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Interact CardioVasc Thorac Surg 2008;7:179-183. doi:10.1510/icvts.2007.167569
© 2008 European Association of Cardio-Thoracic Surgery
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Work in progress report - Valves

Transcranial Doppler and acoustic pressure fluctuations for the assessment of cavitation and thromboembolism in patients with mechanical heart valves

Rosendo A. Rodrigueza,*, Marc Ruela, Michel Labrosseb and Thierry Mesanaa

a Department of Surgery, Division of Cardiac Surgery, University of Ottawa Heart Institute, Room H-4403, 40 Ruskin Street, Ottawa, Ontario, K1Y 4W7, Canada
b Department of Mechanical Engineering, Faculty of Engineering, University of Ottawa, Ottawa, Ontario, Canada

Received 12 September 2007; received in revised form 12 November 2007; accepted 14 November 2007

*Corresponding author. Tel.: +1-613-761-4263; fax: +1-613-761-4392.

E-mail address: Rrodriguez{at}ottawaheart.ca (R.A. Rodriguez).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Conclusions
 Acknowledgements
 References
 
The formation and collapse of vapor-filled bubbles near a mechanical heart valve is called cavitation. Such microbubbles are suspected to have strong pro-coagulant effects. Therefore, cavitation may be a contributing factor to the pro-thrombotic effects of mechanical valves. Herein, we systematically review the available evidence linking cavitation and thrombosis. We also critically appraise the potential usefulness of transcranial Doppler and other new non-invasive diagnostic methods to study cavitation and cerebral embolism in mechanical valve patients. Experimental studies indicate that cavitation microbubbles cause platelet aggregation, complement-activation, fibrinolysis, release of tissue-factor, and endothelial damage. Administration of 100% oxygen to mechanical valve patients during transcranial Doppler examination can transiently decrease the counts of Doppler-detected cerebral microemboli compared with room air. This is associated with removal of most circulating gaseous emboli from cavitation. This method may therefore be applied to the study of cavitation and thromboembolism. Additionally, the analysis of high-frequency acoustic-pressure fluctuations detected from the implosion of cavitation bubbles is a promising method for assessment of cavitation in vivo; however, this requires further development. A better understanding of cavitation is important in order to adequately investigate its role in the overall pro-thrombotic effects in mechanical valve patients. Such studies may allow establishing guidelines for new valve designs.

Key Words: Heart valve prosthesis; Thromboembolism; Transcranial Doppler; Air embolism


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Conclusions
 Acknowledgements
 References
 
Two factors that hinder the safety of mechanical heart valves (MHV) as permanent substitutes of native heart valves are the complexity of their closure dynamics and a higher propensity for thromboembolic events [1]. Embolic events in MHV patients result from the interaction of patient-related factors with other more or less understood mechanisms causing the inherent thrombogenicity of the MHV [1–3]. A number of reports [1–5] suggest that the rapid development of microscopic air bubbles in an area of low pressure near the MHV, a process called cavitation, is one of these potential mechanisms that may contribute to the risk of thromboembolism. Findings of pitting and erosion on the surface of valves explanted due to thromboembolism [3], the increased platelet activity associated with abnormal flow patterns across the valve [4] and the evidence of the effects of the blood-bubble interface on platelet and complement activation [5], all support a potential mechanistic involvement for this biomechanical process. Moreover, the detection of abnormal intra-cardiac echoes by echocardiography [6] and the presence of emboli in the brain circulation [2] detected by transcranial Doppler (TCD) in MHV recipients support the notion that cavitation occurs in vivo, and that some of its effects can be measured in the brain circulation. The well-documented observation that the administration of 100% oxygen to MHV patients during TCD examination transiently eliminates most gaseous emboli derived from cavitation [7] opens the possibility that this method could be applied to the study of cavitation and thromboembolism. The recognition that the collapse of cavitation bubbles in the heart generates measurable acoustic pressure changes called high-frequency pressure fluctuations [1], which can be recorded from the patient's chest, has led to the implementation of non-invasive methods for measuring these acoustic signals in vivo. This paper reviews the currently available evidence pertaining to the relationship between cavitation and thrombosis. We also critically appraise the potential usefulness of transcranial Doppler and other new non-invasive diagnostic methods of cavitation in studying the effects of cavitation on the occurrence of cerebral embolic events in MHV patients.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Conclusions
 Acknowledgements
 References
 
2.1. Data sources

A literature search was performed using MEDLINE and Scopus from the earliest available date to December 2006. A total of 458 citations were obtained, screened and the relevant literature was systematically reviewed by a multidisciplinary team of surgeons, structural engineer and physicist, valve outcomes researcher, and transcranial Doppler specialist.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Conclusions
 Acknowledgements
 References
 
3.1. Physics of valve cavitation

Cavitation is the rapid formation and collapse of vapor-filled bubbles when a fluid is exposed to rapid reductions in pressure below the liquid vapor pressure [1]. When cavitation occurs near the surface of a MHV, the bubbles’ collapse (‘implosion’) generates high-speed micro jets and high-pressure shock waves that may cause mechanical damage to the valve structure and blood elements [1, 3–5]. Fig. 1 summarizes the mechanisms involved in MHV cavitation and the currently known factors that may modify the amount of cavitation. Fig. 2 illustrates the morphologic characteristics of the different forms of cavitation.


Figure 1
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  		Fig. 1. Schematic representation of the mechanisms leading to sharp pressure drops in the mechanical valve that have been associated with vapor bubble formation due to cavitation and the currently known factors (in valve design, fluid and patient characteristics) that may modify the intensity of cavitation.

 

Figure 2
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  		Fig. 2. Morphology of the three main mechanisms of cavitation that can occur along a mechanical heart valve, better illustrated with a Björk-Shiley monostrut valve using high-speed video imaging. Adapted from Expert Rev Med Devices 2006;1(1), 95–104, with permission.

 
3.2. Pro-thrombotic effects of cavitation

3.2.1. Effects of cavitation bubbles on platelet activation
Several studies have shown that inert gases including air bubbles have strong pro-coagulant effects in human blood [1, 5]. Fig. 3 summarizes some of those mechanisms. The pro-thrombotic effects of microbubbles have been studied under conditions that mimic the formation of cavitation bubbles such as during testing of high-intensity focused-ultrasound [8]. These studies have shown that platelet activity [8] and vascular damage [5] are stimulated through the formation of gas microbubbles. Also, these experiments have shown that gas microbubbles oscillate causing high shear stress, which leads to a wide range of effects on platelets from aggregation to destruction [5]. However, if the shear force is sufficiently high, platelets can be destroyed liberating tissue factor, which plays an important role in the generation of thromboembolic complications [1, 5, 8].


Figure 3
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  		Fig. 3. Flow diagram of several of the postulated mechanisms involved in the effects of cavitation on cerebral embolization, thrombus formation, vascular damage, complement activation, and pitting and erosion in mechanical heart valve patients. MHV, mechanical heart valve; PMN, polymorphonuclear cells.

 
The pro-thrombotic effects of cavitation bubbles have also been studied in vivo during conditions of rapid decompression in humans and animals [5]. The rationale for this study was based on an initial observation of a reduced platelet count after decompression sickness. Experiments indeed confirmed that the presence of gas microbubbles generated during decompression is the main cause for this phenomenon [5, 9] through mechanisms that include increased platelet aggregation, fibrinolysis, complement activation, reduced endothelial function and increased leukocyte infiltration [1, 5, 9]. Moreover, it has been shown that platelet aggregation is initiated through the adhesion of plasma proteins (i.e. albumin and fibrinogen) and lipids to the air bubble wall [4, 5] when their fibrinogen receptors are exposed by their interaction with the bubble wall.

3.2.2. Effects of cavitation bubbles on complement activation
Air bubbles have the ability to activate complement in human blood [1, 5]. Nossum et al. [9] documented that when air bubbles are continuously introduced in human serum, the amount of anaphylatoxin C5a increases in a dose-dependent manner compared with controls. The release of the anaphylatoxins mediates a series of inflammatory responses associated with activation of polymorphonuclear leukocytes and mast cells [5, 9]. The activation of these cells increases vascular permeability and endothelial vascular damage due to the release of histamine and cytotoxic substances such as arachidonic acid and active oxygen metabolites [5, 8, 9].

3.3. Diagnostic methods of cavitation in humans

3.3.1. Transcranial Doppler (TCD)
TCD is a non-invasive ultrasound diagnostic method that has been used for the detection of cerebral emboli from different anatomical sources [2, 6]. The brief transient increases in the intensity of the reflected ultrasound, designated as high-intensity-transient-signals (HITS), represent the TCD signatures of the presence of air or solid emboli in the cerebral circulation [2, 6, 7]. Ultrasonic examinations with TCD in a normal healthy population generally produce no HITS [2]. Conversely, HITS are common after surgery in asymptomatic patients with MHV, at rates that are higher than in patients with asymptomatic carotid artery disease or bioprosthetic heart valves [2, 7, 10–12].

3.3.1.1. Limitations of TCD
The clinical relevance of HITS in MHV patients and their association with thromboembolic events or anticoagulant treatment have not yet been established. In some studies, MHV patients with higher HITS counts were more likely to experience central nervous system complications, cognitive deficits and increased levels of platelet-derived micro-particles than patients with lower HITS counts [2, 10]. In contrast, other studies found no correlation between HITS counts and neurological symptoms, cognitive deficits, coagulation markers, platelet aggregates or antithrombotic treatment [7, 11, 12]. Part of the problem is the fact that most embolic signals detected in the brain circulation of MHV patients appear to correspond with air microbubbles presumably derived from cavitation [1, 7, 11]. Several in vitro studies have demonstrated the formation of small vapor microbubbles at the time of closure of the MHV, a phenomenon that was associated with cavitation [1]. Some of these studies documented that vapor microbubbles subsequently migrated and grew into stable air bubbles escaping downstream into the distal circulation of the in vitro model where typical images of HITS were detected by ultrasound [6]. These studies suggested that the same phenomenon occurs in MHV patients where some of the long lasting air bubbles may reach the systemic and cerebral circulations and they could be detected by TCD. Deklunder et al. [6] documented that most MHV patients display abnormal intra-cavitary echoes suggestive of intra-cardiac microbubbles that are not present in bioprosthetic valve recipients and that a large proportion of MHV patients with higher HITS counts frequently show higher rates of intra-cavitary echoes of moderate density.

3.3.1.2. Improvements on TCD
A major limitation of previous studies that have used HITS counts as indicators of the risk of cerebral thromboembolic events in MHV patients is that currently available TCD systems do not provide information on the composition of emboli (i.e. air and solid) and their size [7, 11]. This is important as previous studies suggest that embolus composition could have a significant impact on the severity of brain damage [2, 6, 7]. Georgiadis et al. [7] found that when 100% oxygen was administered to MHV patients during TCD examination, the HITS counts were decreased compared with room air. This oxygen-dependent reduction in the HITS counts was associated with the elimination of air bubbles through the mechanism of blood de-nitrogenation [7]. Since the continuous administration of oxygen does not have any effect on solid particulates while eliminating air bubbles, it is assumed that this method may improve the ability of TCD for differentiating solid from gaseous emboli in MHV patients.

Recently, our group studied MHV patients with TCD in the first week after surgery using random sequences of 30 min while breathing room air, and 30 min breathing 100% oxygen. HITS detected during 100% oxygen had different characteristics as regarding ultrasonic intensity and sample-volume-length compared with those detected in room air. We speculate that if a difference in the ultrasonic characteristics of HITS between the two testing conditions would be demonstrated, it would support the assumption that 100% oxygen may be useful to improve the correlation between the count of HITS and outcome indicators or pro-thrombotic markers in MHV patients.

3.3.2. Analysis of high-frequency-pressure-fluctuations (HFPF)
3.3.2.1. High-pass filtering method
The ‘implosion’ of cavitation bubbles within the heart cavities of MHV patients creates sound pressure changes called HFPF, which are transmitted to the thoracic cavity and picked up as an acoustic signal by using a high-sensitivity hydrophone on the patient's chest [1]. Garrison et al. [13] initially reported a correlation between cavitation bubbles and HFPF. Their study established that most of the energy of cavitation was localized at frequencies between 35 and 300 kHz, while that of the mechanical resonance of the prosthesis closure was contained in a lower frequency range. This indicated that the acoustic components of cavitation could be separated from the valve closing sound by using a high-pass filter. Subsequently, Johansen et al. [14] found that this filtering method was dependent on the type of MHV as the resonance frequency of the valve varies according to the valve design (41 and 66 kHz) and overlaps with the lower edge of the cavitation spectrum (35–50 Hz). Consequently, the use of this method requires previous knowledge of the valve-dependent resonance characteristics so as to choose the most appropriate high-pass filter cut-off capable to separate cavitation signals.

3.3.2.2. Deterministic/non-deterministic method
Recently, another method was proposed for in vivo evaluation of cavitation, which does not require any knowledge about the characteristics of the valve implanted, and is not subject to bandwidth limitations [14]. This method hypothesizes that the acoustic component associated with the mechanical resonance of the prosthesis closing sound is predictable, while that related to the collapse of cavitation bubbles is chaotic and therefore random. Based on this principle, a processing method that considers cavitation signals as non-deterministic and the closing sound of a MHV as deterministic was developed. This signal can be extracted from raw data by removing the signal of the deterministic closing sounds of the MHV averaged over several heart beats. However, this method is not well suited for bileaflet valves due to the asynchronous closing of the leaflets, which prohibits averaging inherently dissimilar heart beats [1].

3.3.2.3. Wavelet-transform method
Herbertson et al. [15] recently proposed an analysis based on wavelet transforms and statistical thresholding, which offers unprecedented high-resolution. Briefly, the signal is decomposed into a high-scale, low-frequency component of certain waveform, and multiple low-scale, high-frequency components. With this approach, acoustic signals are analyzed as depending on both time and frequency, and processed so as to create a denoised signal of high-resolution. Cavitation events can then be organized based on their position within the closing cycle using their characteristics of duration and intensity. Such signal decomposition method has an interesting potential but requires more continued efforts before it can be implemented in vivo.


   4. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Conclusions
Acknowledgements
 References
 
The existing in vitro and in vivo evidence that cavitation bubbles have strong pro-coagulant effects justifies the hypothesis that cavitation may be involved in some of the pro-thrombotic effects associated with MHV. Currently, no clinical study has investigated whether this is true in MHV patients. Such a study is critical for establishing the role of cavitation on the pro-coagulant activity of MHV in vivo, and its potential association with the risk of thromboembolic events. Future developments in the methods of in vivo detection of cavitation and improvements on TCD examination in MHV patients may lead to a better understanding of the role of cavitation on the risk of cerebral embolization and thromboembolism. Such studies may in turn allow for the validation of new strategies to improve valve design in order to minimize cavitation and its effects.


   Acknowledgements
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Conclusions
 Acknowledgements
References
 
The authors acknowledge the contribution of Dr. Natalie Baddour in reviewing this work.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Conclusions
 Acknowledgements
 References
 

  1. Johansen P. Mechanical heart valve cavitation. Expert Rev Med Devices 2004;1:95–104.[CrossRef][Medline]
  2. Geiser T, Sturzenegger M, Genewein U, Haeberli A, Beer JH. Mechanism of cerebrovascular events as assessed by procoagulant activity, cerebral microemboli, and platelet microparticles in patients with prosthetic heart valves. Stroke 1998;29:1170–1177.
  3. Kafesjian R, Howanec M, Ward GD, Diep L, Wagstaff L, Rhee R. Cavitation damage of pyrolytic carbon in mechanical heart valves. J Heart Valve Dis 1994;3(Suppl_1):S2–S7.[Medline]
  4. Bluestein D, Yin W, Affeld K, Jesty J. Flow-induced platelet activation in mechanical heart valves. J Heart Valve Dis 2004;13:501–508.[Medline]
  5. Barak M, Katz Y. Microbubbles: pathophysiology and clinical implications. Chest 2005;128:2918–2932.[CrossRef][Medline]
  6. Deklunder G, Lecroart JL, Savoye C, Coquet B, Houdas Y. Transcranial high-intensity Doppler signals in patients with mechanical heart valve prostheses: their relationship with abnormal intracavitary echoes. J Heart Valve Dis 1996;5:662–667.[Medline]
  7. Georgiadis D, Wenzel A, Lehmann D, Lindner A, Zerkowski HR, Zierz S, Spencer MP. Influence of oxygen ventilation on Doppler microemboli signals in patients with artificial heart valves. Stroke 1997;28:2189–2194.[Abstract/Free Full Text]
  8. Poliachik SL, Chandler WL, Ollos RJ, Bailey MR, Crum LA. The relation between cavitation and platelet aggregation during exposure to high-intensity focused ultrasound. Ultrasound Med Biol 2004;30:261–269.[CrossRef][Medline]
  9. Nossum V, Hjelde A, Bergh K, Ustad AL, Brubakk AO. Anti-C5a monoclonal antibodies and pulmonary polymorphonuclear leukocyte infiltration–endothelial dysfunction by venous gas embolism. Eur J Appl Physiol 2003;89:243–248.[Medline]
  10. Deklunder G, Roussel M, Lecroart JL, Prat A, Gautier C. Microemboli in cerebral circulation and alteration of cognitive abilities in patients with mechanical prosthetic heart valves. Stroke 1998;29:1821–1826.[Abstract/Free Full Text]
  11. Milano A, D'Alfonso A, Codecasa R, De Carlo M, Nardi C, Orlandi G, Landucci L, Bortolotti U. Prospective evaluation of frequency and nature of transcranial high-intensity Doppler signals in prosthetic valve recipients. J Heart Valve Dis 1999;8:488–494.[Medline]
  12. Raco L, Belcher PR, Sim I, McGarrity A, Bernacca GM, Wheatley DJ. Platelet aggregation and high-intensity transient signals (HITS) in a sheep model of mitral valve replacement. J Heart Valve Dis 1999;8:476–480.[Medline]
  13. Garrison LA, Lamson TC, Deutsch S, Geselowitz DB, Gaumond RP, Tarbell JM. An in vitro investigation of prosthetic heart valve cavitation in blood. J Heart Valve Dis 1994;3(Suppl 1):S8–S24.[Medline]
  14. Johansen P, Manning KB, Tarbell JM, Fontaine AA, Deutsch S, Nygaard H. A new method for evaluation of cavitation near mechanical heart valves. J Biomech Eng 2003;125:663–670.[CrossRef][Medline]
  15. Herbertson LH, Reddy V, Manning KB, Welz JP, Fontaine AA, Deutsch S. Wavelet transforms in the analysis of mechanical heart valve cavitation. J Biomech Eng 2006;128:217–222.[CrossRef][Medline]




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