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Background and Aim of the Study: Thromboembolic and bleeding complications detract from outcome for patients with prosthetic heart valves. The study aim was to investigate whether measurement of coagulation activation markers and transcranial Doppler ultrasound microembolic signals (MES) could identify patients at subsequent higher risk of thromboembolism or bleeding events., Methods: A total of 526 patients (mean age 66 years; 266 males, 260 females) who underwent elective valve replacement surgery was enrolled between April 1999 and October 2002. Clinical assessment and blood sampling for coagulation activation markers was performed preoperatively and at three and 12 months postoperatively. Transcranial Doppler MES were recorded in the first 144 patients. Status was reviewed between 21st April and 9th June 2005, with 99.4% follow up., Results: Among patients, 62% had an aortic valve replaced, and mechanical valves constituted 60% of all implants. The mean follow up was 3.61 years; total follow up was 1,899.2 patient-years (pt-yr). In total, 115 patients died, while 61 experienced a total of 80 thromboembolic events: linearized event rates were 3.94% (mechanical valves) and 4.4% (bioprostheses). There was no difference between mitral and aortic implants, or among bileaflet, tilting-disc mechanical and porcine valves. Atrial fibrillation was not influential. Coagulation activation markers were not associated with thromboembolic events, except for an elevated von Willebrand factor (vWF), which was associated with a five-fold increase in embolic event rate. Fifty-one patients experienced 59 bleeding events; eight patients experienced multiple events. Linearized event rates were 3.37% (mechanical valves) and 2.49% (bioprostheses). The INR was suboptimal in 44-58% of patients. Transcranial Doppler MES were not associated with blood coagulation markers or thromboembolic events., Conclusion: Coagulation activation markers (except vWF) and MES did not predict thromboembolic events in valve replacement patients. Thromboembolic and bleeding event rates for West of Scotland patients generally exceeded reported rates: suboptimal anticoagulation appeared common and most likely influenced thromboembolic and bleeding event rates more than any other factor.

Background and Aim of the Study: The performance of novel prosthetic heart valves is assessed using in-vitro hydrodynamic function tests. The study aim was to examine the problem of objective discrimination of hydrodynamic performance to determine significant differences between valve designs, and illustrate proposed methodology using data collected from five different polyurethane tri-leaflet valve designs., Methods: Two engineering designs were manufactured with leaflets of the same polyurethane (GE, LE); design L was manufactured using three further leaflet materials of differing material modulus (LL, L4, L5). Six valves were made in each design, each tested at five flow rates in a standard hydrodynamic test rig, with five test replications for each valve. The data were analyzed using multilevel statistical modeling methods, allowing simultaneous comparison of multiple regression lines describing valve performance. The multilevel model is hierarchical in structure, in this case with two levels of data, describing individual valves at level 2 and test replicates at level 1. In all cases, the multilevel model uses the hydrodynamic function measure of interest, e.g. mean pressure gradient or leakage, with logarithmic transformation as required as the dependent variable, Y. The independent variable, X, is, in all cases, the natural logarithm of the RMS flow measured through the valve., Results: The two-design multilevel model enabled quantitative discrimination of designs GE and LE, showing that design GE had significantly better hydrodynamic function overall than design LE in this case (mean pressure gradient was estimated as 0.93 mmHg lower at low cardiac output, 14.74 mmHg lower at 9.6 l/min). The five-design multilevel model showed clearly the relatively poor hydrodynamic performance of designs L4 and L5 compared with others. The procedure was straightforward, and produced a statistical comparison among valve designs that is not easily achieved by other means., Conclusion: This methodology provides a useful means of objective assessment of valve function for valve developers. Variance estimates provided by the analysis also provide a basis for quality control of valve production and testing.

Background and Aim of the Study: The synthetic flexible tri-leaflet heart valve offers considerable potential for improvement in both hydrodynamic and biomechanical performance of replacement heart valves. To date, success with the synthetic leaflet heart valve has been limited, partly due to limitations in the biostability of the polyurethanes used. With the synthesis of new biostable polyurethanes, the integration of advancing technology, and better knowledge of the functional and biomechanical design requirements necessary to increase the long-term durability of the polyurethane heart valve, novel clinical solutions are now in sight., Methods: This study describes the design characteristics, hydrodynamic and biomechanical performance of a new design of polyurethane heart valve. The function and durability characteristics of this novel design of heart valve, manufactured using a proven durable non-biostable polyurethane, was compared with that of a single AorTech porcine bioprosthetic heart valve and a single tilting disc mechanical heart valve, the Björk-Shiley Monostrut valve (BSM), of similar size., Results: For equivalent sizes of valve, the new polyurethane heart valve design had significantly lower pressure gradients compared with the porcine valve at all flow rates and to the BSM valve at the higher flow rates. The effective orifice area of the polyurethane valve was greater than the other two valves studied; regurgitation and total energy loss were less. The new polyurethane valve design reached over 360 million cycles in an accelerated durability tester, without failure., Conclusion: This new design of polyurethane heart valve showed improved hydrodynamic function in comparison with either the porcine bioprosthetic or the BSM mechanical heart valve. The pulsatile flow results showed a lower total energy loss associated with this valve, indicating improved potential patient benefit. The durability of this new design of polyurethane heart valve was demonstrated when manufactured using a medical-grade polyurethane.

Background and Aim of the Study: There is renewed interest in the pericardial heart valve as an alternative to the porcine bioprosthesis. The long-term results of a randomized trial comparing a second-generation pericardial valve against a well-tested porcine bioprosthesis are presented. Seven-year follow up has been reported previously. Production of the Bioflo pericardial prosthesis used in this trial was discontinued due to fears related to bovine spongiform encephalopathy., Methods: Between February 1987 and March 1990, 170 patients undergoing aortic (AVR) or mitral (MVR) valve replacement were assigned randomly to receive either the Bioflo pericardial bioprosthesis or the Carpentier-Edwards (CE) supra-annular porcine bioprosthesis. Eighty-five patients received 93 Bioflo valves (46 AVR, 31 MVR, eight AVR+MVR), and the remaining 85 received 99 CE valves (48 AVR, 23 MVR, 14 AVR+MVR). Mean patient age was 61.0 years (range: 38-77 years) for the Bioflo group and 62.1 years (range: 41-77 years) for the CE group. Current follow up is 100% complete and totals 1,391 patient-years; mean +/- SD follow up was 8.2 +/- 3.4 years (maximum 12.2 years)., Results: The operative mortality rate was 4.12%. There were 70 patients still at risk at 11 years (31 Bioflo, 39 CE); of these, 91.4% were in NYHA classes I/II. No significant difference in survival or valve-related complications was seen between the groups. Mean (+/- SEM) survival at 11 years was 41.4 +/- 6.8% in the Bioflo group and 55.3 +/- 6.8% in the CE group (p = 0.15). There were 16 valve-related deaths (nine in the Bioflo group, seven in the CE group). At 11 years, freedom from valve-related mortality was 89.5 +/- 3.9% for the Bioflo group and 91.0 +/- 3.5% for the CE group (p = 0.4). Valve position had no impact on survival. At 11 years, freedom from structural valve deterioration was 83.9 +/- 5.4% and 87.5 +/- 4.2% in the Bioflo and CE groups, respectively (p = 0.9)., Conclusion: Over the 11-year period of follow up, clinical performance of the Bioflo pericardial valve was comparable with that of the Carpentier-Edwards supra-annular porcine bioprosthesis. No difference was apparent between the two valve types when implanted in either the aortic or the mitral position.

Background and Aims of the Study: The composition of microemboli detected as high-intensity transient signals (HITS) by Doppler ultrasound in patients with prosthetic heart valves is still debated. Here, platelet aggregation and HITS were investigated in a sheep model., Methods: Insonation of the carotid artery was performed in 20 sheep with either a mechanical or a biological mitral valve prosthesis in place. The effect of ICI 170809, a 5HT2a antagonist, on the frequency of HITS and on platelet aggregates, counted in arterial blood smears per nine high-power fields, was assessed at three and six months after valve implantation. The mitral transvalvular gradient was measured by transthoracic echocardiography at three and six months., Results: Data are expressed as median and interquartile range. At three months, there were 36 (20-114) HITS/h in the mechanical group, and 0 (0-15) HITS/h in the biological group. At six months, there were 21 (0-82) and 0 (0-2) HITS/h, respectively. The occurrence of HITS was unaffected by either ICI 170809, or by duration of implant in either group. Platelet aggregate counts were higher with the mechanical than with the biological valve at three months, but not at six months. ICI 170809 reduced platelet aggregate counts in both valve types; the reduction was not significant in the bioprosthetic valve group. The pressure gradient across the bioprosthesis increased during the study from 2 (2-3) mmHg to 7.5 (6-10) mmHg, but was unchanged in the mechanical valve., Conclusions: (i) It was confirmed that the frequency of HITS is higher with the mechanical prosthesis than the bioprosthesis; (ii) circulating platelet aggregates in the bioprosthetic valve group tended to increase as structural valve deterioration occurred; (iii) the frequency of HITS was not influenced by either an increase or a decrease in circulating platelet aggregates; and (iv) HITS detected in patients with prosthetic valves are unlikely to be due to circulating platelet aggregates.

Background and Aims of the Study: Flexible trileaflet polyurethane heart valves can be designed which have good hydrodynamic function in vitro. The choice of polyurethane for fabrication of such valves is not simple; several similar polyurethanes are available, but relatively minor differences in their structure and composition may have profound effects on long term fatigue behavior with little effect on their short term mechanical properties., Methods: The relative functional characteristics of flexible trileaflet polyurethane valves made from two different polyetherurethanes were compared before and after long term fatigue testing. The polyetherurethanes had similar gross mechanical properties, differing in that one was chain-extended with butanediol (PEU) and the other with ethylene diamine (PEUE). Six valves of each type, with similar leaflet thickness distributions, were studied., Results: Hydrodynamic function of both valve types was similar to a similarly sized porcine aortic valve. Mean pressure drop across the open valve was higher in PEU valves than in PEUE valves, although PEUE valves had greater energy losses during closure and when closed. Reverse flow decreased with time in the fatigue tester. In long term fatigue tests, all six PEU valves failed by 307 million cycles, with failure primarily by development of holes at the coaptation region of the leaflets associated with localized calcification. Three PEUE valves exceeded 800 million cycles without failure and all PEUE valves exceeded 450 million cycles., Conclusions: A combination of good phase separation of polyurethane soft and hard segments with good rubbery characteristics can explain the better results achieved in the PEUE valves compared with similar PEU valves. These results suggest the general type of polyurethane structure suitable for heart valve fabrication and have implications for development of novel polyurethanes for this application.

The application of transcranial Doppler (TCD) ultrasonography to asymptomatic prosthetic heart valve patients can result in detection of localized bursts of high intensity signals, similar to those caused by the passage of emboli. The origin of these signals is not known. In order to investigate this phenomenon in a simplified, more controllable environment, a TCD machine was used to record flow downstream from mechanical prosthetic heart valves in a mock circulatory loop. The model, which uses a saline solution seeded with silk particles (< 15 micrometers) as the circulatory fluid, recreates the principal hydrodynamic characteristics of the left heart and systemic circulation. Reproducibility of the system was established through repeated testing of a Monostrut valve. Three different mechanical valve types, (Monostrut, Medtronic Hall, St. Jude Medical) were tested over a range of simulated cardiac outputs, and the effect of valve size was investigated with four Omniscience tilting disc valves (21, 23, 25 and 29 mm). Average energy of the reflected Doppler signal was used to quantify the amount of high intensity Doppler signal, QTCD. TCD signals recorded in vitro were visually and aurally similar to those found in prosthetic heart valve patients. All valve types generated exponentially more QTCD with increasing simulated cardiac output. Differences amongst valve types were only significant at higher flow outputs, with the Monostrut valve producing the greatest QTCD. Larger valves consistently generated greater QTCD than smaller valves. In conclusion, TCD signals found in prosthetic heart valve patients can be reproduced, at least qualitatively, using a mock circulatory loop which does not incorporate the formed elements of blood.(ABSTRACT TRUNCATED AT 250 WORDS)

Previous work in our laboratory has demonstrated a simple, dynamic in vitro calcification method for studying bovine pericardial heart valves. The calcification produced closely resembled that found in clinical explant valves. The current study extends this technique to the porcine aortic bioprosthesis. Five Carpentier-Edwards porcine aortic bioprostheses were calcified in vitro in a modified wear tester. All valves calcified to a similar degree as bovine pericardial valves. Calcification predominated on the ribbed tissue structures near the commissures on the outflow surfaces. The same calcification pattern was seen in clinical explant valves. A number of anti-calcification modifications of porcine aortic valves were also investigated. These had all previously inhibited calcification of bovine pericardium in a rat subdermal implant model but had failed to reduce calcification in whole pericardial valves calcified in vitro under dynamic conditions. The modified porcine valves produced similar results: no modification achieved reduction of calcification on exposure to the functional valve calcification model. The dynamic in vitro calcification test has been shown to be useful for the study of both main types of bioprostheses, bovine pericardial and porcine aortic valves, and for the assessment of alterations to these biomaterials.

Calcification of bioprosthetic heart valves is a major factor limiting their long-term function. Current methods of microscopic examination of calcific deposits require dehydration and processing of the leaflet material, e.g. wax embedding, sectioning, gold coating. Confocal laser scanning microscopy is a new technique which allows serial optical sectioning of thick biological specimens in their normal hydrated state. The current study has examined bovine pericardium and porcine aortic valve materials calcified in vitro under static and dynamic conditions. A series of clinical explants of bovine pericardial and porcine aortic valve types has also been examined. The calcium-specific stain, Alizarin Red S, has been used as a fluorescent marker for calcium deposits. Fluorescent images, generated by Argon ion laser light at 488nm, have been obtained at varying depths into samples. These have been reconstructed to demonstrate the relationship between calcium deposits and autofluorescent collagen fibers. The patterns of calcification were similar in both in vitro and explant valve material. The calcification was of three main patterns: calcium depositing longitudinally on collagen fiber bundles; calcium forming a banded pattern perpendicular to the fiber direction and large, dense, focal deposits obliterating the underlying collagen structure. Involvement of collagen fibers in the calcification pattern was a consistent finding in all sample types. The method is a useful addition to the tools available for study of calcification processes. The potential exists for three-dimensional reconstruction of leaflet architecture and its inter-relationship with calcium deposition, in a normally hydrated state.

The lifetime of bioprosthetic heart valves is limited by primary tissue failure and calcification of the valve leaflets. There are indications that synthetic elastomeric materials may also be subject to this problem. The mechanism of calcification is not known, but it is of interest that calcification can be induced in tissue even in the absence of cellular mechanisms, outside the body. Many hypotheses relate to inhibitory or promotory factors rather than primary instigators of calcification and none has led to a satisfactory solution of the problem. The study of calcification in replacement valves generally utilises in vivo test methods i.e. complex biologic systems. This creates difficulty in defining the primary factors involved. The use of in vitro test methods, including a novel fatigue tester method, has been reviewed. Various test media have been used, including simple salt solutions (allowing definition and controlled modification of the calcification medium) and bovine plasma. Comparison of static and dynamic in vitro methods with the rat subcutaneous implant model indicated a lower degree of calcification in vitro: the calcification achieved was, however, significantly greater than similar material not subject to calcification processes. Dynamic in vitro tests produced greater calcification than static in vitro tests. Porcine aortic valve material, in static tests, behaved similarly to bovine pericardium. In vitro calcification testing has a useful role to play in the economic screening of new materials or modifications of existing materials prior to in vivo testing. It may also aid the definition of the mechanism of calcification and hence the development of solutions to the problem.