Mechanical valve replacement for patients with rheumatic heart disease: the reality of INR control in Africa and beyond.

The majority of patients requiring heart valve replacement in low- to middle-income countries (LMICs) need it for rheumatic heart disease (RHD). While the young age of such patients largely prescribes replacement with mechanical prostheses, reliable anticoagulation management is often unattainable under the prevailing socioeconomic circumstances. Cases of patients with clotted valves presenting for emergency surgery as a consequence of poor adherence to anticoagulation control are frequent. The operative mortality rates of reoperations for thrombosed mechanical valves are several times higher than those for tissue valves, and long-term results are also disappointing. Under-anticoagulation prevails in these regions that has clearly been linked to poor international normalised ratio (INR) monitoring. In industrialised countries, safe anticoagulation is defined as >60%-70% of the time in the therapeutic range (TTR). In LMICs, the TTR has been found to be in the range of twenty to forty percent. In this study, we analysed >20,000 INR test results of 552 consecutive patients receiving a mechanical valve for RHD. Only 27% of these test results were in the therapeutic range, with the vast majority (61%) being sub-therapeutic. Interestingly, the post-operative frequency of INR tests of one every 3-4 weeks in year 1 had dropped to less than 1 per year by year 7. LMICs need to use clinical judgement and assess the probability of insufficient INR monitoring prior to uncritically applying Western guidelines predominantly based on chronological age. The process of identification of high-risk subgroups in terms of non-adherence to anticoagulation control should take into account both the adherence history of >50% of patients with RHD who were in chronic atrial fibrillation prior to surgery as well as geographic and socioeconomic circumstances.

The impact of COVID-19 on a South African pediatric cardiac service: implications and insights into service capacity.

Background and Objectives: The Western Cape public pediatric cardiac service is under-resourced. COVID-19 regulations are likely to have long-term effects on patient care but may provide insight into service capacity requirements. As such, we aimed to quantify the impact of COVID-19 regulations on this service. Methods: An uncontrolled retrospective pre-post study of all presenting patients over two, one-year periods; the pre-COVID-19 period (01/03/2019-29/02/2020) and the peri-COVID-19 period (01/03/2020-28/02/2021). Results: Admissions decreased by 39% (624 to 378) and cardiac surgeries decreased by 29% (293 to 208) in the peri-COVID-19 period, with an increase in urgent cases (PR:5.99, 95%CI:3.58-10.02, p < 0.001). Age at surgery was lower in the peri-COVID-19 period, 7.2 (2.4-20.4) vs. 10.8 (4.8-49.2) months (p < 0.05), likewise, age at surgery for transposition of the great arteries (TGA) was lower peri-COVID-19, 15 (IQR:11.2-25.5) vs. 46 (IQR:11-62.5) days (p < 0.05). Length of stay 6 (IQR:2-14) vs. 3 days (IQR:1-9) (p < 0.001), complications (PR:1.21, 95%CI:1.01-1.43, p < 0.05), and age-adjusted delayed-sternal-closure rates (PR:3.20, 95%CI:1.09-9.33, p < 0.05) increased peri-COVID-19. Conclusion: Cardiac procedures were significantly reduced in the peri-COVID-19 period which will have implications on an overburdened service and ultimately, patient outcomes. COVID-19 restrictions on elective procedures freed capacity for urgent cases, demonstrated by the absolute increase in urgent cases and significant decrease in age at TGA-surgery. This facilitated intervention at the point of physiological need, albeit at the expense of elective procedures, and also revealed insights into capacity requirements of the Western Cape. These data emphasize the need for an informed strategy to increase capacity and reduce backlog whilst ensuring minimal morbidity and mortality.Graphical Abstract.

Modified fibrin hydrogel for sustained delivery of RNAi lipopolyplexes in skeletal muscle.

RNA interference is a promising therapeutical approach presently hindered by delivery concerns such as rapid RNA degradation and targeting of individual tissues. Injectable hydrogels are one potentially simple and direct route towards overcoming these barriers. Here we report on the utility of a combination of a mildly modified form of the clinically utilised fibrin hydrogel with Invivofectamine® 3.0, a lipid nonviral transfection vector, for local and sustained release. PEGylation of fibrin allowed for controlled release of small interfering RNA (siRNA)-lipopolyplexes for at least 10 days and greatly increased the stability of fibrin in vitro and in vivo. A 3D cell culture model and a release study showed transfection efficacy of siRNA-lipopolyplexes was retained for a minimum of 7 days. Injection in conjunction with PEGylated-fibrinogen significantly increased retention of siRNA-lipopolyplexes in mouse skeletal muscle and enhanced knockdown of myostatin mRNA that correlated with muscle growth. Thus, the increased efficacy observed here for the combination of a lipid nanoparticle, the only type of nonviral vector approved for the clinic, with fibrin, might allow for more rapid translation of injectable hydrogel-based RNA interference.

Investigation of Copy Number Variation in South African Patients With Congenital Heart Defects.

BACKGROUND: Congenital heart disease (CHD) is a leading non-infectious cause of pediatric morbidity and mortality worldwide. Although the etiology of CHD is poorly understood, genetic factors including copy number variants (CNVs) contribute to the risk of CHD in individuals of European ancestry. The presence of rare CNVs in African CHD populations is unknown. This study aimed to identify pathogenic and likely pathogenic CNVs in South African patients with CHD. METHODS: Genotyping was performed on 90 patients with nonsyndromic CHD using the Affymetrix CytoScan HD platform. These data were used to identify large, rare CNVs in known CHD-associated genes and candidate genes. RESULTS: We identified eight CNVs overlapping known CHD-associated genes (GATA4, CRKL, TBX1, FLT4, B3GAT3, NSD1) in six patients. The analysis also revealed CNVs encompassing five candidate genes likely to play a role in the development of CHD (DGCR8, KDM2A, JARID2, FSTL1, CYFIP1) in five patients. One patient was found to have 47, XXY karyotype. We report a total discovery yield of 6.7%, with 5.6% of the cohort carrying pathogenic or likely pathogenic CNVs expected to cause the observed phenotypes. CONCLUSIONS: In this study, we show that chromosomal microarray is an effective technique for identifying CNVs in African patients diagnosed with CHD and have demonstrated results similar to previous CHD genetic studies in Europeans. Novel potential CHD genes were also identified, indicating the value of genetic studies of CHD in ancestrally diverse populations.

The Technological Basis of a Balloon-Expandable TAVR System: Non-occlusive Deployment, Anchorage in the Absence of Calcification and Polymer Leaflets.

Leaflet durability and costs restrict contemporary trans-catheter aortic valve replacement (TAVR) largely to elderly patients in affluent countries. TAVR that are easily deployable, avoid secondary procedures and are also suitable for younger patients and non-calcific aortic regurgitation (AR) would significantly expand their global reach. Recognizing the reduced need for post-implantation pacemakers in balloon-expandable (BE) TAVR and the recent advances with potentially superior leaflet materials, a trans-catheter BE-system was developed that allows tactile, non-occlusive deployment without rapid pacing, direct attachment of both bioprosthetic and polymer leaflets onto a shape-stabilized scallop and anchorage achieved by plastic deformation even in the absence of calcification. Three sizes were developed from nickel-cobalt-chromium MP35N alloy tubes: Small/23 mm, Medium/26 mm and Large/29 mm. Crimp-diameters of valves with both bioprosthetic (sandwich-crosslinked decellularized pericardium) and polymer leaflets (triblock polyurethane combining siloxane and carbonate segments) match those of modern clinically used BE TAVR. Balloon expansion favors the wing-structures of the stent thereby creating supra-annular anchors whose diameter exceeds the outer diameter at the waist level by a quarter. In the pulse duplicator, polymer and bioprosthetic TAVR showed equivalent fluid dynamics with excellent EOA, pressure gradients and regurgitation volumes. Post-deployment fatigue resistance surpassed ISO requirements. The radial force of the helical deployment balloon at different filling pressures resulted in a fully developed anchorage profile of the valves from two thirds of their maximum deployment diameter onwards. By combining a unique balloon-expandable TAVR system that also caters for non-calcific AR with polymer leaflets, a powerful, potentially disruptive technology for heart valve disease has been incorporated into a TAVR that addresses global needs. While fulfilling key prerequisites for expanding the scope of TAVR to the vast number of patients of low- to middle income countries living with rheumatic heart disease the system may eventually also bring hope to patients of high-income countries presently excluded from TAVR for being too young.

Outcomes After Bidirectional Glenn Shunt in a Tertiary-Care Pediatric Hospital in South Africa.

OBJECTIVES: Large data sets have been published on short- and long-term outcomes following bidirectional Glenn surgery (BDG), or partial cavopulmonary connection, in high-income countries. Data from low-income and middle-income countries are few and often limited to the immediate postoperative period. The primary outcome was any in-hospital postoperative complication, assessed according to predefined criteria, in children who underwent BDG surgery at Red Cross War Memorial Children's Hospital. DESIGN: A retrospective cohort study. SETTING: A tertiary teaching hospital. PARTICIPANTS: The study authors identified 61 children (<18 years of age) who underwent BDG over 8 years. The median age of patients undergoing BDG was 2.5 years (interquartile range, 1.4-5.5 years). INTERVENTIONS: BDG surgery. MEASUREMENTS AND MAIN RESULTS: Thirty-five patients (57.4%) had a postoperative complication, with some patients (17 of 61, 27.9%) having more than 1 complication. The most frequent complications were infective (29.5%). Univariate analysis found that postoperative complications were associated with the use of nitric oxide (p = 0.004) and a longer duration of anesthesia (p = 0.045) and surgery (p = 0.004). Patients with complications spent longer in the pediatric intensive care unit (ICU) (p < 0.001) and in the hospital (p < 0.012). On multivariate analysis, a priori risk factors based on previous studies were not found to be statistically significant. A total of 37.3% of patients completed their single-ventricle palliation, and 30.5% of patients were lost to follow-up. CONCLUSIONS: Important findings were the older age at which the BDG was performed compared to high-income countries, an acceptable mortality rate of 3.3%, infection being the most common complication, the association of a complication with increased ICU and hospital lengths of stay, and the high rate of patients lost to follow-up.

PROTEA, A Southern African Multicenter Congenital Heart Disease Registry and Biorepository: Rationale, Design, and Initial Results.

Objectives: The PartneRships in cOngeniTal hEart disease (PROTEA) project aims to establish a densely phenotyped and genotyped Congenital Heart Disease (CHD) cohort for southern Africa. This will facilitate research into the epidemiology and genetic determinants of CHD in the region. This paper introduces the PROTEA project, characterizes its initial cohort, from the Western Cape Province of South Africa, and compares the proportion or "cohort-prevalences" of CHD-subtypes with international findings. Methods: PROTEA is a prospective multicenter CHD registry and biorepository. The initial cohort was recruited from seven hospitals in the Western Cape Province of South Africa from 1 April 2017 to 31 March 2019. All patients with structural CHD were eligible for inclusion. Descriptive data for the preliminary cohort are presented. In addition, cohort-prevalences (i.e., the proportion of patients within the cohort with a specific CHD-subtype) of 26 CHD-subtypes in PROTEA's pediatric cohort were compared with the cohort-prevalences of CHD-subtypes in two global birth-prevalence studies. Results: The study enrolled 1,473 participants over 2 years, median age was 1.9 (IQR 0.4-7.1) years. Predominant subtypes included ventricular septal defect (VSD) (339, 20%), atrial septal defect (ASD) (174, 11%), patent ductus arteriosus (185, 11%), atrioventricular septal defect (AVSD) (124, 7%), and tetralogy of Fallot (121, 7%). VSDs were 1.8 (95% CI, 1.6-2.0) times and ASDs 1.4 (95% CI, 1.2-1.6) times more common in global prevalence estimates than in PROTEA's pediatric cohort. AVSDs were 2.1 (95% CI, 1.7-2.5) times more common in PROTEA and pulmonary stenosis and double outlet right ventricle were also significantly more common compared to global estimates. Median maternal age at delivery was 28 (IQR 23-34) years. Eighty-two percent (347/425) of mothers used no pre-conception supplementation and 42% (105/250) used no first trimester supplements. Conclusions: The cohort-prevalence of certain mild CHD subtypes is lower than for international estimates and the cohort-prevalence of certain severe subtypes is higher. PROTEA is not a prevalence study, and these inconsistencies are unlikely the result of true differences in prevalence. However, these findings may indicate under-diagnosis of mild to moderate CHD and differences in CHD management and outcomes. This reemphasizes the need for robust CHD epidemiological research in the region.

Long-Term Stability and Biocompatibility of Pericardial Bioprosthetic Heart Valves.

The use of bioprostheses for heart valve therapy has gradually evolved over several decades and both surgical and transcatheter devices are now highly successful. The rapid expansion of the transcatheter concept has clearly placed a significant onus on the need for improved production methods, particularly the pre-treatment of bovine pericardium. Two of the difficulties associated with the biocompatibility of bioprosthetic valves are the possibilities of immune responses and calcification, which have led to either catastrophic failure or slow dystrophic changes. These have been addressed by evolutionary trends in cross-linking and decellularization techniques and, over the last two decades, the improvements have resulted in somewhat greater durability. However, as the need to consider the use of bioprosthetic valves in younger patients has become an important clinical and sociological issue, the requirement for even greater longevity and safety is now paramount. This is especially true with respect to potential therapies for young people who are afflicted by rheumatic heart disease, mostly in low- to middle-income countries, for whom no clinically acceptable and cost-effective treatments currently exist. To extend longevity to this new level, it has been necessary to evaluate the mechanisms of pericardium biocompatibility, with special emphasis on the interplay between cross-linking, decellularization and anti-immunogenicity processes. These mechanisms are reviewed in this paper. On the basis of a better understanding of these mechanisms, a few alternative treatment protocols have been developed in the last few years. The most promising protocol here is based on a carefully designed combination of phases of tissue-protective decellularization with a finely-titrated cross-linking sequence. Such refined protocols offer considerable potential in the progress toward superior longevity of pericardial heart valves and introduce a scientific dimension beyond the largely disappointing 'anti-calcification' treatments of past decades.

Residual Bioprosthetic Valve Immunogenicity: Forgotten, Not Lost.

Despite early realization of the need to control inherent immunogenicity of bioprosthetic replacement heart valves and thereby mitigate the ensuing host response and its associated pathology, including dystrophic calcification, the problem remains unresolved to this day. Concerns over mechanical stiffness associated with prerequisite high cross-link density to effect abrogation of this response, together with the insinuated role of leaching glutaraldehyde monomer in subsequent dystrophic mineralization, have understandably introduced compromises. These have become so entrenched as a benchmark standard that residual immunogenicity of the extracellular matrix has seemingly been relegated to a very subordinate role. Instead, focus has shifted toward the removal of cellular compartment antigens renowned for their implication in the failure of vascularized organ xenotransplants. While decellularization certainly offers advantages, this review aims to refocus attention on the unresolved matter of the host response to the extracellular matrix. Furthermore, by implicating remnant immune and inflammatory processes to bioprosthetic valve pathology, including pannus overgrowth and mineralization, the validity of a preeminent focus on decellularization, in the context of inefficient antigen and possible residual microbial remnant removal, is questioned.

Analysis of the regenerative capacity of human serum exosomes after a simple multistep separation from lipoproteins.

Due to the abundance of lipoproteins in blood, it is challenging to characterize the biological functions and components of blood-derived extracellular vesicles. The aim of this study was to develop a multiple-step purification protocol to separate serum exosomes from serum proteins and lipoproteins and assess their regenerative potential. Exosomes were isolated by concentrating them in human serum using ultracentrifugation (UC), followed sequentially by density gradient (DG) UC and size exclusion chromatography (SEC). Purity and characterization were assessed by western blots, Lipoprint®, enzyme-linked immunosorbent assay, electron microscopy, mass spectrometry, and nanoparticle tracking analysis. Functionality was assessed by cell proliferation analysis and with an in vivo subcutaneous angiogenesis model. SEC alone isolated nano-sized vesicles possessing vesicle markers TSG101 and CD9, but there was a substantial presence of apolipoprotein B, predominantly derived from very-low- and intermediate-density lipoprotein particles. This was reduced to an undetectable level using the combined UC DG SEC approach. Mass spectrometry identified 224 proteins in UC DG SEC isolates relative to the 135 from SEC, with considerable increases in exosome-related proteins and reductions in lipoproteins. A consistent but limited increase in human dermal fibroblast proliferation and evidence of neovascularization enhancement were observed after exposure to UC DG SEC exosomes. An UC DG SEC purification protocol considerably improved the removal of lipoproteins during isolation of serum exosomes. The purified exosomes stimulated cell proliferation and potentially increased an in vivo angiogenic response. This multistep purification allows for more accurate identification of serum exosome functional activity and composition.

Decellularization and engineered crosslinking: a promising dual approach towards bioprosthetic heart valve longevity.

OBJECTIVES: While decellularization has previously significantly improved the durability of bioprosthetic tissue, remnant immunogenicity may yet necessitate masking through crosslinking. To alleviate the fears of reintroducing the risk of calcific degeneration, we investigated the application of rationally designed crosslinking chemistry, capable of abrogating mineralization in isolation, in decellularized tissue. METHODS: Bovine and porcine pericardium were decellularized using the standard Triton X/sodium deoxycholate/DNAse/RNAse methodology and thereafter combined incrementally with components of a four-stage high-density dialdehyde-based fixation regimen. Mechanical properties prior to, and calcium levels following, subcutaneous implantation for 6 and 10 weeks in rats were assessed. RESULTS: Enhanced four-stage crosslinking, independent of decellularization, or decellularization followed by any of the crosslinking regimens, achieved sustained, near-elimination of tissue calcification. Decellularization additionally resulted in significantly lower tissue stiffness and higher fatigue resistance in all groups compared to their non-decellularized counterparts. CONCLUSIONS: The dual approach of combining decellularization with enhanced crosslinking chemistry in xenogeneic pericardial tissue offers much promise in extending bioprosthetic heart valve longevity.

A Patient-Specific CFD Pipeline Using Doppler Echocardiography for Application in Coarctation of the Aorta in a Limited Resource Clinical Context.

Congenital heart disease (CHD) is the most common birth defect globally and coarctation of the aorta (CoA) is one of the commoner CHD conditions, affecting around 1/1800 live births. CoA is considered a CHD of critical severity. Unfortunately, the prognosis for a child born in a low and lower-middle income country (LLMICs) with CoA is far worse than in a high-income country. Reduced diagnostic and interventional capacities of specialists in these regions lead to delayed diagnosis and treatment, which in turn lead to more cases presenting at an advanced stage. Computational fluid dynamics (CFD) is an important tool in this context since it can provide additional diagnostic data in the form of hemodynamic parameters. It also provides an in silico framework, both to test potential procedures and to assess the risk of further complications arising post-repair. Although this concept is already in practice in high income countries, the clinical infrastructure in LLMICs can be sparse, and access to advanced imaging modalities such as phase contrast magnetic resonance imaging (PC-MRI) is limited, if not impossible. In this study, a pipeline was developed in conjunction with clinicians at the Red Cross War Memorial Children's Hospital, Cape Town and was applied to perform a patient-specific CFD study of CoA. The pipeline uses data acquired from CT angiography and Doppler transthoracic echocardiography (both much more clinically available than MRI in LLMICs), while segmentation is conducted via SimVascular and simulation is realized using OpenFOAM. The reduction in cost through use of open-source software and the use of broadly available imaging modalities makes the methodology clinically feasible and repeatable within resource-constrained environments. The project identifies the key role of Doppler echocardiography, despite its disadvantages, as an intrinsic component of the pipeline if it is to be used routinely in LLMICs.

Preclinical evaluation of a transcatheter aortic valve replacement system for patients with rheumatic heart disease.

AIMS: Cardiac surgery in middle-income countries differs significantly from that in high-income countries regarding prevailing heart valve pathologies and access to cardiac surgery. Typically, rheumatic aortic regurgitation in the absence of calcification by far outweighs stenosis. As such, entirely different transcatheter aortic valve implantation (TAVI) concepts are required for these regions. The aim of the study was to evaluate the five-month performance of the SAT (Strait Access Technologies, Cape Town, South Africa) pericardial TAVI system in the orthotopic aortic position of juvenile sheep. METHODS AND RESULTS: A self-homing, non-occlusive balloon-expandable TAVI system comprising a hollow balloon, stabilising locator trunks, a scalloped CoCr stent with elevating anchorage arms and decellularised, sandwich-crosslinked pericardium was compared with control surgical valves (Edwards PERIMOUNT) in sheep. The implantation period was five months. The tactile placement of the TAVI valves was accomplished without the need for rapid pacing. At termination, no structural degeneration was observed in either group. The TAVIs were well healed with the stent struts largely embedded in tissue. Correlating with sheep growth (weight gain of 40.4±13.0%) during the implantation period, mean transvalvular gradients increased from 3.08±1.95 mmHg to 8.50±5.38 mmHg (p=0.044) after five months. CONCLUSIONS: A single-stage, balloon-expandable, easy to place TAVI system with antigen-depleted and antigen-masked bioprosthetic leaflets promises to address the distinct needs of low- and middle-income countries with regard to TAVI better than conventional systems.

Isolated mechanical aortic valve replacement in rheumatic patients in a low- to middle-income country.

OBJECTIVE: Although the results of aortic valve replacement are well documented for industrialized countries, the outcome in patients with rheumatic aortic valve disease in low- to middle-income countries is less well explored. The aim of this study was to determine the long-term survival and clinical outcomes after isolated aortic valve replacement in patients with rheumatic heart disease in a Sub-Saharan country where follow-up of indigent patients is often challenging. METHODS: A retrospective review of 969 aortic valve replacements performed between 2003 and 2013 was conducted at Cape Town's Groote Schuur Hospital. Patients who underwent concomitant procedures (n = 664) or had nonrheumatic valve pathology (n = 185) were excluded. The mean age of the rheumatic cohort (n = 121) was 43.1 ± 11.6 years with a mean follow-up period of 6.14 ± 3.44 years. The primary end points were survival and valve-related complications. RESULTS: A 15% cardiac- or valve-related 10-year mortality after receiving a mechanical prosthesis corresponded with a significantly higher mortality rate than that of a matched population. Overall cumulative survival at 1, 5, and 10 years was 93.5% (87.0-96.9), 86.4% (78.4-91.8), and 78.1% (67.5-86.0), respectively, and the corresponding cumulative freedom from combined thromboembolism and bleeding was 94.4% (88.2-97.5), 87.4% (79.4-92.5), and 86.1% (77.9-91.6), respectively. CONCLUSIONS: In low- to middle-income countries, with their unique mix of indigent and "First World" patients, rheumatic heart disease still accounts for a significant proportion of patients requiring isolated aortic valve replacement. Although mechanical prostheses are often selected in these young adults, survival remains suboptimal. Major bleeding and thromboembolic events account for the majority (77%) of the reported valve-related complications.

The Neglected Villain of Bioprosthetic Degeneration: Inflammatory and Immune Processes.

In an attempt to avoid the destructive process of bioprosthetic heart-valve calcification associated with the use of glutaraldehyde, valves are today prepared using low concentrations of the crosslinking reagent. In this review, we summarize our findings and those of others that confirm that the immunogenicity of such tissue is not sufficiently masked and that a defined humoral response is indeed mounted against a repertoire of antigens unrelated to those associated with vascularized and non—cross-linked xenograft organs. We demonstrate the need for increased cross-linking of tissue to satisfactorily mitigate that response; furthermore, we examine the impact of increased cross-link density on the macrophage as antigen presenting cell with respect to its involvement in both tissue erosion and pannus overgrowth. Finally we present evidence for a role of circulating antibodies in bioprosthesis calcification.

Assessment of the immunogenicity of mechanically induced interferon aggregates in a transgenic mouse model.

Pump delivery of human interferon alpha-2B (IFNα2b) has the potential for inducing immunogenic drug aggregates. We therefore evaluated the immunogenicity of mechanically induced IFNα2b aggregates to assess this risk. Transgenic human-IFNα2b (TG) and wild-type (WT) FVB/N mice (n = 8 and n = 9/group, respectively) were administered mechanically agitated drug [45 Hz for 6 h (LLA) or 24 h (HLA)], chemically modified drug [low pH (pH 4.0) or metal oxidized (OXD)] or unstressed drug (native). Mice received IFNα2b (50 µg; 100 µg/mL; s.c.) formulations on days 0, 7, 14, and 21. Drug-binding and neutralizing antibody titers were determined after 28 d. Aggregate concentrations were highest in OXD and HLA formulations but OXD had more dimers/trimers. Geometric mean titers were 1:131, 1:728, 1:1573, 1:871, and 1:10,240 for WT mice (n = 9) and 1:207, 1:587, 1:1810, 1:571, and 1:2,153 for TG mice (n = 8) for native, LLA, HLA, pH4, and OXD groups, respectively. Mechanical agitation of IFNα2b induced equivalent titers of immunoglobulin to that of metal oxidation, both capable of binding to or neutralizing the drug in WT and TG mice. Thus, by limiting metal contamination and by inclusion of a stabilizing agent to mitigate drug aggregation, the risk of anti-drug immunoglobulin may be reduced in a pump delivery scenario.

Protective constriction of coronary vein grafts with knitted nitinol.

OBJECTIVES: Different flow patterns and shear forces were shown to cause significantly more luminal narrowing and neointimal tissue proliferation in coronary than in infrainguinal vein grafts. As constrictive external mesh support of vein grafts led to the complete suppression of intimal hyperplasia (IH) in infrainguinal grafts, we investigated whether mesh constriction is equally effective in the coronary position. METHODS: Eighteen senescent Chacma baboons (28.8 ± 3.6 kg) received aorto-coronary bypass grafts to the left anterior descending artery (LAD). Three groups of saphenous vein grafts were compared: untreated controls (CO); fibrin sealant-sprayed controls (CO + FS) and nitinol mesh-constricted grafts (ME + FS). Meshes consisted of pulse-compliant, knitted nitinol (eight needles; 50 µm wire thickness; 3.4 mm resting inner diameter, ID) spray attached to the vein grafts with FS. After 180 days of implantation, luminal dimensions and IH were analysed using post-explant angiography and macroscopic and histological image analysis. RESULTS: At implantation, the calibre mismatch between control grafts and the LAD expressed as cross-sectional quotient (Qc) was pronounced [Qc = 0.21 ± 0.07 (CO) and 0.18 ± 0.05 (CO + FS)]. Mesh constriction resulted in a 29 ± 7% reduction of the outer diameter of the vein grafts from 5.23 ± 0.51 to 3.68 ± 0 mm, significantly reducing the calibre discrepancy to a Qc of 0.41 ± 0.17 (P < 0.02). After 6 months of implantation, explant angiography showed distinct luminal irregularities in control grafts (ID difference between widest and narrowest segment 74 ± 45%), while diameter variations were mild in mesh-constricted grafts. In all control grafts, thick neointimal tissue was present [600 ± 63 µm (CO); 627 ± 204 µm (CO + FS)] as opposed to thin, eccentric layers of 249 ± 83 µm in mesh-constricted grafts (ME + FS; P < 0.002). The total wall thickness had increased by 363 ± 39% (P < 0.00001) in CO and 312 ± 61% (P < 0.00001) in CO + FS vs 82 ± 61% in ME + FS (P < 0.007). CONCLUSIONS: In a senescent non-human primate model for coronary artery bypass grafts, constrictive, external mesh support of saphenous veins with knitted nitinol prevented focal, irregular graft narrowing and suppressed neointimal tissue proliferation by a factor of 2.5. The lower degree of suppression of IH compared with previous infrainguinal grafts coincided with a lesser reduction of calibre mismatch in the coronary grafts.

Rheumatic mitral repair versus replacement in a threshold country: the impact of commissural fusion.

BACKGROUND AND AIM OF THE STUDY: In developing countries rheumatic heart disease is the predominant indication for cardiac surgery. As the disease tends to progress, reoperation rates for mitral valve repairs are high. Against this background, the predictors of failure were assessed and the overall performance of repairs compared with replacements in a 10-year cohort of rheumatic single mitral valve procedures. METHODS: Between 2000 and 2010, a total of 646 consecutive adult (aged >15 years) patients underwent primary, single mitral valve procedures. All 87 percutaneous balloon valvuloplasties (100%) were rheumatic, compared to 280 of the 345 primary mitral valve replacements (81%) and 69 of the 215 primary mitral valve repairs (32%). As the study aim was to compare the outcome of mitral valve repair versus replacement in rheumatic patients of a threshold country, all 69 repair patients were propensity-matched with 69 of the replacement patients. Based on propensity score analysis, Kaplan-Meier actuarial analysis with log-rank testing was used to evaluate survival and morbidity. RESULTS: The follow up was 100% complete (n = 138), and ranged from 0.6 to 132 months (mean 53.3 +/- 36.5 months). Actuarial freedom from valve-related mortality was 96 +/- 3% and 92 +/- 4% at five years, and 96 +/- 3% and 80 +/- 11% at 10 years for repairs and replacements, respectively (p = NS). Actuarial freedom from all valve-related events (deaths, reoperations and morbidity) was 80 +/- 6% and 86 +/- 5% at five years, and 70 +/- 8% and 69 +/- 11% at 10 years (p = NS). Actuarial freedom from all valve-related events was 57 +/- 11% and 96 +/- 3% at five years (p = 0.0008), and 42 +/- 12% and 96 +/- 3% at 10 years (p < 0.001) for those mitral valve repairs with and without commissural fusion, respectively (p = 0.0002 overall). CONCLUSION: The long-term results for mitral valve replacement in an indigent, rheumatic heart disease population of a developing country were better than generally perceived. Notwithstanding, mitral valve repair has a superior long-term outcome in those patients who do not show commissural fusion at operation.

Remodeling leads to distinctly more intimal hyperplasia in coronary than in infrainguinal vein grafts.

BACKGROUND: Flow patterns and shear forces in native coronary arteries are more protective against neointimal hyperplasia than those in femoral arteries. Yet, the caliber mismatch with their target arteries makes coronary artery bypass grafts more likely to encounter intimal hyperplasia than their infrainguinal counterparts due to the resultant slow flow velocity and decreased wall stress. To allow a site-specific, flow-related comparison of remodeling behavior, saphenous vein bypass grafts were simultaneously implanted in femoral and coronary positions. METHODS: Saphenous vein grafts were concomitantly implanted as coronary and femoral bypass grafts using a senescent nonhuman primate model. Duplex ultrasound-based blood flow velocity profiles and vein graft and target artery dimensions were correlated with dimensional and histomorphologic graft remodeling in large, senescent Chacma baboons (n = 8; 28.1 ± 4.9 kg) during a 24-week period. RESULTS: At implantation, the cross-sectional quotient (Q(c)) between target arteries and vein grafts was 0.62 ± 0.10 for femoral grafts vs 0.17 ± 0.06 for coronary grafts, resulting in a dimensional graft-to-artery mismatch 3.6 times higher (P < .0001) in coronary grafts. Together with different velocity profiles, these site-specific dimensional discrepancies resulted in a 57.9% ± 19.4% lower maximum flow velocity (P = .0048), 48.1% ± 23.6% lower maximal cycling wall shear stress (P = .012), and 62.2% ± 21.2% lower mean velocity (P = .007) in coronary grafts. After 24 weeks, the luminal diameter of all coronary grafts had contracted by 63%, from an inner diameter of 4.49 ± 0.60 to 1.68 ± 0.63 mm (P < .0001; subintimal diameter: -41.5%; P = .002), whereas 57% of the femoral interposition grafts had dilated by 31%, from 4.21 ± 0.25 to 5.53 ± 1.30 mm (P = .020). Neointimal tissue was 2.3 times thicker in coronary than in femoral grafts (561 ± 73 vs 240 ± 149 µm; P = .001). Overall, the luminal area of coronary grafts was an average of 4.1 times smaller than that of femoral grafts. CONCLUSIONS: Although coronary and infrainguinal bypass surgery uses saphenous veins as conduits, they undergo significantly different remodeling processes in these two anatomic positions.

Pulmonary artery banding: still a valuable option in developing countries?

OBJECTIVE: We examined whether the socio-economic circumstances of a developing country justify pulmonary artery banding (PAB) for the deferral of perceived high-risk patients requiring biventricular repair. METHODS: A retrospective cohort analysis was done on 143 consecutive patients with ventricular anatomy suitable for a biventricular repair, who had a pulmonary artery band applied between 1 January 2002 and 31 December 2007 as they were considered too high a risk to undergo corrective surgery. The goal in all patients was to lower their risk of definitive surgery by improving their clinical condition. The minimum follow-up period was 2 years with the closing date for data collection being 31 January 2010. The mean weight and age at PAB was 5.34 ± 2.94 kg and 9.9 ± 17.3 months. The endpoints of the study were mortality, interval hospital readmission, growth pattern post-banding, whether or not definitive correction was achieved, and the current follow-up status of uncorrected patients. RESULTS: The hospital mortality was 8% (n = 12), the inter-stage mortality 21% (n = 30), and the total mortality 29% (n = 42). Positive growth was not shown in 50% following the banding procedure. The mean number of inter-current hospital admissions was 1.5 ± 2 times per patient. At the termination of data collection, after a mean interval of 24.5 ± 14.3 months, debanding and full correction was achieved in 43% (n = 62). In addition to the 29% (n = 42) that were confirmed to be dead, an additional 28% (n = 39) were not corrected and of these almost half were regarded as lost to follow-up. Thus, of the entire cohort of patients, 57% (n = 81) have not achieved definitive correction at the termination of data collection. CONCLUSION: A strategy of deferring biventricular repair by the application of a pulmonary artery band is ineffective under Third World conditions largely due to lack of patient compliance. This study shows that the overall mortality in the inter-stage period following PAB is high prior to definitive correction. Less than half of patients will eventually be repaired in a reasonable time frame and patient follow-up is unreliable. We conclude that consideration should be given to early definitive repair even in perceived high-risk cases.