Two decades of recipient and donor referrals for heart transplantation to Groote Schuur Hospital, Cape Town, South Africa: A retrospective study.

BACKGROUND: Heart transplantation in South Africa faces numerous challenges related to organ scarcity and unequal access to advanced heart therapy. There is an urgent need to analyse the current transplant referral pathway to optimise equitable access to transplantation. OBJECTIVES: To provide an audit of heart transplant referrals to Groote Schuur Hospital, Cape Town, over a 23-year period, focusing on patient demographics, indications for referral, waiting-list dynamics, and transplant referral outcomes. METHODS: The study utilised a retrospective patient folder review for the period 1 January 1997 - 31 December 2019 and audited the trends in heart transplant referrals and associated outcomes of the referral at a tertiary academic hospital. RESULTS: A total of 625 recipients were referred for heart transplantation, with the majority being male (n=412; 65.9%), while gender was undocumented for 69 cases (11.0%). The mean age was 38.1 (14.6) years, and 153 (24.5%) were listed for transplant, while 215 (34.4%) were deemed ineligible for listing. Contraindications for listing included social (n=106; 49.3%), medical (n=83; 38.6%) and psychological (n=26; 12.0%) factors, while 134 patients (21.4%) were considered too well. Poor social circumstances (n=38; 39.6%), poor insight (n=28; 29.2%) and poor compliance (n=21; 21.9%) were the most common non-medical reasons for not listing recipients, while obesity (n=30; 31.3%) and smoking (n=23; 24.0%) were notable medical contraindications. Forty-nine patients (7.8%) died during work-up, while 130 (85.0%) of the listed patients received a heart transplant. Of the 429 donor referrals, 139 (32.4%) were accepted for organ procurement. Reasons for declining donors included unsuitability for transplantation (30.3%), lack of capacity (1.8%), and recipient-donor mismatch (66.9%). CONCLUSION: Three-quarters of the referred patients were deemed unsuitable for heart transplantation for medical and/or social reasons. The ratio of referral to listing has decreased over time. However, once listed, the likelihood of receiving a transplant was high.

Making a difference: 5 years of Cardiac Surgery Intersociety Alliance (CSIA).

SUMMARY: Informed by the almost unimaginable unmet need for cardiac surgery in the developing regions of the world, leading surgeons, cardiologists, editors in chief of the major cardiothoracic journals as well as representatives of medical industry and government convened in December 2017 to address this unacceptable disparity in access to care. The ensuing "Cape Town Declaration" constituted a clarion call to cardiac surgical societies to jointly advocate the strengthening of sustainable, local cardiac surgical capacity in the developing world. The Cardiac Surgery Intersociety Alliance (CSIA) was thus created, comprising The Society of Thoracic Surgeons (STS), the American Association for Thoracic Surgery (AATS), the Asian Society for Cardiovascular and Thoracic Surgery (ASCVTS), the European Association for Cardio-Thoracic Surgery (EACTS) and the World Heart Federation (WHF). The guiding principle was advocacy for sustainable cardiac surgical capacity in low-income countries. As a first step, a global needs assessment confirmed rheumatic heart disease as the overwhelming pathology requiring cardiac surgery in these regions. Subsequently, CSIA published a request for proposals to support fledgling programmes that could demonstrate the backing by their governments and health care institution. Out of 11 applicants, and following an evaluation of the sites, including site visits to the 3 finalists, Mozambique and Rwanda were selected as the first Pilot Sites. Subsequently, a mentorship and training agreement was completed between Mozambique and the University of Cape Town, a middle-income country with a comparable burden of rheumatic heart disease. The agreement entails regular video calls between the heart teams, targeted training across all aspects of cardiac surgery, as well as on-site presence of mentoring teams for complex cases with the strict observance of 'assisting only'. In Rwanda, Team Heart, a US and Rwanda-based non-governmental organization (NGO) that has been performing cardiac surgery in Rwanda and helping to train the cardiac surgery workforce since 2008, has agreed to continue providing mentorship for the local team and to assist in the establishment of independent cardiac surgery with all that entails. This involves intermittent virtual conferences between Rwandan and US cardiologists for surgical case selection. Five years after CSIA was founded, it's 'Seal of Approval' for the sustainability of endorsed programmes in Mozambique and Rwanda has resulted in higher case numbers, a stronger government commitment, significant upgrades of infrastructure, the nurturing of generous consumable donations by industry and the commencement of negotiations with global donors for major grants. Extending the CSIA Seal to additional deserving programmes could further align the international cardiac surgical community with the principle of local cardiac surgery capacity-building in developing countries.

Making a difference: 5 years of Cardiac Surgery Intersociety Alliance (CSIA).

Informed by the almost unimaginable unmet need for cardiac surgery in the developing regions of the world, leading surgeons, cardiologists, editors in chief of the major cardiothoracic journals as well as representatives of medical industry and government convened in December 2017 to address this unacceptable disparity in access to care. The ensuing "Cape Town Declaration" constituted a clarion call to cardiac surgical societies to jointly advocate the strengthening of sustainable, local cardiac surgical capacity in the developing world. The Cardiac Surgery Intersociety Alliance (CSIA) was thus created, comprising The Society of Thoracic Surgeons (STS), the American Association for Thoracic Surgery (AATS), the Asian Society for Cardiovascular and Thoracic Surgery (ASCVTS), the European Association for Cardio-Thoracic Surgery (EACTS) and the World Heart Federation (WHF). The guiding principle was advocacy for sustainable cardiac surgical capacity in low-income countries. As a first step, a global needs assessment confirmed rheumatic heart disease as the overwhelming pathology requiring cardiac surgery in these regions. Subsequently, CSIA published a request for proposals to support fledgling programs that could demonstrate the backing by their governments and health care institution. Out of 11 applicants, and following an evaluation of the sites, including site visits to the 3 finalists, Mozambique and Rwanda were selected as the first Pilot Sites. Subsequently, a mentorship and training agreement was completed between Mozambique and the University of Cape Town, a middle-income country with a comparable burden of rheumatic heart disease. The agreement entails regular video calls between the heart teams, targeted training across all aspects of cardiac surgery, as well as on-site presence of mentoring teams for complex cases with the strict observance of "assisting only." In Rwanda, Team Heart, a US and Rwanda-based nongovernmental organization (NGO) that has been performing cardiac surgery in Rwanda and helping to train the cardiac surgery workforce since 2008, has agreed to continue providing mentorship for the local team and to assist in the establishment of independent cardiac surgery with all that entails. This involves intermittent virtual conferences between Rwandan and US cardiologists for surgical case selection. Five years after CSIA was founded, its "Seal of Approval" for the sustainability of endorsed programs in Mozambique and Rwanda has resulted in higher case numbers, a stronger government commitment, significant upgrades of infrastructure, the nurturing of generous consumable donations by industry and the commencement of negotiations with global donors for major grants. Extending the CSIA Seal to additional deserving programs could further align the international cardiac surgical community with the principle of local cardiac surgery capacity-building in developing countries.

Making a difference: 5 years of Cardiac Surgery Intersociety Alliance (CSIA).

Informed by the almost unimaginable unmet need for cardiac surgery in the developing regions of the world, leading surgeons, cardiologists, editors in chief of the major cardiothoracic journals as well as representatives of medical industry and government convened in December 2017 to address this unacceptable disparity in access to care. The ensuing "Cape Town Declaration" constituted a clarion call to cardiac surgical societies to jointly advocate the strengthening of sustainable, local cardiac surgical capacity in the developing world. The Cardiac Surgery Intersociety Alliance (CSIA) was thus created, comprising The Society of Thoracic Surgeons (STS), the American Association for Thoracic Surgery (AATS), the Asian Society for Cardiovascular and Thoracic Surgery (ASCVTS), the European Association for Cardio-Thoracic Surgery (EACTS) and the World Heart Federation (WHF). The guiding principle was advocacy for sustainable cardiac surgical capacity in low-income countries. As a first step, a global needs assessment confirmed rheumatic heart disease as the overwhelming pathology requiring cardiac surgery in these regions. Subsequently, CSIA published a request for proposals to support fledgling programmes that could demonstrate the backing by their governments and health care institution. Out of 11 applicants, and following an evaluation of the sites, including site visits to the 3 finalists, Mozambique and Rwanda were selected as the first Pilot Sites. Subsequently, a mentorship and training agreement was completed between Mozambique and the University of Cape Town, a middle-income country with a comparable burden of rheumatic heart disease. The agreement entails regular video calls between the heart teams, targeted training across all aspects of cardiac surgery, as well as on-site presence of mentoring teams for complex cases with the strict observance of 'assisting only'. In Rwanda, Team Heart, a US and Rwanda-based non-governmental organization (NGO) that has been performing cardiac surgery in Rwanda and helping to train the cardiac surgery workforce since 2008, has agreed to continue providing mentorship for the local team and to assist in the establishment of independent cardiac surgery with all that entails. This involves intermittent virtual conferences between Rwandan and US cardiologists for surgical case selection. Five years after CSIA was founded, its 'Seal of Approval' for the sustainability of endorsed programmes in Mozambique and Rwanda has resulted in higher case numbers, a stronger government commitment, significant upgrades of infrastructure, the nurturing of generous consumable donations by industry and the commencement of negotiations with global donors for major grants. Extending the CSIA Seal to additional deserving programmes could further align the international cardiac surgical community with the principle of local cardiac surgery capacity-building in developing countries.

Making a Difference: 5 Years of Cardiac Surgery Intersociety Alliance (CSIA).

Informed by the almost unimaginable unmet need for cardiac surgery in the developing regions of the world, leading surgeons, cardiologists, editors in chief of the major cardiothoracic journals as well as representatives of medical industry and government convened in December 2017 to address this unacceptable disparity in access to care. The ensuing "Cape Town Declaration" constituted a clarion call to cardiac surgical societies to jointly advocate the strengthening of sustainable, local cardiac surgical capacity in the developing world. The Cardiac Surgery Intersociety Alliance (CSIA) was thus created, comprising The Society of Thoracic Surgeons (STS), the American Association for Thoracic Surgery (AATS), the Asian Society for Cardiovascular and Thoracic Surgery (ASCVTS), the European Association for Cardio-Thoracic Surgery (EACTS) and the World Heart Federation (WHF). The guiding principle was advocacy for sustainable cardiac surgical capacity in low-income countries. As a first step, a global needs assessment confirmed rheumatic heart disease as the overwhelming pathology requiring cardiac surgery in these regions. Subsequently, CSIA published a request for proposals to support fledgling programs that could demonstrate the backing by their governments and health care institution. Out of 11 applicants, and following an evaluation of the sites, including site visits to the 3 finalists, Mozambique and Rwanda were selected as the first Pilot Sites. Subsequently, a mentorship and training agreement was completed between Mozambique and the University of Cape Town, a middle-income country with a comparable burden of rheumatic heart disease. The agreement entails regular video calls between the heart teams, targeted training across all aspects of cardiac surgery, as well as on-site presence of mentoring teams for complex cases with the strict observance of "assisting only." In Rwanda, Team Heart, a US and Rwanda-based non-governmental organization (NGO) that has been performing cardiac surgery in Rwanda and helping to train the cardiac surgery workforce since 2008, has agreed to continue providing mentorship for the local team and to assist in the establishment of independent cardiac surgery with all that entails. This involves intermittent virtual conferences between Rwandan and US cardiologists for surgical case selection. Five years after CSIA was founded, its "Seal of Approval" for the sustainability of endorsed programs in Mozambique and Rwanda has resulted in higher case numbers, a stronger government commitment, significant upgrades of infrastructure, the nurturing of generous consumable donations by industry and the commencement of negotiations with global donors for major grants. Extending the CSIA Seal to additional deserving programs could further align the international cardiac surgical community with the principle of local cardiac surgery capacity-building in developing countries.

The Cape Town Declaration on Access to Cardiac Surgery in the Developing World.

Twelve years after cardiologists and cardiac surgeons from all over the world issued the 'Drakensberg Declaration on the Control of Rheumatic Fever and Rheumatic Heart Disease in Africa', calling on the world community to address the prevention and treatment of rheumatic heart disease (RHD) through improving living conditions, to develop pilot programmes at selected sites for control of rheumatic fever and RHD, and to periodically review progress made and challenges that remain, RHD still accounts for a major proportion of cardiovascular diseases in children and young adults in low- and middle-income countries, where more than 80% of the world population live. Globally equal in prevalence to human immunodeficiency virus infection, RHD affects 33 million people worldwide. Prevention efforts have been important but have failed to eradicate the disease. At the present time, the only effective treatment for symptomatic RHD is open heart surgery, yet that life-saving cardiac surgery is woefully absent in many endemic regions. In this declaration, we propose a framework structure to create a co-ordinated and transparent international alliance to address this inequality.

The Cape Town Declaration on Access to Cardiac Surgery in the Developing World.

Mission: to urge all relevant entities within the international cardiac surgery, industry and government sectors to commit to develop and implement an effective strategy to address the scourge of rheumatic heart disease in the developing world through increased access to life-saving cardiac surgery.

Celebrating 50 years of heart transplant surgery: A missed opportunity to honour Hamilton Naki.

Reply to Mankahla N, Dlamini S, Taunyane IC, Maqungo S, Cairncross L, Chiliza B. Celebrating 50 years of heart transplant surgery: A missed opportunity to honour Hamilton Naki. S Afr Med J 2018;108(3):151. https://doi.org/10.7196/SAMJ.2018.v108i3.13114.

Regulation of tissue ingrowth into proteolytically degradable hydrogels.

Regulation of the rate of cell ingrowth into and within a matrix is desirable for efficient tissue regeneration. Polyethylene glycol hydrogels crosslinked with matrix metalloproteinase (MMP) susceptible peptide sequences permit cell-controlled invasion. In this study, hydrogels of the same stiffness polymerised using different ratios of a readily degradable MMP peptide sequence (PAN-MMP) and a MMP peptide with a limited degradation capacity (MMP-9) were assessed both in vitro and in vivo for cellular invasion. The degree of invasion into the various hydrogels was found to be tightly linked to the relative proportion of each peptide both in vitro and in vivo. Furthermore a good correlation between in vitro and in vivo ingrowth was observed. These findings demonstrate a highly tunable model for regulating cellular invasion which is readily translatable to in vivo models. This finding may allow for further optimisation of aspects of regenerative scaffolds such as tissue invasion, growth factor release and cellular encapsulation. STATEMENT OF SIGNIFICANCE: Degradable hydrogels are used in a wide range of tissue regeneration approaches. A particularly advantageous variant of these hydrogels is where due to peptide based crosslinking of the polymeric hydrogels, cell invasion rate is dependent on cellular enzymatic activity. This present study demonstrates a further refinement whereby both cellular and tissue invasion rates are finely regulated through the polymerisation of a hydrogel with varying combinations of enzymatically degradable peptides. Importantly this allows for invasion rates to be controlled without altering the biomechanical properties of the hydrogel such as stiffness. The latter can further influence cellular behaviour thus potentially interfering with the desired outcome.

A simple fluid-structure coupling algorithm for the study of the anastomotic mechanics of vascular grafts.

Vascular anastomoses constitute a main factor in poor graft performance due to mismatches in distensibility between the host artery and the graft. This work aims at computational fluid-structure investigations of proximal and distal anastomoses of vein grafts and synthetic grafts. Finite element and finite volume models were developed and coupled with a user-defined algorithm. Emphasis was placed on the simplicity of the coupling algorithm. An artery and vein graft showed a larger dilation mismatch than an artery and synthetic graft. The vein graft distended nearly twice as much as the artery while the synthetic graft displayed only approximately half the arterial dilation. For the vein graft, luminal mismatching was aggravated by development of an anastomotic pseudo-stenosis. While this study focused on end-to-end anastomoses as a vehicle for developing the coupling algorithm, it may serve as useful point of departure for further investigations such as other anastomotic configurations, refined modelling of sutures and fully transient behaviour.

Mechanical loadings on pectoral pacemaker implants: correlation of in-line and transverse force of the Pectoralis major.

Recently we presented a method for the assessment of in vivo forces on pectoral device implants motivated from technological and clinical advancements toward smaller implantable cardiac pacemakers and the altered structural demands arising from the reduced device size. Objective of this study was the investigation of the intra-species proportionality of in-line force and transverse reaction force of the Pectoralis major for the characterization of mechanical in vivo loadings on pectoral implants. Two Chacma baboons (23.9 ± 1.2 kg) received bilaterally one chronic and one acute pectoral sub-muscular instrumented pacemaker (IPM) implant. The Pectoralis major muscle was electrically stimulated and resulting in-line and transverse muscle force were measured. The correlation of in-line force and transverse force of the Pectoralis major was investigated using linear regression analyses. The proportionality of in-line and transverse force of the Pectoralis major was found to be subject-specific (R² = 0.17, p < 0.003). Including morphometric parameters, i.e., length along line of action, width over implant and stress, in the regression analysis provided a strong intra-species correlation between in-line and transverse force (R² = 0.71, p < 10⁻7). The novel intra-species correlation provides a tool toward the characterization of mechanical in vivo loading conditions of pectoral device implants.

Modification, crosslinking and reactive electrospinning of a thermoplastic medical polyurethane for vascular graft applications.

Thermoplastic polyurethanes are used in a variety of medical devices and experimental tissue engineering scaffolds. Despite advances in polymer composition to improve their stability, the correct balance between chemical and mechanical properties is not always achieved. A model compound (MC) simulating the structure of a widely used medical polyurethane (Pellethane) was synthesized and reacted with aliphatic and olefinic acyl chlorides to study the reaction site and conditions. After adopting the conditions to the olefinic modification of Pellethane, processing into flat sheets, and crosslinking by thermal initiation or ultraviolet radiation, mechanical properties were determined. The modified polyurethane was additionally electrospun under ultraviolet light to produce a crosslinked tubular vascular graft prototype. Model compound studies showed reaction at the carbamide nitrogen, and the modification of Pellethane with pentenoyl chloride could be accurately controlled to up to 20% (correlation: rho=0.99). Successful crosslinking was confirmed by insolubility of the materials. Initiator concentrations were optimized and the crosslink densities shown to increase with increasing modification. Crosslinking of Pellethane containing an increasing number of pentenoyl groups resulted in decreases (up to 42%, p<0.01) in the hysteresis and 44% in creep (p<0.05), and in a significant improvement in degradation resistance in vitro. Modified Pellethane was successfully electrospun into tubular grafts and crosslinked using UV irradiation during and after spinning to render them insoluble. Prototype grafts had sufficient burst pressure (>550 mm Hg), and compliances of 12.1+/-0.8 and 6.2+/-0.3%/100 mm Hg for uncrosslinked and crosslinked samples, respectively. It is concluded that the viscoelastic properties of a standard thermoplastic polyurethane can be improved by modification and subsequent crosslinking, and that the modified material may be electrospun and initiated to yield crosslinked scaffolds. Such materials hold promise for the production of vascular and other porous scaffolds, where decreased hysteresis and creep may be required to prevent aneurismal dilation.

Aortic valve leaflet mechanical properties facilitate diastolic valve function.

This work was concerned with the numerical simulation of the behaviour of aortic valves whose material can be modelled as non-linear elastic anisotropic. Linear elastic models for the valve leaflets with parameters used in previous studies were compared with hyperelastic models, incorporating leaflet anisotropy with pronounced stiffness in the circumferential direction through a transverse isotropic model. The parameters for the hyperelastic models were obtained from fits to results of orthogonal uniaxial tensile tests on porcine aortic valve leaflets. The computational results indicated the significant impact of transverse isotropy and hyperelastic effects on leaflet mechanics; in particular, increased coaptation with peak values of stress and strain in the elastic limit. The alignment of maximum principal stresses in all models follows approximately the coarse collagen fibre distribution found in aortic valve leaflets. The non-linear elastic leaflets also demonstrated more evenly distributed stress and strain which appears relevant to long-term scaffold stability and mechanotransduction.

The use of finite element methods and genetic algorithms in search of an optimal fabric reinforced porous graft system.

The mechanics of arteries result from the properties of the soft tissue constituents and the interaction of the wall layers, predominantly media and adventitia. This concept was adopted in this study for the design of a tissue regenerative vascular graft. To achieve the desired structural properties of the graft, most importantly a diametric compliance of 6%/100 mmHg, finite element methods and genetic algorithms were used in an integrated approach to identify the mechanical properties of an adventitial fabric layer that were required to optimally complement an intimal/medial polyurethane layer with interconnected porosity of three different size classes. The models predicted a compliance of 16.0, 19.2, and 31.5%/100 mmHg for the non-reinforced grafts and 5.3, 5.5, and 6.0%/100 mmHg for the fabric-reinforced grafts. The latter, featuring fabrics manufactured according to the required non-linear mechanical characteristics numerically predicted, exhibited an in vitro compliance of 2.1 +/- 0.8, 3.0 +/- 2.4, and 4.0 +/- 0.7% /100 mmHg. The combination of finite element methods and genetic algorithms was shown to be able to successfully optimize the mechanical design of the composite graft. The method offers potential for the application to alternative concepts of modular vascular grafts and the incorporation of tissue ingrowth and biodegradation.

The selective modulation of endothelial cell mobility on RGD peptide containing surfaces by YIGSR peptides.

The ability of the biomimetic peptides YIGSR, PHSRN and RGD to selectively affect adhesion and migration of human microvascular endothelial cells (MVEC) and vascular smooth muscle cells (HVSMC) was evaluated. Cell mobility was quantified by time-lapse video microscopy of single cells migrating on peptide modified surfaces. Polyethylene glycol (PEG) hydrogels modified with YIGSR or PHSRN allowed only limited adhesion and no spreading of MVEC and HVSMC. However, when these peptides were individually combined with the strong cell binding peptide RGD in PEG hydrogels, the YIGSR peptide was found to selectively enhance the migration of MVEC by 25% over that of MVEC on RGD alone (p<0.05). No corresponding effect was observed for HVSMC. This suggests that the desired response of specific cell types to tissue engineering scaffolds could be optimized through a combinatory approach to the use of biomimetic peptides.

Fixation-related autolysis and bioprosthetic aortic wall calcification.

BACKGROUND AND AIM OF THE STUDY: It has been established previously that immediate fixation and increased glutaraldehyde (GA) concentrations are required to prevent severe autolytic tissue damage during bioprosthetic aortic root production. The study aim was to verify that structure-preserving fixation also reduces aortic wall calcification. METHODS: Porcine aortic roots were fixed either instantly or after being kept on ice for 48 h (phosphate-buffered saline, PBS). Two concentrations of GA (0.2% and 3.0%) were chosen (4 degrees C, seven days, PBS). Discs of aortic wall tissue (1.2 cm diameter) were implanted subcutaneously in rats for 60 days (n = 10 per group), while aortic roots were implanted in the distal aortic arch of sheep for six weeks (n = 3 per group) and six months (n = 4 per group). Calcification was assessed by atomic absorption spectrophotometry and light microscopy. Fixation-related tissue damage was determined by transmission electron microscopy, and correlated with calcification. RESULTS: No significant difference in calcification was found between immediate and delayed fixation if tissue was fixed with 0.2% GA. In the 3.0% GA group, both animal models showed a significantly lower level of calcification if tissue was immediately fixed. In the subcutaneous rat model, immediate fixation reduced calcification by 26% (p <0.0001). In the circulatory sheep model immediate fixation did not affect calcification in the short-term six-week implants, but markedly lowered it by 37% (p = 0.035) after six months. Ultrastructurally, there was a significant correlation between membrane damage, vacuolization and vesicle shedding on the one hand, and calcification on the other. CONCLUSION: Coincidental fixation-related ultrastructural damage and increased calcification was demonstrated in bioprosthetic aortic wall tissue.

Engineering of vascular ingrowth matrices: are protein domains an alternative to peptides?

Anastomotic intimal hyperplasia and surface thrombogenicity are the main reasons for the high failure rate of prosthetic small-diameter vascular grafts. While anastomotic intimal hyperplasia is a multifactorial event, ongoing surface thrombogenicity is primarily caused by the lack of an endothelium, even after years of clinical implantation. After decades of poorly performing synthetic artery-grafts, tissue engineering has emerged as a promising approach to generate biologically functional bio-synthetic hybrid grafts mimicking native arteries regarding the presence of an endothelial lining on the blood surface. "In vitro endothelialization" represented the first generation of such tissue-engineered vascular grafts, utilising cell culture techniques for the creation of a confluent autologous endothelium on ePTFE grafts. The clinical long-term results with this method in almost 200 patients are highly encouraging, showing patencies equal to vein grafts. Since "in vitro endothelialization" requires cell culture facilities, it will always be confined to large centres. Therefore, research of the 1990s turned to the development of spontaneously endothelializing implants, to make tissue-engineered grafts amenable to the entire vascular-surgical community. Apart from scaffold designs allowing transmural ingrowth, biological signalling through a facilitating ingrowth matrix holds a key to spontaneous endothelialization. In biological signalling, the increasingly deeper understanding of bio-active molecules and the discovery of domains and peptide sequences during the 1980s created the expectation in the 1990s that peptide signalling may be all that is needed. This present review highlights the possible problems associated with such a reductionist approach. Using the fibronectin molecule, we demonstrated that domains may be more suitable modules in tissue engineering than peptide sequences.

Cyclic stretch induces the expression of vascular endothelial growth factor in vascular smooth muscle cells.

OBJECTIVE: Accumulating evidence links the release of vascular endothelial growth factor (VEGF) by vascular smooth muscle cells (VSMC) to normal endothelial cell (EC) function, repair and maintenance. Using an in vitro model we investigate the role of cyclic stretch on both the release of VEGF by VSMC and the phosphorylation of a VEGF receptor on EC. METHODS: Bovine VSMC and EC were exposed to 10% cyclic strain for 4 hours. VEGF mRNA steady-state levels of VSMC were analysed by northern blot hybridisation. The presence of secreted VEGF from VSMC was determined by assaying the migration of EC. VEGF receptor phosphorylation on stretched EC was assayed by immunoblotting. RESULTS: The steady-state level of VEGF mRNA in stretched VSMC increased 3.3 (+/- 0.6) fold above that of unstretched VSMC (p < 0.005). Migration of EC was stimulated 8.3 (+/- 1.1) and 14.6 (+/- 1.3) fold by media from unstretched and stretched VSMC respectively, demonstrating a 1.8 fold increase due to stretch alone (p < 0.05). Cyclic stretch resulted in phosphorylation of the VEGF receptor KDR. CONCLUSION: Exposure of VSMC to physiological levels of stretch induces a biologically significant increase in VEGF secretion and may provide an arterial stimulus for maintenance of steady state levels of VEGF essential for EC survival.