The past, present, and future of bioresorbable

European Heart Journal (2014) 35, 745–752 doi:10.1093/eurheartj/ehu057

The past, present, and future of bioresorbable vascular scaffolds In a few years we will not understand why we put metal in the coronary arteries, says Patrick W. Serruys that’, says Serruys. ‘Now we will see if this new stent is an interesting alternative to the polymer in polylactide’. As yet there is no clear picture of which patients benefit most from BVS. Initially, it was thought that young patients were the prime candidates because they start their disease earlier and it would be desirable to avoid repeat implantation of metal stents. But it has been shown that it i’s also possible to reconstruct the anatomy in elderly patients. Even in individuals with some degree of calcification of the coronary artery, a cardiologist can reconstruct the lumen with a nice endothelium lining. Serruys says: ‘People don’t know what to do with acute coronary syndromes and vulnerable plaque’. He adds: ‘When the BVS is bioresorbed you have the return of vasomotion and shear stress so it is very different from metal, which cages the coronary artery forever. In vulnerable plaque, instead of a thin cap you are able to create a protective layer’. The main downside with BVS is that with the polymer, the range of dilatation is somewhat limited. Ranges of 3 –3.5 or 3.5– 4 mm are possible, but not 3 –4 mm. This is not a problem with the metallic bioresorbable stent. And because the bioresorbable polymer stent is weaker than metal, the struts are thicker than the metallic struts. ‘There are some concerns about the alteration of shear stress and the possibility of being more prone to stent thrombosis or scaffold thrombosis’, says Serruys. ‘So far we have not seen the difference between the polymer and metallic stents and we need data from a randomised trial to make any valid statement about the absence or difference of stent thrombosis’. The benefits of BVS include the return of the flexibility, conformability, and vasomotricity of the vessels. Serruys says: ‘It’s a kind of restoration, it’s not a permanent foreign body caging the vessel’. Another advantage which people are talking about—but robust data are still needed—is that patients with BVS appear to have less chest pain than patients implanted with permanent stents. It i’s unclear why this might occur, but it could be related to ischaemia or the fact that the structure disappears and is not stretching the vessel with metal. Serruys says: ‘That’s something we have to watch carefully because it might be an important element for the patient and for quality of life’. The price of BVS was initially very high but Serruys says the major corporations have understood that the cost was not viable. Recently, companies have unofficially agreed to charge just 10 –20% more

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The history of bioresorbable vascular scaffolds (BVS) began in 1988 when the biodegradable scaffold was developed by the Thoraxcenter in Rotterdam, the Netherlands, and Duke University in Durham, North Carolina. ‘As clinicians we were very embarrassed to put metal in biological structures like the coronary arteries’, says Patrick W. Serruys (Netherlands). ‘But the biodegradable scaffold we developed was not of sufficient quality to be used in clinical situations’. In 2000, Japanese researchers treated 70 patients with the PLLA Igaki-Tamai biodegradable stent. But it was not drug eluting. Two technologies emerged in 2006/07. One was a metallic stent that was bioabsorbable in magnesium, the BIOTRONIK Bioabsorbable Magnesium Scaffold. A second innovation was the first generation of Abbott’s bioresorbable scaffold, which eluted everolimus to prevent restenosis. Over the last 7 years, more than 15 companies including Medtronic have developed either a bioresorbable polymeric scaffold in polylactide or polyglycolide, or a bioresorbable metallic scaffold with magnesium. Today, there are two BVS that have a CE mark in Europe but only Abbott’s is commercialized. The technology has not been approved by the US Food and Drug Administration (FDA) and the official pivotal trials in China, Japan, the USA, and Europe have yet to report their results on safety and efficacy. The most advanced trial is in Europe, which is complete and will reveal 1 year follow-up findings in about June 2014. While the world awaits the results of the classical randomized pivotal trials, clinicians across the globe are testing Abbott’s BVS in all kinds of syndromes, lesions, and situations. Reports are emerging of short series in acute myocardial infarction, bifurcation, main stem, total occlusion, diabetes, and others. Serruys says: ‘Because the device is available you see a lot of “pioneers” who are testing it in a somewhat chaotic and freelance style. It’s difficult to track all the studies that are going on and we don’t like that situation but it’s a fact of life.’ He adds: ‘It is unusual to have the pivotal trials coming so late after commercialisation. In the case of the Cypher we had at least the RAVEL Study before it was commercialised’. BIOTRONIK is working on the third-generation magnesium stent called the Drug Eluting Absorbable Metal Scaffold (DREAMS) which now elutes sirolimus and a trial will have started by the beginning of 2014. ‘Before, it eluted paclitaxel and they were not happy with

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New knowledge around using BVS in other vessels and organs is rapidly becoming available and Serruys sees them being implanted in the kidney, aorta, carotid artery, and elsewhere, with slow release of a drug. He says: ‘Beyond the hype I think that in a few years we will not understand anymore why we put metal in the coronary arteries. You don’t need the strength and the kilopascal of the metallic strut to keep a vessel open’. BVS will be around for a decade or two, says Serruys. Balloon angioplasty had its day during 1977–87, and then there were bare metal stents from 1987 to 93, which were followed by the drug eluting stent in 2000. The biodegradable stent has been gaining prominence since 2006. At some point in the future, the boundaries will be pushed away again by nanotechnology and gene technology.

The Barbra Streisand Women’s Heart Center, Cedars-Sinai Heart Institute, Los Angeles, USA Prominent US Cardiologist Noel Bairey Merz MD, FACC, FAHA, talks to Judy Ozkan about her role as Director of the Cedars-Sinai Heart Institute’s Barbra Streisand Women’s Heart Center and the Linda Joy Pollin Women’s Healthy Heart Program

Bairey Merz (left) and Barbra Streisand (right) In the early days of her career, Dr Bairey Merz became aware that gender differences posed a major impediment to women with heart disease and that advances made in cardiovascular science and medicine were not as effective at saving lives. She consequently focused on closing the gender gap through research, clinical practice, public health campaigning, and awareness raising. Her message struck a chord with high-profile donors and she engaged among others, singing and film legend Barbra Streisand and US philanthropist and businesswoman Irene Pollin. The stark inequality of women’s heart health shocked Streisand so much that she raised a staggering $22 million to establish a permanent endowment at Cedars-Sinai now known as the Barbra Streisand Women’s Heart Center, dedicated

to researching and developing new diagnostic tools and advancing specialized care to women with heart disease. The Center draws on over 18 years of research and clinical experience which Dr Bairey Merz believes will help recalibrate the gender imbalance and counteract the women’s heart disease epidemic. She says: ‘Although 500 000 women die of heart disease each year in the United States, our assessment and treatment of the condition was, until recently, based entirely on medical research performed on men. As a cardiologist I didn’t see any of what we had learned being adopted in clinical or community practice’. The National Heart, Lung, and Blood Institute’s Women’s Ischemic Syndrome Evaluation initiative (WISE), which has been running over the last two decades, and which Dr Bairey Merz leads, informs about much of the work done at the Center.1 This landmark study was the first study of its kind to examine large cohorts of women for long periods of time and to date has generated about 300 publications. Dr Bairey Merz describes it as the ‘biggest contributor to understanding the gender disparity gap’. She is currently seeking funding for Wise 3 in which she hopes to look at ‘mechanistic pathways’ and test hypotheses on micro-vascular ischaemia. Awareness raising initiatives such as the National Heart, Lung and Blood Institute Heart Truth Campaign are also vital components of the Centre’s work. ‘Breast cancer campaigners were very successful in


for BVS than the older drug-eluting stents, which he believes is acceptable. In Germany, BVS are reimbursed because they are considered a novel technology that should be supported by the state. ‘That’s not the case in the other countries of Europe but I think that there is much less concern than one or two years ago when the price was astronomical’, says Serruys. BVS are popular in India, the Middle East, Indonesia, and other countries such as Japan where patients dislike the concept of foreign bodies. ‘They believe that you get an intact body from your parents and then you should not alter the structures of it’, says Serruys. ‘So they don’t like surgery, they don’t even like metallic stents. They very much like the concept of something which is bioresorbable, which does its job and then disappears’. Serruys said in a Circulation article in 2010 that by 2012/13, this disruptive technology would come into place and become disseminated in different countries. ‘I think that at a certain point the community will embrace that, not only for the coronary arteries but also potentially for the valve’, he says. ‘And also as a reservoir for elution of drugs in other organs’.

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her lab time to studying sex differences in bio-markers. That the team at the Center can embark on such pieces of research would have been impossible if the donors had not stepped in because, according to Dr Bairey Merz, the federal government is not according women’s heart disease sufficient funding. But more than this she suggests that a deeper commitment is needed in the form of a much more comprehensive inclusion of women’s heart health in medical school curricula to board certification exams. With the right political will, Dr Bairey Merz believes progress will follow. She attended a recent congress in Chile where she learned how ‘dismal’ treatment rates of women following myocardial infarction had been improved by over 50% within 4 years, just by passing a relatively simple law that required all patients, including women, should receive treatment for myocardial infarctions. Despite Cedars-Sinai’s proximity to the entertainment industry and its roll-call of celebrity patients and famous donors, according to Bairey Merz there are no Hollywood-style happy endings in sight for the women’s heart disease epidemic. She says: ‘We need to keep up the pressure at all times because the fact remains that every year more women continue to die from heart disease than men’.

Dr Bairey Merz is also keen to point out that studying heart disease in women has enormous benefits for the wider male community, as demonstrated by a recent publication in PLOS ONE. ‘We showed for the first time that if an artery constricted, it is a powerful predictor of death in women and because this doesn’t typically happen in men, no-one had actually looked at that’.2 A valued addition in 2013 to the research expertise at the Center is Jennifer Van Eyk PhD, from the John Hopkins School of Medicine. The internationally renowned scientist will devote a proportion of

References 1. Shaw LJ, Bairey Merz CN, Pepine CJ, Reis SE, Bittner V, Kelsey SF, Olson M, Johnson BD, Mankad S, Sharaf BL, Rogers WJ, Wessel TR, Arant CB, Pohost GM, Lerman A, Quyyumi AA, Sopko G; WISE Investigators. Insights from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study: Part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies. J Am Coll Cardiol. 2006;47:(3 suppl):S4 –S20. 2. Mohandas R, Sautina L, Li S, Wen X, Huo T, Handberg E, Chi Y-Y, Merz CNB, Pepine CJ, Segal MS. Number and Function of Bone-Marrow Derived Angiogenic Cells and Coronary Flow Reserve in Women without Obstructive Coronary Artery Disease: A Substudy of the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE). PLOS One, doi: 10.0.1371/journal.pone.0081595. First published online 2 December 2013.

When the blood flow becomes bright Dr Keiichi Itatani presented the latest data on intraventricular flow patterns from normality to pathology at EuroEcho-Imaging 2013 Recently, there have been emerging trends and interests in the novel imaging techniques developed to visualize and measure blood flow in the circulatory system, to reveal the haemodynamics and pathophysiology of cardiovascular diseases.1,2 Cardiac MRI is a well-known method and PC (phase contrast) MRI can provide spatial and temporal distribution of flow velocity vector components3 – 7 and their reconstruction facilitates the creation of fascinating colour videos of the flow vectors or streamlines.8,9 Because echocardiography is non-invasive and portable, visualizing flow using echocardiography has been expected for clinical applications1 and several novel techniques have been reported.10 – 15 We have developed a flow visualization method called vector flow mapping (VFM), which is a modification of a colour Doppler-based method reported by Garcia et al.13 especially for detecting accurate near wall flow, in order to calculate several

haemodynamic parameters essential for the diagnosis of cardiovascular diseases.14 These flow visualization techniques have revealed the normal blood flow pattern in a right or left ventricle and shed light on circulatory physiology.1 – 3,6,14,16 Findings from these studies including normal and abnormal vortex formation patterns helped us to assess abnormal blood flow patterns in the cardiovascular system.6,17 In order to obtain diagnostic or prognostic information from the visualized flow or vortex, several haemodynamic or fluid mechanical parameters should be measured. Perhaps physicians and surgeons would like to know their patients’ cardiac workload due to an abnormal vortex, or to determine strategies to achieve physiological flow. In addition to vorticity, which is often used to evaluate the strength and direction of the swirling vortex flow,18 we have developed a method for measuring the estimated flow


getting women to own their own bodies and raising awareness, and we are aiming for similar results’. Advocacy and lobbying on a local, national, and international scale will complement research and clinical activities. Establishing ‘gender institutes’ along the lines of the one at the Charite´ University of Medicine in Berlin is one way forward. Working to correct disparities in clinical journals and scientific publications is also a necessity. ‘Two things are very clearly evident: the majority of scientific experiments that are published in scholarly journals do not stratify the data or sometimes even indicate the sex of the cell and that is not acceptable; then number 2, very few journals have women reviewing or serving as editors or even submitting papers. There is a large sex disparity despite the fact that women in the US are as competitive in getting grants and doing work as men’. Current evidence suggests that there has been some improvement in closing the gender gap and the 50-year disparity identified 10 years ago, has now narrowed to a 40- to 35-year gap. Mortality among women has started to fall since the turn of the new millennium but on a more worrying note, Dr Bairey Merz has not seen any broad evidence that women-appropriate guidelines are being adopted or that gender specific care is routinely being delivered.

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energy loss (EL) with viscous dissipation defined by the formula:14,19,20 m ∂ui ∂uj 2 + dv, i,j 2 ∂x ∂xi j

(1)

Left ventricular flow pattern in a normal case and cases after valve surgery Figure 1 illustrates flow in a normal left ventricular chamber measured by VFM. During systole, a large vortex forms at the basal portion during the isovolumic systolic phase, and facilitates a smooth outflow during the early systolic phase. In this process, EL was

Figure 1 Intraventricular blood flow of a normal case, and its flow energy loss (EL).


where i and j are the coordinates of the 2D, or 3D Euclidean space, and m is the blood viscosity. This parameter indicates energy dissipation due to blood viscosity in a turbulent flow. The kernel of the integral displays the distribution of the dissipated energy caused by the inefficient flow, which is integrated with spatial increments dv. Several previous reports defined energy loss (EL) as the total pressure drop between the inlets and outlets,21 – 25 and discussed its relation to the cardiac workloads and prognoses of afterload increasing diseases.24,25 Energy loss in definition (1) based on viscous dissipation is consistent to and also a substitute of the one defined with total pressure drop.19,20 Because it does not include static pressure in definition (1), it is measurable by flow visualization techniques such as VFM or PC-MRI. Here, we discuss the process in which a normal left ventricle (LV) forms a vortex to save energy, complicated cases in which flow visualization is thought to be useful and the physiological and clinical meaning of flow EL measurement.

small inside the vortex, preserving energy to perform efficient ejection. During systole, EL was not significant because the velocity vectors were well aligned towards the outflow. During the early diastolic filling phase, clockwise and counter clockwise vortices formed around the anterior and posterior leaflets of the mitral valve along the trans-mitral flow, shown in blue and red in vortices with negative and positive values, respectively. In mid-diastole, the red vortex around the posterior leaflet decreased in size, whereas the blue vortex around the anterior leaflet enlarged. In late diastole, EL in the left ventricle decreased. In end-diastole after atrial contraction, a straight flow with low EL was observed. Figure 2 shows the intraventricular flow vector, flow streamlines, and flow vorticity in cases after various types of mitral valve procedures that we observed using VFM. In a case with a mechanical valve placed in an anti-anatomical position, in which the leaflets aligned side-by-side, trans-mitral flow collided with the anteroseptal wall which was then directed to the apical and to the posterolateral wall, resulting in a large counter clockwise vortex. In a case with a mechanical valve placed in an anatomical position, as with anatomical anterior and posterior leaflets, a vortex from the posterior wall to the anteroseptal wall as in a normal LV vortex flow was formed. In a case with a tri-leaflet bio-prosthetic valve, perhaps because of the flexible soft valve leaflets, a counter clockwise vortex in the basal portion and a clockwise vortex in the apical portion were observed. In a case after mitral valve plasty, the LV vortex flow appeared as a physiological flow pattern with a large clockwise vortex. We compared our method with PC-MRI in a patient after aortic valve replacement for aortic stenosis (Figure 3). This patient had a thickened ventricular wall with normal contractility. In the PC-MRI, we segmented the lumen of the left ventricle using the superposed image taken with steady-state free procession, which afforded a clearer contrast than did PC-MR angiogram. Although the flow EL

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in PC-MRI was lower than that in VFM, order and patterns became quite similar. During systole, slightly elevated EL was detected in the curved outflow along the thickened septal wall, whereas during diastole, trans mitral flow formed a vortex localized at the basal portion of the LV and slightly dissipated the flow energy.

Preload increase cases: aortic regurgitation Figure 4 shows the comparison of flow EL between a severe aortic regurgitation (AR) case and a normal case. According to the latest ACC/AHA guideline for patient management of chronic aortic regurgitation,26 indication for aortic valve surgery is predominantly based on the presenting symptoms, in addition to the decreased systolic function or the dilated LV chamber. It is our goal to establish a quantitative evaluation method of cardiac workload affected by inefficient regurgitation flow. In a severe AR case, the regurgitation jet itself dissipated energy, and the turbulent vortex flow also dissipated the high EL (Figure 4B). The EL

inside the ventricle was predominately higher in the AR case than in normal cases, not only in the diastolic phase when the regurgitation jet was prominent but also during systole due to the volume load or the preload of the LV. Energy loss caused by the turbulent flow and preload was supposed to be compensated by the ventricular wall ejection power. Therefore, the loss itself would be considered to be the burden or load of the ventricular wall. We had a complicated case with moderate AR after a mechanical mitral valve replacement in an anti-anatomical position. Because LV size, reduced contractility, and symptoms were the indications for aortic valve surgery,4 Left ventricular diastolic and systolic dimensions were 40.5 mm, and 23.5 mm, respectively, and were not significant because the mitral annulus was fixed with a mechanical valve. This patient suffered from dyspnoea on exertion, but the symptoms were quite difficult to interpret, because she also suffered from interstitial pneumonia due to SLE. Catheter examination revealed a high enddiastolic pressure (21 mmHg) and the patient was selected for valve replacement. Vector flow mapping revealed that the AR jet collided with the trans-mitral flow directed to the anteroseptal wall thorough the mechanical valve. The trans-mitral flow collided with the regurgitation


Figure 2 Intraventricular vortex after mitral valve surgery.

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Figure 4 Intraventricular flow energy loss (EL) distribution during diastole and EL profile in one cardiac cycle. (A) A normal case. (B) A case with severe aortic regurgitation (AR).


Figure 3 Intraventricular flow vector and flow energy loss measured with (A) vector flow mapping and (B) MRI.

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Figure 6 Our hypothesis: schema of the clinical contribution of energy loss measurements.


Figure 5 Intraventricular flow of a case with moderate aortic regurgitation after mechanical mitral valve replacement. Diastolic flow and energy loss in one cardiac cycle measured by vector flow mapping. Aliasing of the colour Doppler data was manually corrected.

752 jet, which created a counter clockwise vortex flow during diastole in the ventricle. A persistent regurgitation jet directed towards the anteroseptal wall was observed, resulting in high EL even at the end-diastolic phase (Figure 5).

Energy loss as an index of cardiac workload

Jennifer Taylor, MPhil

References 1. Sengupta PP, Pedrizzetti G, Kilner PJ, Kheradvar A, Ebbers T, Tonti G, Fraser AG, Narula J. Emerging trends in CV flow visualization. JACC Cardiovasc Imaging 2012;5: 305 –316. 2. Rodriguez Munõz D, Markl M, Moya Mur JL, Barker A, Fernańdez-Golfıń C, Lancellotti P, Zamorano Go´mez JL. Intracardiac flow visualization: current status and future directions. Eur Heart J Cardiovasc Imaging 2013;14:1029 –1038.

3. Kim WY, Walker PG, Pedersen EM, Poulsen JK, Oyre S, Houlind K, Yoganathan AP. Left ventricular blood flow patterns in normal subjects: a quantitative analysis by three-dimensional magnetic resonance velocity mapping. J Am Coll Cardiol 1995; 26:224 – 238. 4. Wigstro¨m L, Sjo¨qvist L, Wranne B. Temporally resolved 3D phase-contrast imaging. Magn Reson Med 1996;36:800 –803. 5. Markl M, Draney MT, Hope MD, Levin JM, Chan FP, Alley MT, Pelc NJ, Herfkens RJ. Time-resolved 3-dimensional velocity mapping in the thoracic aorta: visualization of 3-directional blood flow patterns in healthy volunteers and patients. J Comput Assist Tomogr 2004;28:459–468. 6. Kvitting JP, Ebbers T, Wigstro¨m L, Engvall J, Olin CL, Bolger AF. Flow patterns in the aortic root and the aorta studied with time-resolved, 3-dimensional, phase-contrast magnetic resonance imaging: implications for aortic valve-sparing surgery. J Thorac Cardiovasc Surg 2004;127:1602 –1607. 7. Dyverfeldt P, Kvitting JP, Sigfridsson A, Engvall J, Bolger AF, Ebbers T. Assessment of fluctuating velocities in disturbed cardiovascular blood flow: in vivo feasibility of generalized phase-contrast MRI. J Magn Reson Imaging 2008;28:655 –663. 8. Lee N, Taylor MD, Hor KN, Banerjee RK. Non-invasive evaluation of energy loss in the pulmonary arteries using 4D phase contrast MR measurement: a proof of concept. Biomed Eng Online 2013;12:93. 9. Barker AJ, van Ooij P, Bandi K, Garcia J, Albaghdadi M, McCarthy P, Bonow RO, Carr J, Collins J, Malaisrie SC, Markl M. Viscous energy loss in the presence of abnormal aortic flow. Magn Reson Med, doi: 10.1002/mrm.24962. First published online 2 October 2013. 10. Ohtsuki S, Tanaka M. The flow velocity distribution from the Doppler information on a plane in three-dimensional flow. J Visual 2006;9:69 –82. 11. Hong GR, Pedrizzetti G, Tonti G, Li P, Wei Z, Kim JK, Baweja A, Liu S, Chung N, Houle H, Narula J, Vannan MA. Characterization and quantification of vortex flow in the human left ventricle by contrast echocardiography using vector particle image velocimetry. JACC Cardiovasc Imaging 2008;1:705 –717. 12. Uejima T, Koike A, Sawada H, Aizawa T, Ohtsuki S, Tanaka M, Furukawa T, Fraser AG. A new echocardiographic method for identifying vortex flow in the left ventricle: numerical validation. Ultrasound Med Biol 2010;36:772–788. 13. Garcia D, Del Alamo JC, Tanne D, Yotti R, Cortina C, Bertrand E, Antoranz JC, Perez-David E, Rieu R, Fernandez-Aviles F, Bermejo J. Two-dimensional intraventricular flow mapping by digital processing conventional color-Doppler echocardiography images. IEEE Trans Med Imaging 2010;29:1701 – 1713. 14. Itatani K, Okada T, Uejima T, Tanaka T, Ono M, Miyaji K, Takenaka K. Intraventricular flow velocity vector visualization based on the continuity equation and measurements of vorticity and wall shear stress. Jpn J Appl Phys 2013;52:07HF16. 15. Mehregan F, Tournoux F, Muth S, Pibarot P, Rieu R, Cloutier G, Garcia D. Doppler vortography: a color Doppler approach to quantification of intraventricular blood flow vortices. Ultrasound Med Biol 2014;40:210 – 221. 16. Mangual JO, Domenichini F, Pedrizzetti G. Describing the highly three dimensional Right Ventricle flow. Ann Biomed Eng 2012;40:1790 – 1801. 17. Mangual JO, De Luca A, Kraigher-Krainer E, Toncelli L, Shah A, Solomon S, Galanti G, Domenichini F, Pedrizzetti G. Comparative numerical study on left ventricular fluid dynamics after dilated cardiomyopathy. J Biomech 2013;46:1611 –1617. 18. Faludi R, Szulik M, D’hooge J, Herijgers P, Rademakers F, Pedrizzetti G, Voigt JU. Left ventricular flow patterns in healthy subjects and patients with prosthetic mitral valves: an in vivo study using echocardiographic particle image velocimetry. J Thorac Cardiovasc Surg. 2010;139:1501 –1510. 19. Itatani K, Ono M. Blood flow visualizing diagnostic device. Patent WO 2013077013 A1. 20. Itatani K. Fluid dynamical considerations on the single ventricular physiology: Energetic optimization of the Fontan and Norwood procedure. 2011. PhD Thesis, the University of Tokyo, Tokyo, Japan. 21. Garcia D, Pibarot P, Dumesnil JG, Sakr F, Durand LG. Assessment of aortic valve stenosis severity: a new index based on the energy loss concept. Circulation 2000; 101:765 – 771. 22. Itatani K, Miyaji K, Nakahata Y, Ohara K, Takamoto S, Ishii M. The lower limit of the pulmonary artery index for the extracardiac Fontan circulation. J Thorac Cardiovasc Surg. 2011;142:127 –135. 23. Itatani K, Miyaji K, Qian Y, Liu JL, Miyakoshi T, Murakami A, Ono M, Umezu M. Influence of surgical arch reconstruction methods on single ventricle workload in the Norwood procedure. J Thorac Cardiovasc Surg 2012;144:130–138. 24. Bahlmann E, Gerdts E, Cramariuc D, Gohlke-Baerwolf C, Nienaber CA, Wachtell K, Seifert R, Chambers JB, Kuck KH, Ray S. Prognostic value of energy loss index in asymptomatic aortic stenosis. Circulation. 2013;127:1149 –1156. 25. Honda T, Itatani K, Takanashi M, Mineo E, Kitagawa A, Ando H, Kimura S, Nakahata Y, Oka N, Miyaji K, Ishii M. Quantitative Evaluation of Hemodynamics in the Fontan circulation: a cross-sectional study measuring energy loss in vivo. Pediatr Cardiol 2013; 35:361–367.


We have shown that in AR cases, EL increases are caused by the preload increase. We have reported a case with pulmonary stenosis after repair of the tetralogy of Fallot, which can be considered an example of an afterload increasing disease of the right ventricle.27 The prominent increase of EL detected in the vortex at the post-stenotic dilated site was drastically reduced by the pulmonary valve plasty with a commissurotomy.27 Other recent other reports proved that EL based on total pressure24,25 and on viscous dissipation9 predicted the prognosis of the afterload increasing diseases. A normal clinical examination of cardiac function could indicate the performance or energy producing forces of the ventricle, whereas EL would indicate the disadvantage of turbulent flow itself,9,14,19 – 25 and have the potential to estimate the cardiac workload including both preload and afterload. Figure 6 illustrates our hypothesis regarding the clinical contribution of EL estimation. In a normal case, the ventricle efficiently generates large energy, resulting in little EL. However, when inefficient non-physiological flow occurs due to cardiovascular disease, cardiac workload increases as the flow EL increases, but function would be preserved for a while, and compensate for the workload. If the overload becomes too large, the ventricle decompensates resulting in heart failure, in which the EL decreases because the ventricle cannot generate sufficient energy. Diagnostic parameters usually obtained in our clinical practice mainly measure the ventricular energy generating function; however, more practically, a parameter that would estimate the cardiac workload would be more desirable so that we would not miss the optimal timing for therapeutic interventions in cardiovascular diseases. Although flow visualization methods have been experimentally validated,13,28 flow EL with viscous dissipation as in formula (1) is a novel parameter and more clinical evidence and experimental validation warrants further studies. However, from our observations in the clinical cases described above, among others, this method has a potential to reveal the pathophysiology of cardiovascular diseases. Because EL can be derived by recently developed blood flow visualization techniques and because it enables not only the visualization of diseased flow, but also quantitatively estimates the energy dimension value, this novel approach will provide a more accurate estimation of the cardiac workload.

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26. ACC/AHA. 2006 Guidelines for the management of patients with valvular heart disease: 3.2.3 Chronic aortic regurgitation. JACC 2006;48:e111 –e121. 27. Honda T, Itatani K, Miyaji K, Ishii M. Assessment of the vortex flow in the poststenotic dilatation above the pulmonary valve stenosis in an infant using echocardiography vector flow mapping. Eur Heart J 2013;35:306–311.

28. Prinz C, Faludi R, Walker A, Amzulescu M, Gao H, Uejima T, Fraser AG, Voigt JU. Can echocardiographic particle image velocimetry correctly detect motion patterns as they occur in blood inside heart chambers? A validation study using moving phantoms. Cardiovasc Ultrasound 2012;6: 10 – 24.


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