Preoperative Prediction of Aortic Insufficiency During

3

Review

Preoperative Prediction of Aortic Insufficiency During Ventricular Assist Device TreatmentTeruhiko Imamura,1 MD and Koichiro Kinugawa,1 MD

Summary

Survival rate in patients with stage D heart failure has improved significantly owing to the development of continu-ous flow left ventricular assist devices (LVAD), but aortic insufficiency (AI) still remains one of the major unsolved com-plications that impairs patient quality of life. There are no established treatments for AI, and preoperative prediction and prevention of AI is needed. The opening of a native aortic valve (AV) is a sufficient condition for prevention of AI, and improvement of LV ejection fraction due to LV reverse remodeling (LVRR) is essential to open a native AV. Preoperative insufficient β-blocker treatment and pulsatile flow LVAD usage are keys for LVRR, opening of an AV, and prevention of AI. The second mechanism that leads to AI is remodeling of the aortic root and degeneration of a native AV, which re-sults from reduced pulse pressure during LVAD support. Centrifugal or pulsatile flow LVAD usage has an advantage in terms of preserving pulsatility, and may prevent AI compared with an axial pump. There is less probability of avoiding AI with sufficient β-blocker treatment, and these patients may be good candidates for concomitant surgical intervention to a native AV at the time of LVAD implantation. (Int Heart J 2016; 57: 3-10)

Key words: Pulsatility, VAD, Carvedilol, Aortic valve

C urrently, the survival rate in patients with advanced heart failure (HF) has improved due to the develop-ment of continuous flow (CF) left ventricular assist

device (LVAD) treatment and improvement of perioperative management procedures.1-9) However, quality of life during CF LVAD is still not satisfactory because of several unresolved postoperative complications.4,10,11) One of the major complica-tions is aortic insufficiency (AI), which is characterized as continuous aortic regurgitation during both systolic and diasto-lic phases through a degenerated and occasionally fusional na-tive aortic valve (AV) (Figure 1AB).12,13) Native AV, which is apparently normal before LVAD implantation, can be associat-ed with a considerable level of AI after LVAD implantation. Post-LVAD AI can develop even in the preoperative setting in which there is no aortic regurgitation at all.12,14,15)

In 2000, Rose, et al first documented acquired AV disease during pulsatile flow (PF) LVAD. They identified evidence of commissural fusion of native AV.16) In 2006, Frazier, et al sum-marized the relationship between commissural fusion of native AV and development of AI during CF LVAD treatment.17) We also showed that AI was more frequently observed in patients with CF LVAD as compared with PF pump in 2011 (Figure 1C).18) Since then, a number of single-center studies have doc-umented a wide-ranging prevalence of AI during LVAD treat-ment.15,19-21)

The development of AI during LVAD treatment is consid-ered to be a multifactorial phenomenon and a result of altered AV and aortic root biomechanics due to chronic and continu-

ous ventricular unloading. Unloading of LV results in ventricu-lar decompression, and the combination of systolic dysfunc-tion and low preload cannot generate sufficient pressure to open the native AV. With scarce opening of a native AV, arterial pressure becomes minimally pulsatile. Thus, a native AV is ex-posed to elevated diastolic aortic pressure and increased trans-valvular pressure. The incremental transvalvular pressure is re-versely directed toward native AV since aortic pressure is higher than LV pressure for most of the cardiac cycle, and it is not at all physiological. The increases in magnitude and dura-tion of transvalvular pressure load may make native AV degen-erate along with annular deformation, which ultimately lead to regurgitation.22-24)

AI reduces systemic output because LVAD flow is stolen backward. Not surprisingly, AI worsens the HF symptoms with elevated LV filling pressure due to retrograde aortic flow as we showed previously.25) Consistently, AI decreases patient exer-cise tolerability, because LVAD flow alone cannot satisfy out-put demand during exercise (Figure 2A).12) Many studies in-cluding ours 12,14,26) (Figure 2B) have agreed that the development of AI did not increase mortality, although this is still controversial.27) However, the re-admission rate due to cardio-vascular events (ventricular tachyarrhythmias or stroke) was higher in patients with AI (Figure 2B).12) Enhanced intra-cardi-ac pressure may precipitate the risk of ventricular tachyar-rhythmias. Turbulence due to scarce forward flow through a native AV may facilitate the formation of thrombus in the aor-tic root.28)

From the 1 Department of Therapeutic Strategy for Heart Failure, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.Address for correspondence: Koichiro Kinugawa, MD, Department of Therapeutic Strategy for Heart Failure, Graduate School of Medicine, The University of Tokyo,

7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: [email protected] for publication June 22, 2015. Accepted July 10, 2015.Released in advance online on J-STAGE January 6, 2016.All rights reserved by the International Heart Journal Association.

4Int Heart J

January 2016IMAMURA, ET AL

Figure 1. A typical case of AI in a patient with EVAHEART. A long-axis parasternal view of transthoracic echocardiogra-phy (A). Partial fusion formation of native AV between right coronary and non-coronary cusps was observed at the timing of heart transplantation (B). Freedom rate from AI is compared between patients with PF and those with CF LVAD (C).

Figure 2. Exercise tolerability (A) and prognosis in patients (B) with or without AI. PVO2 indicates peak oxygen consump-tion; and 6MWD, 6-minute walk distance. *P < 0.05 by the log-rank test, †P < 0.05 by unpaired t-test compared with AI group.

5Vol 57No 1 PREDICTION OF AI DURING LVAD TREATMENT

According to the ISHLT guidelines, more than mild aor-tic regurgitation should prompt consideration for surgical inter-vention at the time of LVAD implantation (Class I, Level of Evidence C) to avoid hemodynamic loss of LVAD flow.29) Aor-tic mechanical prostheses are never recommended because subvalvular thrombosis is more likely to occur with infrequent opening of the AV. Therefore, a bioprosthetic valve is a com-mon choice for this situation.

On the other hand, there are no established treatments for post-LVAD AI. Lower rotation speed is sometimes indicated to reduce the grade of AI,14,30) but it may be associated with a higher risk of pump thrombosis, lower exercise tolerability,31) or inadequate stimulation of sympathetic activity.32,33) Some authors reported successful trans-catheter aortic valve replace-ment during LVAD support, but the procedure has a risk of mi-gration of the replaced device owing to the strong vacuum of blood into apical VAD inflow.34) Native AV can be replaced with a bioprosthetic valve, but newly placed biologic valves are still at risk for the development of postoperative AI.18) Park, et al first reported a simple technique of concomitant AV repair at the time of LVAD implantation (Park’s stitch),35,36) but the repair also carries a risk for recurrence of AI. Patch closure of the outflow tract is another strategy.37) While the procedure can be a definite solution for AI, it ruins the possibility of myocar-dial recovery, and increases the risk of serious decompensation or fatality with device malfunction. Native AV closure by an Amplatzer septal occluder has also been reported.38)

As such, once AI develops during LVAD treatment, an-other open-heart surgical procedure or catheter-based interven-tion may be needed with inevitably high risk. If a precise pre-diction of AI before LVAD implantation can be made, some appropriate intervention may be performed concomitantly with LVAD surgery at a relatively low risk. Recently, we have re-ported several predictors for AI development after LVAD im-plantation, and we will summarize them in this review.

Previously Reported Predictors of Post-LVAD AI

So far, several preoperative predictors of post-LVAD AI have been reported: CF LVAD usage,15,19,30) smaller body size,19) female gender,19) and large baseline aortic root diame-ter.20) We observed a consistently higher prevalence of AI in patients with CF LVAD.18) A recent meta-analysis revealed that preoperative predictors of AI were higher age and CF LVAD usage.13) Correlates of development or worsening of AI follow-ing LVAD implantation include increasing aortic root diame-ter,19,20) less frequent opening of native AV,19,20,27) AV commis-sural fusion,39) higher pump speeds,19,20) increased mitral regurgitation,27) and higher levels of B-type natriuretic pep-tide.18)

We recently proposed a “2-hit theory” for the develop-ment of AI (Figure 3).12) Few patients suffer AI when a native AV is open at rest.26,27) Slaughter, et al have stated that the opening of native AV at least once per 3 native heart beats may be sufficient to avoid development of AI,40) and we and others define the opening of a native AV at > 30% of the native heart beats as “open”.12,26) On the other hand, AI always develops in patients with closed native AV. Closed AV is the first and suffi-cient condition for the development of AI.

Preoperative β-blocker Treatment and LV Reverse Remodeling (LVRR)

Native AV opens when the intra-cardiac pressure exceeds the pressure of the aortic root during the systolic phase.41) Un-der the circumstances with decreased preload by LV unload-ing, considerable recovery of systolic function may be indis-pensable to generate sufficient systemic pressure. As is well known, improvement of LV systolic function as well as reduc-tion in LV cavity are observed among many patients under LVAD support, ie, LVRR. Therefore, we believe that LVRR is a key to open native AV and prevent AI.

As for the etiology, fulminant myocarditis or peripartum cardiomyopathy often recovers in terms of cardiac function and has an advantage over ischemic cardiomyopathy from the viewpoint of LVRR.42-44) Patients with a broad scar lesion, which is assessed by end-myocardial biopsy, cardiac magnetic resonance imaging, or myocardial scintigraphy, have less chance to achieve LVRR.45,46) Simon, et al showed that a short duration of HF is a positive factor to achieve LVRR during LVAD treatment, because remodeling is not severe in such myocardium and there is a chance to recover.47)

We have demonstrated that preoperative “insufficient” β-blocker treatment is a strong predictor of LVRR during LVAD treatment.48) The amount of β-blocker treatment here is quantified as a cumulative dose of β-blocker during the entire duration of HF. Patients with preoperative insufficient β-blocker treatment typically have too short a period to try suf-ficient β-blocker titration because of acute deterioration in he-modynamics, but many of them are responders to the post-LVAD titration of β-blocker.49) Cases with acute myocarditis or peripartum cardiomyopathy are usually treated for a relatively short period (less than 6 months) before LVAD insertion, and the etiology is by itself closely related with the cumulative amount of β-blocker in such cases. A low cumulative dose of β-blocker (less than 4.5 g of carvedilol-equivalent dose) was associated with considerable improvement of LVEF (> 25%).49) Among them, patients with a very low cumulative dose of β-blocker (less than 1.6 g of carvedilol-equivalent dose) were super-responders in terms of LVRR (LVEF ≥ 35% and/or explantation of LVAD within 6 months).48,50)

In contrast, patients who eventually received LVAD im-plantation despite preoperative sufficient β-blocker treatment are inevitably non-responders to β-blockers, and such patients rarely achieve LVRR even with unloading by LVAD. In animal

Figure 3. A schema of “2-hit theory” for the development of AI.

6Int Heart J


models, prolonged sufficient LV unloading by LVAD without β-blocker treatment could not facilitate LVRR, but rather in-creased the ratio of the myocardial fibrotic area, myocardial apoptosis, and cardiac stiffness.51,52) Considering the results, postoperative responsiveness to β-blocker may be essential to achieve LVRR in addition to the LV unloading.

We would like to note that this theory does not at all rec-ommend intentional insufficient β-blocker treatment. We can-not predict responders to β-blocker beforehand. In many cases, we initiate and titrate the drug with every effort, and after 3-6 months of treatment we can finally determine the responsive-ness of a β-blocker.53) Our idea for the cumulative dose of β-blocker with respect to LVRR is based on such a clinical set-ting that all cardiologists must have made every attempt in or-der to introduce a higher dose of β-blocker. If we are somehow able to determine the responsiveness to a β-blocker without treatment of the drug by a certain novel technique in the future, we may not need to take into account the history of HF treat-ment before LVAD implantation. We would have to completely rewrite our paper then, but we believe that it is not yet the time to do that.

Pulsatile Device and LVRR

Not only preoperative β-blocker therapy but also device selection may have a huge impact on the achievement of LVRR. PF devices unload the ventricle only during a certain part of the cardiac cycle, whereas CF devices do so continu-ously throughout the overall cardiac cycle.54) In animal experi-mental models, Bartoli, et al demonstrated that continuous un-loading altered the physiologic profile of myocardial and vascular hemodynamic energy utilization, in contrast to pulsa-tile unloading that preserved normal physiology.55) Ootaki, et al showed a decrease in coronary blood flow by strong contin-uous LV unloading.56) Loebe, et al revealed that a PF LVAD was associated with less stimulation of the systemic inflamma-tory system as compared with a CF device.57) Accordingly, in-termittent LV unloading may correlate positively to successful LVRR. We have also demonstrated in a clinical setting that PF LVAD had an advantage over CF pumps in terms of LVRR.18,48)

Now is the era of CF LVAD, and PF devices have a number of drawbacks compared with CF devices in terms of higher morbidity and mortality rates.3,4,7) However, when pa-tients receive significantly insufficient β-blocker treatment pre-operatively, it may be preferable to consider PF LVAD as a tar-

Figure 4. Native AV and LV observed by M-mode transthoracic echocardiography at rest (A) and during exercise (B) in a typical case. HR indicates heart rate; and LVDd, left ventricular end-diastolic diameter.


geting bridge to recovery that includes device explantation.

Opening of Native AV and AI

Responders to β-blocker treatment experience LVRR with LVEF > 25%, and their native AV are open for at least 30% of total heart beats at rest. With sufficient opening of na-tive AV, such patients can avoid development of AI.49) Super-responders to β-blockers can achieve significant improvement of LVEF during LVAD treatment (LVEF ≥ 35%), and their na-tive AV opens in 100% of heart beats. They never experience AI, and we can even explant LVAD in some of them.48)

We have recently shown that some patients experience the opening of native AV only during exercise (see the typical case in Figure 4AB).25) LVRR is not observed since their LVEF remain ≦ 25% and their native AV does not open at rest. In this sense, they are non-responders to β-blocker treatment, but they somehow maintain cardiac reserve for exercise. Such pa-tients also avoid AI. Native AV might open frequently during daily life under light exertion. Although the “intermittent low speed” mode of the Jarvik 2000 may have an advantage in the prevention of AI due to the forced opening of native AV for 8 seconds per minute,28) no studies including ours have thus far demonstrated its clinical advantage.12) More frequent opening of native AV may be required, and active daily life as well as cardiac rehabilitation must be important, especially among pa-tients with persistently closed AV at rest.

Definite non-responders to β-blocker treatment, who re-ceived sufficient β-blocker treatment preoperatively, rarely achieve LVRR, and their LVEF remains at a low level (≦ 25%), and their native AV never opens at rest or during exer-cise. Not surprisingly, we observed AI development in these patients very frequently.

Pulsatility, Remodeling of Aortic Root, and AI (Figure 6)

Those who had persistently closed native AV throughout their daily life were already treated with high doses of β-blockers for long periods preoperatively.49) LVRR was never observed and cardiac reserve during exercise was lost in these patients. However, not everyone suffers AI among such pa-tients (Figure 3). What is the watershed point for the develop-ment of AI? We have to hypothesize additional conditions for the development of AI, and we have proposed that reduced pulsatility in the aortic root may be crucial.

Reduced pulsatility may be a key to the development of AI from the viewpoint of remodeling of the aortic root (Figure 6). Westaby, et al and Nishimura, et al have demonstrated that

Figure 5. Parasternal long-axis views and color Doppler images of transthoracic echocardiography in 3 typical cases.

Figure 6. Relationship between pulse pressure, remodeling of aortic root, dilatation of native AV, and development of AI.

8Int Heart J


remodeling of the aortic root emerges along with thinning of the aortic wall under reduced pulsatility, which is attributable to apoptosis of smooth muscle cells and fragmentation of elas-tic fibers.58,59) Remodeling and dilatation of the aortic root is associated with a higher prevalence of AI as well as the degen-eration of the aortic valve and enlargement of the aortic ring.20)

Other than reduced pulsatility, we have to take into con-sideration geometric alteration of AV by commissural fusion and flow turbulence in the ascending aorta. Commissural fu-sion of native AV is not always observed in patients with AI,60) and may not be a mainstay of AI development. In contrast, flow turbulence, which increases wall shear stress and retro-grade pressure in the aortic root, develops during LVAD sup-port, especially when a native AV is closed.61) The degree of turbulence may also be affected by the location or direction of the LVAD outflow conduit anastomosis on the aorta.62) Inade-quately excessive flow into the ascending aorta by LVAD pump may be another factor for increasing turbulence.30)

Although lower rotation speed is usually associated with higher pulse pressure and appears to have an advantage in pre-venting AI, it has a risk of pump thrombosis or low output syn-drome. Pulsatility is more preserved during centrifugal LVAD support than during axial pump support, because pump flow changes more dramatically depending on the pressure gradient between the LV and aorta in a centrifugal pump as compared with an axial device.63,64) Consistently, we previously showed that patients receiving a centrifugal pump had larger pulse pressure than those with an axial pump.12) The differences in pulse pressure may be attributable to a less enlarged aortic root and less frequent AI in patients with centrifugal LVAD.12) When patients received sufficient β-blocker treatment during long-term HF duration preoperatively, a centrifugal pump may be a better selection than an axial pump, targeting both preser-vation of pulse pressure and prevention of AI (Figure 7D).

Although the clinical relevance of pulsatile device is de-creasing nowadays, pulsatility can be best preserved with PF LVAD by its nature. Pulsatile flow by itself facilitates LVRR as described above, but preserved pulsatility in the aortic pressure also contributes to minimize the development of AI. Accord-ingly, both LVRR and preserved pulsatility well explain the advantage of PF LVAD over CF LVAD in terms of AI develop-ment.65)

The advantage of preserved pulsatility has increasingly been acknowledged, and several attempts during CF LVAD treatment are emerging.7) A centrifugal HeartWare LVAD has a cyclic controlled speed change function (Lavare Cycle) mode; this allows for changes in LV filling and flow rate.66) Another centrifugal HeartMate III LVAD has an induced pulse mode for achieving an increased level of pulsatility with CF assist-ance.67) An effort to preserve pulse pressure during LVAD ther-apy would be a future direction, although the precise target level of pulsatility remains uncertain.

Relationship Between Preoperative Condition and Post-LVAD AI

Finally, we would like to summarize the relationship be-tween the preoperative condition and post-LVAD AI in Figure 7. Patients with insufficient β-blocker treatment (in other words, those who do not have enough time for the titration of β-blocker) can achieve LVRR with full opening of a native AV, and avoid AI. HF duration in these patients is usually less than

1 year. Such patients enjoy good clinical courses including ex-plantation of LVAD or at least stable hemodynamics without AI (Figure 7A). Some patients can achieve partial LVRR, and they experience the partial opening of native AV at rest (Figure 7B). Others do not achieve LVRR but maintain cardiac reserve for exercise. They do not have any opening of their native AV at rest but do during exercise (Figure 7C). These two scenarios also avoid AI, and are good indications for stable LVAD treat-ment. With respect to HF duration, they typically have suffered for a couple of years.

In contrast, patients with preoperative sufficient β-blocker treatment (ie, those with a long history of HF > 3 years) rarely achieve LVRR and lose cardiac reserve along with a persist-ently closed native AV (Figure 7D). In these cases, a centrifu-gal pump may have an advantage with respect to preventing AI during LVAD support. Concomitant surgical intervention of native AV at the time of LVAD implantation may also be con-sidered in such patients.

Concomitant patch closure may be the most reasonable choice to prevent AI, considering the low recurrence rate after the procedure. However, candidates should be carefully select-ed, because the procedure eliminates the possibility of future explantation of LVAD and increases the risk of sudden death with device malfunction. In Japan, patients often wait several years on LVAD support for a transplant, and AI becomes a se-rious threat that can decrease the quality of life of the patient for a long time. Therefore, concomitant patch closure may be better indicated for not only the candidates of destination ther-apy but also for those of bridge to transplantation when pa-tients have received sufficient β-blocker treatment preopera-tively (Figure 7D).Conclusion: Preoperative insufficient β-blocker treatment and pulsatility-preserving device usage such as PF or a centrifugal pump are keys to prevent AI during LVAD treatment.

Disclosure

None

Figure 7. Summary of the relationship between preoperative condition and post-LVAD AI. HF indicates HF duration; BB, cumulative dose of β-blocker (dose is presented as an equivalent one of carvedilol); and Ao, aortic root.


References

1. Imamura T, Kinugawa K, Hatano M, et al. Bosentan improved persistent pulmonary hypertension in a case after implantation of a left ventricular assist device. J Artif Organs 2013; 16: 101-4.

2. Imamura T, Kinugawa K, Shiga T, et al. Correction of hy-ponatremia by tolvaptan before left ventricular assist device im-plantation. Int Heart J 2012; 53: 391-3.

3. Kinugawa K. How to treat stage D heart failure? - When to im-plant left ventricular assist devices in the era of continuous flow pumps? Circ J 2011; 75: 2038-45. (Review)

4. Kirklin JK, Naftel DC, Pagani FD, et al. Sixth INTERMACS an-nual report: a 10,000-patient database. J Heart Lung Transplant 2014; 33: 555-64.

5. Saito S, Yamazaki K, Nishinaka T, et al. Post-approval study of a highly pulsed, low-shear-rate, continuous-flow, left ventricular as-sist device, EVAHEART: a Japanese multicenter study using J-MACS. J Heart Lung Transplant 2014; 33: 599-608.

6. Imamura T, Kinugawa K, Hatano M, et al. Low cardiac output stimulates vasopressin release in patients with stage d heart failure. Circ J 2014; 78: 2259-67.

7. Barić D. Why pulsatility still matters: a review of current knowl-edge. Croat Med J 2014; 55: 609-20. (Review)

8. Imamura T, Kinugawa K, Hatano M, et al. Acute pulmonary vaso-reactivity test with sildenafil or nitric monoxide before left ven-tricular assist device implantation. J Artif Organs 2013; 16: 389-92.

9. Imamura T, Kinugawa K, Nitta D, et al. Is the internal jugular vein or femoral vein a better approach site for endomyocardial biopsy in heart transplant recipients? Int Heart J 2015; 56: 67-72.

10. Imamura T, Kinugawa K, Kato N, et al. Late-onset right ventricu-lar failure in patients with preoperative small left ventricle after implantation of continuous flow left ventricular assist device. Circ J 2014; 78: 625-33.

11. Imamura T, Kinugawa K, Nitta D, et al. Readmission due to drive-line infection can be predicted by new score by using serum albu-min and body mass index during long-term left ventricular assist device support. J Artif Organs 2015; 18: 120-7.

12. Imamura T, Kinugawa K, Fujino T, et al. Aortic insufficiency in patients with sustained left ventricular systolic dysfunction after axial flow assist device implantation. Circ J 2015; 79: 104-11.

13. Deo SV, Sharma V, Cho YH, Shah IK, Park SJ. De novo aortic in-sufficiency during long-term support on a left ventricular assist de-vice: a systematic review and meta-analysis. ASAIO J 2014; 60: 183-8. (Review)

14. Hiraoka A, Cohen JE, Shudo Y, et al. Evaluation of late aortic in-sufficiency with continuous flow left ventricular assist device. Eur J Cardiothorac Surg 2015; 48: 400-6.

15. Rajagopal K, Daneshmand MA, Patel CB, et al. Natural history and clinical effect of aortic valve regurgitation after left ventricular assist device implantation. J Thorac Cardiovasc Surg 2013; 145: 1373-9.

16. Rose AG, Park SJ, Bank AJ, Miller LW. Partial aortic valve fusion induced by left ventricular assist device. Ann Thorac Surg 2000; 70: 1270-4.

17. Letsou GV, Connelly JH, Delgado RM 3rd, et al. Is native aortic valve commissural fusion in patients with long-term left ventricu-lar assist devices associated with clinically important aortic insuf-ficiency? J Heart Lung Transplant 2006; 25: 395-9.

18. Hatano M, Kinugawa K, Shiga T, et al. Less frequent opening of the aortic valve and a continuous flow pump are risk factors for postoperative onset of aortic insufficiency in patients with a left ventricular assist device. Circ J 2011; 75: 1147-55.

19. Cowger J, Pagani FD, Haft JW, Romano MA, Aaronson KD, Ko-lias TJ. The development of aortic insufficiency in left ventricular assist device-supported patients. Circ Heart Fail 2010; 3: 668-74.

20. Pak SW, Uriel N, Takayama H, et al. Prevalence of de novo aortic insufficiency during long-term support with left ventricular assist devices. J Heart Lung Transplant 2010; 29: 1172-6.

21. Soleimani B, Haouzi A, Manoskey A, Stephenson ER, El-Banay-

osy A, Pae WE. Development of aortic insufficiency in patients supported with continuous flow left ventricular assist devices. ASAIO J 2012; 58: 326-9.

22. Tuzun E, Rutten M, Dat M, van de Vosse F, Kadipasaoglu C, de Mol B. Continuous-flow cardiac assistance: effects on aortic valve function in a mock loop. J Surg Res 2011; 171: 443-7.

23. Sacks MS, Yoganathan AP. Heart valve function: a biomechanical perspective. Philos Trans R Soc Lond B Biol Sci 2007; 362: 1369-91. (Review)

24. Balachandran K, Sucosky P, Jo H, Yoganathan AP. Elevated cyclic stretch alters matrix remodeling in aortic valve cusps: implications for degenerative aortic valve disease. Am J Physiol Heart Circ Physiol 2009; 296: H756-64.

25. Imamura T, Kinugawa K, Nitta D, Hatano M, Ono M. Opening of Aortic Valve during Exercise is Key to Preventing Development of Aortic Insufficiency during Ventricular Assist Device Treatment. ASAIO J 2015; 61: 514-9.

26. Aggarwal A, Raghuvir R, Eryazici P, et al. The development of aortic insufficiency in continuous-flow left ventricular assist de-vice-supported patients. Ann Thorac Surg 2013; 95: 493-8.

27. Toda K, Fujita T, Domae K, Shimahara Y, Kobayashi J, Nakatani T. Late aortic insufficiency related to poor prognosis during left ven-tricular assist device support. Ann Thorac Surg 2011; 92: 929-34.

28. Tuzun E, Gregoric ID, Conger JL, et al. The effect of intermittent low speed mode upon aortic valve opening in calves supported with a Jarvik 2000 axial flow device. ASAIO J 2005; 51: 139-43.

29. Feldman D, Pamboukian SV, Teuteberg JJ, et al. The 2013 Inter-national Society for Heart and Lung Transplantation Guidelines for mechanical circulatory support: executive summary. J Heart Lung Transplant 2013; 32: 157-87.

30. Jorde UP, Uriel N, Nahumi N, et al. Prevalence, significance, and management of aortic insufficiency in continuous flow left ven-tricular assist device recipients. Circ Heart Fail 2014; 7: 310-9.

31. Jennings DL, Weeks PA. Thrombosis in continuous-flow left ven-tricular assist devices: pathophysiology, prevention, and pharma-cologic management. Pharmacotherapy 2015; 35: 79-98. (Review)

32. Imamura T, Kinugawa K, Okada I, et al. Parasympathetic reinner-vation accompanied by improved post-exercise heart rate recovery and quality of life in heart transplant recipients. Int Heart J 2015; 56: 180-5.

33. Imamura T, Kinugawa K, Nitta D, et al. Lower rotation speed stimulates sympathetic activation during continuous-flow left ven-tricular assist device treatment. J Artif Organs 2015; 18: 20-6.

34. Krause R, Metz D, Bushnaq H. Direct aortic transcatheter aortic valve implantation for pure aortic valve regurgitation after implan-tation of a left ventricular assist device. J Thorac Cardiovasc Surg 2014; 147: e38-41.

35. Park SJ, Liao KK, Segurola R, Madhu KP, Miller LW. Manage-ment of aortic insufficiency in patients with left ventricular assist devices: a simple coaptation stitch method (Park’s stitch). J Thorac Cardiovasc Surg 2004; 127: 264-6.

36. McKellar SH, Deo S, Daly RC, et al. Durability of central aortic valve closure in patients with continuous flow left ventricular as-sist devices. J Thorac Cardiovasc Surg 2014; 147: 344-8.

37. Rao V, Slater JP, Edwards NM, Naka Y, Oz MC. Surgical manage-ment of valvular disease in patients requiring left ventricular assist device support. Ann Thorac Surg 2001; 71: 1448-53.

38. Parikh KS, Mehrotra AK, Russo MJ, et al. Percutaneous tran-scatheter aortic valve closure successfully treats left ventricular as-sist device-associated aortic insufficiency and improves cardiac hemodynamics. JACC Cardiovasc Interv 2013; 6: 84-9.

39. Mudd JO, Cuda JD, Halushka M, Soderlund KA, Conte JV, Rus-sell SD. Fusion of aortic valve commissures in patients supported by a continuous axial flow left ventricular assist device. J Heart Lung Transplant 2008; 27: 1269-74.

40. Slaughter MS, Pagani FD, Rogers JG, et al. Clinical management of continuous-flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant 2010; 29: S1-39.

41. John R, Mantz K, Eckman P, Rose A, May-Newman K. Aortic valve pathophysiology during left ventricular assist device sup-

10Int Heart J


port. J Heart Lung Transplant 2010; 29: 1321-9. (Review) 42. Guglin M, Miller L. Myocardial recovery with left ventricular as-

sist devices. Curr Treat Options Cardiovasc Med 2012; 14: 370-83.

43. Farrar DJ, Holman WR, McBride LR, et al. Long-term follow-up of Thoratec ventricular assist device bridge-to-recovery patients successfully removed from support after recovery of ventricular function. J Heart Lung Transplant 2002; 21: 516-21.

44. Simon MA, Kormos RL, Murali S, et al. Myocardial recovery us-ing ventricular assist devices: prevalence, clinical characteristics, and outcomes. Circulation 2005; 112: I32-6.

45. Saito S, Matsumiya G, Sakaguchi T, et al. Cardiac fibrosis and cellular hypertrophy decrease the degree of reverse remodeling and improvement in cardiac function during left ventricular assist. J Heart Lung Transplant 2010; 29: 672-9.

46. Matsumiya G, Monta O, Fukushima N, et al. Who would be a candidate for bridge to recovery during prolonged mechanical left ventricular support in idiopathic dilated cardiomyopathy? J Thorac Cardiovasc Surg 2005; 130: 699-704.

47. Simon MA, Primack BA, Teuteberg J, et al. Left ventricular re-modeling and myocardial recovery on mechanical circulatory sup-port. J Card Fail 2010; 16: 99-105.

48. Imamura T, Kinugawa K, Hatano M, et al. Preoperative beta-blocker treatment is a key for deciding left ventricular assist device implantation strategy as a bridge to recovery. J Artif Organs 2014; 17: 23-32.

49. Imamura T, Kinugawa K, Nitta D, et al. Opening of native aortic valve accomplished after left ventricular assist device implantation in patients with insufficient preoperative Beta-blocker treatment. Int Heart J 2015; 56: 303-8.

50. Imamura T, Kinugawa K, Nitta D, et al. Novel scoring system us-ing postoperative cardiopulmonary exercise testing predicts future explantation of left ventricular assist device. Circ J 2015; 79: 560-6.

51. Muranaka H, Marui A, Tsukashita M, et al. Prolonged mechanical unloading preserves myocardial contractility but impairs relaxa-tion in rat heart of dilated cardiomyopathy accompanied by myo-cardial stiffness and apoptosis. J Thorac Cardiovasc Surg 2010; 140: 916-22.

52. Kinoshita M, Takano H, Taenaka Y, et al. Cardiac disuse atrophy during LVAD pumping. ASAIO Trans 1988; 34: 208-12.

53. Muraoka H, Imamura T, Kinugawa K. Reverse remodeling achieved by combination therapy with high-dose beta blocker and cardiac resynchronization. Int Heart J 2015; 56: 462-5.

54. Miller LW, Pagani FD, Russell SD, et al. Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med

2007; 357: 885-96. 55. Bartoli CR, Giridharan GA, Litwak KN, et al. Hemodynamic re-

sponses to continuous versus pulsatile mechanical unloading of the failing left ventricle. ASAIO J 2010; 56: 410-6.

56. Ootaki Y, Kamohara K, Akiyama M, et al. Phasic coronary blood flow pattern during a continuous flow left ventricular assist sup-port. Eur J Cardiothorac Surg 2005; 28: 711-6.

57. Loebe M, Koster A, Sänger S, et al. Inflammatory response after implantation of a left ventricular assist device: comparison be-tween the axial flow MicroMed DeBakey VAD and the pulsatile Novacor device. ASAIO J 2001; 47: 272-4.

58. Westaby S, Bertoni GB, Clelland C, Nishinaka T, Frazier OH. Cir-culatory support with attenuated pulse pressure alters human aortic wall morphology. J Thorac Cardiovasc Surg 2007; 133: 575-6.

59. Nishimura T, Tatsumi E, Taenaka Y, et al. Effects of long-term nonpulsatile left heart bypass on the mechanical properties of the aortic wall. ASAIO J 1999; 45: 455-9.

60. Hata H, Fujita T, Ishibashi-Ueda H, Nakatani T, Kobayashi J. Pathological analysis of the aortic valve after long-term left ven-tricular assist device support. Eur J Cardiothorac Surg 2014; 46: 193-7.

61. Karmonik C, Partovi S, Loebe M, et al. Computational fluid dy-namics in patients with continuous-flow left ventricular assist de-vice support show hemodynamic alterations in the ascending aor-ta. J Thorac Cardiovasc Surg 2014; 147: 1326-33.

62. May-Newman K, Hillen B, Dembitsky W. Effect of left ventricu-lar assist device outflow conduit anastomosis location on flow pat-terns in the native aorta. ASAIO J 2006; 52: 132-9.

63. Stanfield JR, Selzman CH. In vitro pulsatility analysis of axial-flow and centrifugal-flow left ventricular assist devices. J Biomech Eng 2013; 135: 34505.

64. Moazami N, Fukamachi K, Kobayashi M, et al. Axial and centrif-ugal continuous-flow rotary pumps: a translation from pump me-chanics to clinical practice. J Heart Lung Transplant 2013; 32: 1-11. (Review)

65. Imamura T, Kinugawa K, Nitta D, et al. Advantage of Pulsatility in Left Ventricular Reverse Remodeling and Aortic Insufficiency Prevention During Left Ventricular Assist Device Treatment. Circ J 2015; 79: 1994-9.

66. Larose JA, Tamez D, Ashenuga M, Reyes C. Design concepts and principle of operation of the HeartWare ventricular assist system. ASAIO J 2010; 56: 285-9.

67. Farrar DJ, Bourque K, Dague CP, Cotter CJ, Poirier VL. Design features, developmental status, and experimental results with the Heartmate III centrifugal left ventricular assist system with a mag-netically levitated rotor. ASAIO J 2007; 53: 310-5.

Documents

Preoperative Prediction of Aortic Insufficiency During