAD Speed as expected. All hemodynamic conditions had similar flow rates for the same VAD Speed, with a Normal MV and Medium CF. Similar to LVP, CF augments Flow only if a functional MV is also present. Also, the AoP closely matches Flow, suggesting they are directly linked. 64 Finally the Aortic TVP increases with increasing VAD Speed because increasing flow increases AoP (Aortic TVP is calculated with equation 3.2) From Study 1 it was learned that without a functioning MV, CF does not affect average LVP or Flow, although modeling the LA in a more physiologically accurate manner could affect these results. Study 2 expanded upon Study 1 by modeling an increasing degree of mitral incompetence and introducing AoP as in independent variable. Also, adjustments were made so that data from the Low CF could be used. Both average LVP and average Flow varied in an unanticipated and irregular manner with changing Mitral Condition. Disassembly and reassembly of the simulator between testing different Mitral Conditions is the assumed source of unanticipated variation. The treatment of AoP as an independent variable may further obscure the resultant flow, as they were seen to be closely linked in Study 1. To ensure meaningful analysis, only Normal MV and Damage 4 MV (referred to as Incompetent MV) were used for the rest of Study 2. Increasing CF always increases pulsatility for both LVP and Flow because CF is the source of pulsatility in an LVAD patient. Increasing VAD Speed, on the other hand, always decreases pulsatility because it reduces the relative role of CF (Table 4.1). Table 4.1. Summary of Study 2 Variable Relationships LVP Average Increasing Cardiac Function Increasing VAD Speed Increasing Aortic Pressure Increasing Mitral Incompetence Flow Pulsatility Average + + + - - + + na - na - - - - + Only with Normal MV Pulsatility + Only with Normal MV Increasing VAD Speed always increases Flow as intended by HM II design. Also, increasing VAD Speed reduced average LVP due to the normal hemodynamic pressure-flow relationship. Increasing CF increases both average LVP and Flow, but only with a Normal MV and not with an Incompetent MV. As in Study 1, CF can only augment LVP and Flow with functional MV. 65 Increasing AoP increases LVP and decreases Flow. LVP increases because the mock aorta and LV are connected without any valves between them and pressure differences are transferred from one to the other. Flow decreases because a higher AoP effectively increases the pumps (LV and LVAD) afterload. Introducing mitral incompetence always decreases pulsatility because it allows regurgitation during LV contraction, thus reducing peak LVP and Flow. Mitral incompetence also decreases both average Flow and LVP for the same reason. The one exception to the relationship between mitral incompetence and average Flow is where CF contributes very little to Flow. Despite differences in experimental design, an overall similarity of function can be observed between this study and previous studies using the SDSU Cardiac Simulator. Since mitral regurgitation cannot be directly measured with the Cardiac Simulator, it must be estimated with Mitral TVP. Regurgitation will occur with an incompetent MV whenever Mitral TVP is positive. Specifically, mitral regurgitation between different hemodynamic conditions can be compared using the area of positive Mitral TVP (mmHg*seconds). Increasing VAD Speed decreases mitral regurgitation while increasing CF or AoP increases mitral regurgitation. These relationships mean regurgitation is worst with low VAD Speed, high CF, and high blood pressure. Unfortunately, the Mitral TVP and, therefore, estimated mitral regurgitation is only affected by changes in the LVP, and not the LAP. A more physiological model of the LA would provide more accurate results. One concern is that CF in LVAD patients could not only fail to augment Flow as shown in Study 1, but could actively impair Flow. The results suggested this may be possible with a low VAD Speed, Hypertension, and an Incompetent MV. Further research needs to be done on this topic as it could cause a positive feedback loop and adversely affect the LV. 4.4 CONCLUSION Since many HF patients have LV dilation, many of them also have mitral regurgitation caused by LV dilation. LVAD patients undergo reverse remodeling which reduces LV dilation. The reversal of LV dilation is able to decrease mitral incompetence, but not eliminate it entirely. 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Burkhoff, "Impact of left ventricular assist device (LVAD) support on the cardiac reverse remodeling process," Progress in Biophysics and Molecular Biology, no. 97, pp. 479-496, 2008. [28] W. L. Holman, R. C. Bourge, P. Fan, J. K. Kirklin, A. D. Pacifico, and N. C. Nanda, "Influence of Left Ventricular Assist on Valvular Regurgitation," Circulation, no. 88, pp. 309-318, 1993. [29] E. G. Thompson and G. Philippides. (2010, June) UCSD Health Library. [Online]. http://myhealth.ucsd.edu/library/healthguide/en-us/support/topic.asp?hwid=zm2794 [30] J. O. Mudd, J. D. Cuda, M. Halushka, K. A. Soderlund, J. V. Conte, and S. D. Russell, "Fusion of Aortic Valve Commissures in Patients Supported by a Continuous Axial Flow Left Ventricular Assist Device," J. of Heart and Lung Transplantation, no. 27, pp. 12691274, 2008. [31] R. M. Adamson, W. P. Dembitsky, S. Sam Baradarian, J. Chammas, K. May-Newman, S. Chillcott, M. Stahovich, V. McCalmont, K. Ortiz, P. Hoagland, and B. Jaski, "Aortic Valve Closure Associated with HeartMate LVAD Support: Technical Considerations and Long-term Results," 2010. Unpublished study from the departments of cardiovascular surgery, cardiology, and nursing at Sharp Memorial Hospital. [32] M. A. Zamarripa Garica, "Characterization and Validation of an In-vitro Cardiac Simulator for Reproducing the Hemodynamics of LVAD Patients," M.S. thesis, Dept. Bioengineering, SDSU, San Deigo, CA, 2006. [33] L. Enriquez-Almaguer, "Biomechanics of Aortic Valve During LVAD Use," M.S. thesis, Dept. Bioengineering, SDSU, San Diego, CA 2009. [34] G. M. Samaroo, "Measurement of Fluid Mechanics in the Ventricle of a Simulated LVAD Patient," M.S. thesis, Dept. Biomengineering, SDSU, San Deigo, CA, 2009. 70 APPENDIX A STUDY 2 DATA 71 This appendix lists all the data recorded during study 2 without any analysis (Table A.1, Table A.2, and Table A.3). mmHg L/min Max Min Diff. PI Max Min Diff. PI na na na Off Off Off Normal Normal Normal Normal Normal Normal 9.7 9.8 9.7 75.0 74.5 0.0 75.5 75.4 2.2 75.5 75.1 5.7 0.1 2.3 5.7 ‐0.7 ‐1.3 ‐2.8 65.6 na 67.0 na 68.2 na na na na na na na na na na na na na na na na 7.5 9.0 10.5 Lo Lo Lo Normal Normal Normal Normal Normal Normal 13.3 21.4 81.4 75.2 1.4 13.4 15.1 80.6 74.5 3.0 13.3 8.3 79.5 73.1 5.3 1.3 3.1 5.4 8.1 1.7 ‐5.0 53.8 80.9 ‐10.0 90.9 4.3 59.4 65.8 ‐17.2 83.0 5.5 64.9 54.7 ‐20.1 74.8 9.0 5.8 7.0 8.3 ‐1.0 1.0 3.9 6.8 6.0 4.4 5.0 2.0 0.8 7.5 9.0 10.5 Med Normal Med Normal Med Normal Normal Normal Normal 13.1 29.1 80.9 74.5 2.2 13.1 21.3 81.1 74.9 3.7 12.8 13.7 81.0 75.1 5.9 2.3 3.8 5.9 16.0 45.4 109.7 ‐14.4 124.1 4.3 8.2 53.5 93.8 ‐19.4 113.2 5.3 0.8 61.4 79.2 ‐27.0 106.2 7.8 7.6 8.6 9.6 ‐0.8 1.2 4.1 8.5 7.4 5.6 3.9 2.0 0.9 7.5 9.0 10.5 Off Off Off Hyper Hyper Hyper Normal Normal Normal na 9.5 9.4 na na na 100.1 99.4 0.4 100.8 100.1 2.5 na 0.4 2.6 na ‐0.9 ‐0.9 na na na na na na na na na na na na na na na 7.5 9.0 10.5 Lo Lo Lo Hyper Hyper Hyper Normal Normal Normal 13.1 31.4 105.9 99.7 0.1 13.2 22.0 107.8 101.6 1.2 13.4 14.6 105.4 99.1 3.2 0.2 1.2 3.3 18.3 68.3 92.5 ‐4.0 96.5 3.1 8.8 79.6 80.9 ‐9.3 90.2 4.1 1.3 84.4 65.6 ‐16.2 81.8 5.6 4.5 5.4 7.1 ‐2.4 ‐1.0 1.3 6.9 6.4 5.8 65.7 5.2 1.8 7.5 9.0 10.5 Med Hyper Med Hyper Med Hyper Normal Normal Normal 13.2 35.5 105.7 99.1 0.8 12.9 27.7 104.9 99.1 2.3 12.9 19.8 106.1 99.7 3.9 0.9 2.5 4.0 22.3 63.6 118.0 ‐9.5 127.5 3.6 14.8 71.4 108.5 ‐15.0 123.5 4.5 6.9 79.9 94.0 ‐23.9 117.9 6.0 6.7 7.8 8.9 ‐2.3 ‐0.7 1.3 9.0 8.5 7.5 10.7 3.8 2.0 7.5 9.0 10.5 Off Off Off Normal Normal Normal Damage 1 Damage 1 Damage 1 9.3 11.4 74.3 75.0 0.1 9.3 10.7 76.0 76.7 2.4 11.6 2.0 77.3 74.2 6.0 0.2 2.7 6.2 2.2 1.4 ‐9.7 63.5 na 66.0 na 72.2 na na na na na na na na na na na na na na na na 7.5 9.0 10.5 Lo Lo Lo Normal Normal Normal Damage 1 Damage 1 Damage 1 12.4 20.1 79.6 75.4 1.4 12.3 13.7 79.3 74.8 3.5 12.9 6.7 79.3 74.6 6.2 1.5 3.8 6.5 7.7 1.4 ‐6.2 55.3 65.0 ‐6.0 71.0 3.5 61.1 52.7 ‐10.0 62.7 4.6 68.0 42.0 ‐15.9 57.9 8.7 5.0 6.6 8.1 ‐0.6 1.8 5.1 5.6 4.8 3.0 4.1 1.4 0.5 7.5 9.0 10.5 Med Normal Med Normal Med Normal Damage 1 Damage 1 Damage 1 12.0 26.3 79.7 75.2 2.1 12.6 19.7 80.1 76.0 4.0 12.3 13.3 79.1 74.5 6.7 2.3 4.2 6.9 14.3 48.9 88.4 ‐7.5 95.9 3.6 7.2 56.3 77.6 ‐13.0 90.6 4.6 1.0 61.1 63.3 ‐20.4 83.7 6.3 6.8 8.0 9.3 ‐0.5 1.7 5.2 7.3 6.3 4.1 3.5 1.6 0.6 7.5 9.0 10.5 Off Off Off Damage 1 Damage 1 Damage 1 na na na na na 9.2 11.1 99.2 100.0 0.5 11.6 4.1 102.3 99.4 2.5 na 0.7 2.8 na 1.9 ‐7.5 na na na na na na na na na na na na na 8.7 8.5 na na 90.7 na 91.6 na na na 88.9 na 95.3 na na na na Pulsatility LVAD Flow (L/min) Pulsatility LVP (mmHg) Aortic dP Mitral dP mmHg 7.5 9.0 10.5 Hyper Hyper Hyper 9.0 8.4 6.9 Aortic Flow LVAD Flow Aortic Press PostLVAD Press LV Press Atria Press Mitral Valve Condition Aortic Pressure Cardiac Simulator LVAD Speed (krpm) Table A.1. Study 2 Data Part 1 na na na na na na na na na na na na na na na na na na na na na 72 mmHg L/min mmHg Pulsatility LVAD Flow (L/min) Pulsatility LVP (mmHg) Aortic dP Mitral dP Aortic Flow LVAD Flow Aortic Press PostLVAD Press LV Press Atria Press Mitral Valve Condition Aortic Pressure Cardiac Simulator LVAD Speed (krpm) Table A.2. Study 2 Data Part 2 Max Min Diff. PI Max Min Diff. PI 7.5 9.0 10.5 Lo Lo Lo Hyper Hyper Hyper Damage 1 Damage 1 Damage 1 12.1 26.9 100.8 96.7 ‐0.1 11.8 20.2 103.5 99.3 1.6 12.0 13.2 104.6 100.4 3.8 0.0 1.6 4.0 14.8 69.8 72.8 1.8 71.0 2.6 8.4 79.1 65.0 ‐2.5 67.5 3.3 1.2 87.2 51.6 ‐10.2 61.8 4.7 3.1 4.8 6.7 ‐2.0 ‐0.2 2.2 5.0 5.0 4.6 ‐56.9 3.2 1.2 7.5 9.0 10.5 Med Hyper Med Hyper Med Hyper Damage 1 Damage 1 Damage 1 11.8 33.2 104.0 100.2 0.5 12.2 25.0 104.4 100.3 2.2 11.7 18.6 104.3 100.1 4.4 0.7 2.4 4.6 21.4 67.0 95.1 ‐0.3 95.4 2.9 12.8 75.3 87.1 ‐7.9 95.0 3.8 6.8 81.5 72.9 ‐14.7 87.6 4.7 5.2 6.9 8.4 ‐2.0 ‐0.3 2.2 7.2 7.1 6.2 13.9 3.2 1.4 7.5 9.0 10.5 Off Off Off Normal Normal Normal Damage 2 Damage 2 Damage 2 9.7 9.1 9.9 8.5 10.0 6.4 73.1 73.7 0.3 73.6 74.5 2.9 73.8 74.6 6.3 0.4 3.2 6.7 ‐0.6 ‐1.4 ‐3.6 na na na na na na na na na na na na na na na 7.5 9.0 10.5 Lo Lo Lo Normal Normal Normal Damage 2 Damage 2 Damage 2 9.6 9.9 9.8 22.1 74.3 74.1 1.9 17.4 75.1 75.5 4.0 10.8 74.4 74.0 6.6 2.1 4.3 7.2 12.5 52.0 70.0 ‐3.7 73.7 3.3 7.5 58.1 58.8 ‐10.9 69.7 4.0 1.0 63.2 48.1 ‐12.9 60.9 5.6 5.6 6.8 8.4 ‐0.1 2.5 5.6 5.7 4.3 2.8 3.0 1.1 0.4 7.5 9.0 10.5 Med Normal Med Normal Med Normal Damage 2 Damage 2 Damage 2 10.1 29.4 73.8 74.2 2.5 10.0 22.3 74.1 74.6 4.6 10.1 17.4 74.7 75.0 7.0 3.0 5.0 7.5 19.4 44.8 97.7 ‐6.5 104.3 3.5 12.3 52.3 81.7 ‐13.2 94.9 4.2 7.3 57.6 72.4 ‐18.2 90.6 5.2 7.1 8.3 9.6 0.0 2.7 5.6 7.2 5.5 4.0 2.8 1.2 0.6 7.5 9.0 10.5 Off Off Off Hyper Hyper Hyper Damage 2 Damage 2 Damage 2 na 9.7 9.7 na 8.7 8.4 na na na 99.0 99.6 0.5 99.5 100.3 3.1 na 0.7 3.5 na ‐0.9 ‐1.4 na na na na na na na na na na na na na na na 7.5 9.0 10.5 Lo Lo Lo Hyper Hyper Hyper Damage 2 Damage 2 Damage 2 9.3 9.8 9.7 30.8 100.0 99.8 0.4 22.6 99.5 99.4 2.0 15.7 99.0 99.2 4.3 0.6 2.1 4.6 21.5 69.1 80.7 4.7 12.9 76.8 69.2 ‐3.2 6.1 83.4 56.0 ‐9.9 76.0 2.5 72.5 3.2 65.9 4.2 3.8 5.4 7.1 ‐1.6 0.1 2.8 5.4 5.3 4.3 14.9 2.7 1.0 7.5 9.0 10.5 Med Hyper Med Hyper Med Hyper Damage 2 Damage 2 Damage 2 9.9 9.7 9.9 35.3 99.0 98.8 1.1 27.6 100.2 99.9 2.6 22.3 99.1 99.2 4.9 1.3 3.0 5.3 25.3 63.5 103.2 ‐1.2 104.4 3.0 17.9 72.4 92.4 ‐4.9 97.3 3.5 12.4 77.0 81.3 ‐12.9 94.2 4.2 6.0 7.3 8.6 ‐1.7 0.1 3.0 7.6 7.2 5.6 7.2 2.8 1.2 7.5 9.0 10.5 Off Off Off Normal Normal Normal Damage 3 Damage 3 Damage 3 8.7 8.6 8.6 10.1 72.6 74.3 0.0 9.0 73.2 74.7 2.8 7.0 71.7 73.6 6.4 ‐0.1 2.9 6.5 1.4 0.4 ‐1.6 na na na na na na na na na na na na na na na 7.5 9.0 10.5 Lo Lo Lo Normal Normal Normal Damage 3 Damage 3 Damage 3 9.4 9.4 9.4 21.1 73.0 73.9 1.9 15.7 74.3 75.0 4.0 9.5 73.9 74.5 6.7 1.7 4.0 6.8 11.7 52.8 71.3 ‐7.6 78.9 3.7 6.4 59.3 57.2 ‐13.3 70.5 4.5 0.1 65.0 47.3 ‐16.0 63.3 6.6 5.7 6.8 8.5 ‐0.1 2.6 5.7 5.9 4.2 2.9 3.2 1.1 0.4 64.6 na 66.0 na 68.3 na na na 90.9 na 91.9 na 64.2 na 65.7 na 66.6 na na na na na na na na na na na na na na na na na na na 73 mmHg L/min mmHg Pulsatility LVAD Flow (L/min) Pulsatility LVP (mmHg) Aortic dP Mitral dP Aortic Flow LVAD Flow Aortic Press PostLVAD Press LV Press Atria Press Mitral Valve Condition Aortic Pressure Cardiac Simulator LVAD Speed (krpm) Table A.3. Study 2 Data Part 3 Max Min Diff. PI Max Min Diff. PI 7.5 9.0 10.5 Med Normal Med Normal Med Normal Damage 3 Damage 3 Damage 3 9.4 9.7 9.7 28.2 74.6 75.1 2.4 21.0 74.0 74.2 4.5 15.7 73.9 74.3 6.9 2.4 4.6 7.1 18.8 46.9 96.7 ‐11.0 107.7 3.8 11.3 53.2 82.8 ‐16.7 99.5 4.7 6.0 58.6 75.1 ‐20.8 95.9 6.1 7.1 8.3 9.5 ‐0.2 2.6 5.5 7.3 5.6 4.1 3.1 1.2 0.6 7.5 9.0 10.5 Off Off Off Hyper Hyper Hyper Damage 3 Damage 3 Damage 3 na 8.3 8.5 na 9.6 9.3 na na na 98.1 99.4 0.3 96.8 98.5 3.3 na 0.1 3.4 na 1.3 0.8 na na na na na na na na na na na na na na na 7.5 9.0 10.5 Lo Lo Lo Hyper Hyper Hyper Damage 3 Damage 3 Damage 3 9.0 9.3 9.3 28.7 98.5 99.3 0.1 21.6 98.8 99.5 1.8 14.2 99.5 99.8 4.2 0.0 1.6 4.3 19.7 70.6 78.6 0.7 78.0 2.7 12.2 78.0 70.5 ‐6.4 76.9 3.6 4.9 85.6 56.3 ‐12.5 68.8 4.8 3.7 5.5 7.0 ‐1.8 0.0 2.8 5.5 5.5 4.2 49.5 3.0 1.0 7.5 9.0 10.5 Med Hyper Med Hyper Med Hyper Damage 3 Damage 3 Damage 3 9.2 9.2 9.4 35.9 99.1 99.6 1.0 27.4 100.8 101.0 2.5 20.8 99.5 100.0 4.6 0.8 2.4 4.7 26.7 63.6 107.6 ‐4.3 111.9 3.1 18.2 73.6 94.7 ‐11.3 106.0 3.9 11.4 79.3 81.2 ‐16.9 98.1 4.7 6.1 7.2 8.5 ‐1.8 0.0 2.6 7.9 7.2 5.9 8.2 3.0 1.3 7.5 9.0 10.5 Off Off Off Normal Normal Normal Damage 4 Damage 4 Damage 4 9.5 9.6 9.6 7.1 6.7 5.0 73.5 74.5 0.2 74.4 75.1 2.8 74.7 75.6 6.4 0.3 3.0 6.7 ‐2.4 ‐2.8 ‐4.6 na na na na na na na na na na na na 7.5 9.0 10.5 Lo Lo Lo Normal Normal Normal Damage 4 Damage 4 Damage 4 13.7 3.7 13.7 0.8 13.9 ‐3.0 79.0 75.0 0.4 80.1 76.1 2.5 79.4 75.0 6.0 0.5 2.8 6.3 ‐10.0 71.3 47.9 ‐19.9 67.8 18.3 2.9 ‐13.0 75.3 41.7 ‐22.9 64.6 84.5 4.9 ‐16.9 78.0 34.1 ‐23.2 57.3 ‐19.0 7.7 ‐0.7 1.5 5.0 3.5 3.4 2.7 8.2 1.4 0.4 7.5 9.0 10.5 Med Normal Med Normal Med Normal Damage 4 Damage 4 Damage 4 13.8 9.2 13.7 4.9 13.9 2.4 78.5 74.7 1.1 78.6 75.1 3.3 79.4 75.2 6.2 1.2 3.6 6.5 ‐4.6 65.5 73.9 ‐28.0 101.9 11.1 5.2 ‐8.8 70.2 67.2 ‐29.6 96.9 19.8 6.9 ‐11.5 72.9 58.5 ‐30.1 88.6 37.4 8.7 ‐0.7 1.7 4.6 5.9 5.2 4.2 5.2 1.6 0.7 7.5 9.0 10.5 Off Off Off Hyper Hyper Hyper Damage 4 Damage 4 Damage 4 na 9.5 9.5 na 6.9 6.5 na na na 99.9 100.8 0.3 99.6 100.7 3.1 na 0.5 3.3 na ‐2.6 ‐3.0 na na na na na na na na na 7.5 9.0 10.5 Lo Lo Lo Hyper Hyper Hyper Damage 4 Damage 4 Damage 4 na na 13.8 3.5 13.5 0.2 na na na 103.8 99.3 0.7 104.9 100.5 2.9 na 0.7 3.2 na na na na na na na ‐10.3 95.8 46.0 ‐20.8 66.8 19.2 2.9 ‐13.3 100.3 39.4 ‐20.5 59.9 293.1 5.0 na ‐0.3 1.8 na 3.2 3.1 na 4.6 1.1 7.5 9.0 10.5 Med Hyper Med Hyper Med Hyper Damage 4 Damage 4 Damage 4 na na 13.4 6.9 13.2 4.1 na na na 103.4 99.5 1.2 104.0 100.4 3.6 na 1.4 3.9 na ‐6.5 ‐9.1 na ‐0.4 1.9 na 5.2 5.1 na 4.3 1.4 na na 89.8 na 89.2 na 67.4 na 68.4 na 70.6 na na na 93.9 na 94.2 na na na na na na na na na na na na na na na na na na na na na na na na na na na na na na na na na na 92.6 71.8 ‐26.4 98.2 14.2 4.7 96.3 63.8 ‐30.5 94.3 23.0 7.1 74 APPENDIX B PRESSURE COUPLING BETWEEN AORTA AND LEFT VENTRICLE 75 The degree to which pulsatility from the LV reaches the aorta of an LVAD patient is of concern because pressure and flow peaks may have an important role in coronary perfusion. AoP is much less pulsatilie than LVP (Figure B.1, and Table B.1). On average AoP amplitude was 75.7% that of LVP, with a range of 8.1%. Normal Mitral Valve Incompetent Mitral Valve (a) (b) (c) (d) . Figure B.1. Comparison of LVP and AoP waveforms for different flow conditions. Low pulsatility refers to Low Cardiac Function and High VAD Speed (10.5 krpm). High pulsatility refers to Medium Cardiac Function and Low VAD Speed (7.5 krpm). 76 Table B.1. Amplitude of LVP and AoP under several Flow Conditions and the Percentage Difference between them Amplitude MV Condition AoP Setting Pulsatility Low High Normal Normal Hypertensive Incompetent Normal Low High Low High LVP (mmHg) 74.84 124.13 81.78 AoP (mmHg) 18.62 28.42 % Difference from LVP to AoP ‐75.1 ‐77.1 23.76 ‐70.9 127.54 57.30 101.91 34.18 ‐73.2 12.04 21.50 Average ‐79.0 ‐78.9 ‐75.7