Difference in coagulation systems of large animal species used in cardiovascular research: a systematic review.

Preclinical testing using animal models is indispensable in cardiovascular research. However, the translation to clinical practice of these animal models is questionable since it is not always clear how representative they are. This systematic review intends to summarize the interspecies differences in the coagulation profile of animal models used in cardiovascular research. It aims to guide future research in choosing the optimal animal species. A literature search of PubMed, Embase, Web of Science (Core Collection) and Cochrane Library was performed using a search string that was well defined and not modified during the study. An overview of the search terms used in each database can be found in the appendix. Articles describing coagulation systems in large animals were included. We identified 30 eligible studies of which 15 were included. Compared to humans, sheep demonstrated a less active external pathway of coagulation. Sheep had a higher platelet count but the platelet activatability and response to biomaterials were lower. Both sheep and pigs displayed no big differences in the internal coagulation system compared to humans. Pigs showed results very similar to those of humans, with the exception of a higher platelet count and stronger platelet aggregation in pigs. Coagulation profiles of different species used for preclinical testing show strong variation. Adequate knowledge of these differences is key in the selection of the appropriate species for preclinical cardiovascular research. Future thrombogenicity research should compare sheep to pig in an identical experimental setup.

Validation of large animal models in mechanical valve research: a histologic comparison.

OBJECTIVES: Mechanical valves still require life-long anticoagulation. Preclinical animal testing is a crucial step in the assessment of valves; however, the chosen animal model should be carefully considered, and a well-controlled animal model of mechanical valve thrombosis has not been established yet. In this study, a histopathologic comparison was performed to evaluate the representativity of pigs and sheep as large animal models in bileaflet mechanical valve thrombosis research. METHODS: 10 pigs and 8 sheep were implanted with a bileaflet mechanical valve in pulmonary position. During follow-up, no anticoagulative therapy was administered. Pigs were sacrificed between 14 and 38 days for explantation and assessment of the valve. Sheep were sacrificed between 71 and 155 days. Thrombus samples were processed and (immuno)histochemical stainings were applied. A pathologist evaluated the samples morphologically and semiquantitatively and compared these samples to available slides from 3 human patients who underwent redo surgery for acute bileaflet mechanical valve thrombosis, caused by insufficient anticoagulation. RESULTS: All pigs showed macroscopically evident thrombi on the mechanical valve surface at sacrifice. In contrast, none of the sheep showed any sign of thrombus formation. Histology showed a high fibrin content in thrombi of both human and porcine cases (3/3 vs 8/10). Porcine thrombi showed more cellular organization (0/3 vs 6/10), more calcification (0/3 vs 9/10) and more endothelialization (0/3 vs 6/10). Inflammatory cells were present in all samples and were considered physiological. CONCLUSIONS: Contrary to sheep, pigs develop thrombi on their mechanical valves in the short-term if no anticoagulation is administered. Histologic comparison of human and porcine thrombi shows comparable findings. The pig model might serve interestingly for further research on valve thrombosis, if it shows not to be an overly aggressive model.

An interventional sheep model of severe aortic valve stenosis hemodynamics for the evaluation of alterations in coronary physiology and microvascular function.

We aimed to develop a large animal model of subcoronary aortic stenosis (AS) to study intracoronary and microcirculatory hemodynamics. A total of three surgical techniques inducing AS were evaluated in 12 sheep. Suturing the leaflets together around a dilator (n = 2) did not result in severe AS. Suturing of a pericardial patch with a variable opening just below the aortic valve (n = 5) created an AS which was poorly tolerated if the aortic valve area (AVA) was too small (0.38-1.02 cm2), but was feasible with an AVA of 1.2 cm2. However, standardization of aortic regurgitation (AR) with this technique is difficult. Therefore, we opted for implantation of an undersized AV-bioprosthesis with narrowing sutures on the leaflets (n = 5). Overall, five sheep survived the immediate postoperative period of which three had severe AS (one patch and two bioprostheses). The surviving sheep with severe AS developed left ventricular hypertrophy and signs of increased filling-pressures. Intracoronary assessment of physiological indices in these AS sheep pointed toward the development of functional microvascular dysfunction, with a significant increase in coronary resting flow and hyperemic coronary resistance, resulting in a significantly higher index of microvascular resistance (IMR) and lower myocardial resistance reserve (MRR). Microscopic analysis showed myocardial hypertrophy and signs of fibrosis without evidence of capillary rarefaction. In a large animal model of AS, microvascular changes are characterized by increased resting coronary flow and hyperemic coronary resistance resulting in increased IMR and decreased MRR. These physiological changes can influence the interpretation of regularly used coronary indices.NEW & NOTEWORTHY In an animal model of aortic valve stenosis (AS), coronary physiological changes are characterized by increased resting coronary flow and hyperemic coronary resistance. These changes can impact coronary indices frequently used to assess concomitant coronary artery disease (CAD). At this point, the best way to assess and treat CAD in AS remains unclear. Our data suggest that fractional flow reserve may underestimate CAD, and nonhyperemic pressure ratios may overestimate CAD severity before aortic valve replacement.

In vivo performance of a tri-leaflet mechanical heart valve prosthesis in an ovine model.

OBJECTIVES: We present the long-term results of a trileaflet (Triflo) versus bileaflet (On-X) mechanical valve in both aortic and pulmonary positions in a sheep model. METHODS: The Triflo valve was implanted in 21 female sheep in aortic (n = 8) and pulmonary position (n = 13). The On-X valve was implanted in 7 female sheep in aortic (n = 1) and pulmonary (n = 6) positions. No antithrombotic medication of any kind was given postoperatively. In the aortic group, survival cohorts were 3 and 5 months. In the pulmonary group, survival cohorts were 10 and 20 weeks. Valve performance was assessed using haematology, echocardiography and acoustic measurements combined with post-mortem pathology analysis of the downstream organs. RESULTS: The mean gradients were lower for the Triflo valve in both pulmonary [4.30 mmHg (3.70-5.73) vs 6.80 mmHg (4.63-7.96), P = 0.012] and aortic [5.1 mmHg (4.2-7.7) vs 10.7 mmHg (8.7-12.9), P = 0.007] positions. Peak gradients were lower for the Triflo valve in both pulmonary [8.05 mmHg (6.75-10.23) vs 13.15 mmHg (9.20-14.76), P = 0.005] and aortic [8.7 mmHg (7.5-12.5) vs 16.5 mmHg (14.2-19.6), P = 0.009] positions. In both positions, leaflets and housing surface were free from any deposits macro- and microscopically and comparable to nonimplanted control valves. Peripheral organs showed no signs of thrombo-embolic damage. Biochemical and haematological were comparable to preoperative. The closing click sound pressure level of the Triflo was significantly lower in both aortic [108.4 sound pressure level (102.0-115.7) vs 111.7 sound pressure level (105.5-117.0), P < 0.001] and pulmonary [103.6 sound pressure level (99.1-108.9) vs 118.5 sound pressure level (116.7-120.2), P < 0.001] position. CONCLUSIONS: Preliminary in vivo results of the Triflo valve are promising in both aortic and pulmonary positions in an ovine model. Excellent haemodynamics, stable long-term function, low valve noise and no thrombo-embolic events in the absence of antithrombotic medication lay the foundation to a future clinical first-in-man trial.

DOACs in the Anticoagulation of Mechanical Valves: A Systematic Review and Future Perspectives.

Valvular heart disease is a common disease often necessitating valve replacement. Mechanical heart valves (MHVs) are often used in younger patients because of their longer durability. Their main disadvantage is the need for lifelong anticoagulation. Warfarin is considered a standard treatment, but it is far from perfect. Direct oral anticoagulants (DOACs) are a new and more patient-friendly alternative to warfarin when anticoagulation is required, but have not yet been approved for the indication of mechanical valves. EVIDENCE ACQUISITION: A literature search of Pubmed, Embase, Web of Science (Core Collection), and Cochrane Library (from inception to May 2023) was performed using a search string that was well defined and not modified during the study. An extensive overview of the search terms used in each database can be found in the Appendix. Only prospective clinical trials were included in this review. A total of 10 publications were included in this review. RELEVANCE TO CLINICAL PRACTICE: This systematic review summarizes the different types of DOACs and their possible use in the anticoagulation of mechanical valves. We aim to propose future directions in anticoagulation research for mechanical valves. CONCLUSIONS: DOAC use in MHVs has been halted due to the failure of both dabigatran and apixaban in two major clinical trials. However, rivaroxaban was successful in two small clinical trials. Ample research is still needed to explore new valve designs as well as new anticoagulation targets.

Sutureless and rapid deployment versus sutured aortic valve replacement: a propensity-matched comparison from the Sutureless and Rapid Deployment International Registry.

OBJECTIVES: To compare procedural and in-hospital outcomes of patients undergoing sutureless (Perceval, Livanova PLC, London, UK) and rapid deployment (Intuity Elite, Edwards Lifesciences, Irvine, CA, USA) aortic valve replacement (group 1) versus sutured aortic valve replacement (group 2). METHODS: Patients receiving isolated aortic valve replacement between 2014 and 2020 were analysed using data from the Sutureless and Rapid Deployment International Registry. Patients in group 1 and group 2 were propensity-score matched in a 1:1 ratio. RESULTS: A total of 7708 patients were included in the study. After matching, 2 groups of 2643 each were created. Patients in group 1 were more likely to undergo minimally invasive approaches and were associated with shorter operative times when compared with group 2. Overall in-hospital mortality was similar between groups. While an increased risk of stroke was observed in group 1 in the first study period (2014-2016; relative risk 3.76, P < 0.001), no difference was found in more recent year period (relative risk 1.66, P = 0.08; P for heterogeneity 0.003). Group 1 was associated with reduced rates of postoperative low cardiac output syndrome, atrial fibrillation and mild aortic regurgitation. New pacemaker implant was three-fold higher in group 1. CONCLUSIONS: Our findings showed significant differences in procedural and clinical outcomes between the study groups. These results suggest that sutureless and rapid deployment aortic valve replacement should be considered as part of a comprehensive valve programme. The knowledge of the respective post-aortic valve replacement benefits for different valve technologies may result in patient-tailored valve selection with improved clinical outcomes.

Thoracoscopic management of iatrogenic cardiac perforations.

AIMS: Iatrogenic cardiac perforation is an uncommon but potentially fatal complication of invasive cardiac procedures. When nonsurgical management fails, urgent cardiac surgery is required. The standard surgical approach is usually through full sternotomy. However, we propose a less invasive and equally effective technique with video-assisted thoracoscopic surgery (VATS). METHODS: This single-center retrospective study in a tertiary hospital identified all patients requiring surgical intervention due to iatrogenic cardiac perforation over a period of 5 years. Patients were grouped by surgical approach, being either sternotomy or VATS. Primary endpoints were operating time, length of ICU stay, hospital stay, 30-day mortality, and all-round mortality. RESULTS: Twenty-five patients were identified: 11 in the sternotomy group and 14 in the VATS-group. Preoperative baseline characteristics were equal. Significant difference was found for 30-day mortality (p < .05). There was no difference for the other endpoints. CONCLUSIONS: VATS is a promising alternative to standard sternotomy for iatrogenic cardiac perforations after invasive cardiac procedures.

Apixaban in a porcine model of mechanical valve thrombosis in pulmonary position-a pilot study.

OBJECTIVES: The newest mechanical valves have low thrombogenicity, making them candidates for anticoagulation with a direct oral anticoagulant. While these drugs hold great promise to replace warfarin, clinical trials have been disappointing so far. We aimed to evaluate apixaban in a porcine model of mechanical valve thrombosis with On-X® (CryoLife) aortic valves implanted in pulmonary position. METHODS: On-X® valves were implanted in pulmonary valve position in 9 Yucatan pigs. Animals received prophylactic enoxaparin 40 mg for 1 week. Pigs in the low-dose group received 5 mg apixaban twice daily for 10 weeks. The intermediary-dose group received 5 mg twice daily for 6 weeks and then 10 mg twice daily afterwards. The high-dose group received 15 mg twice daily for 10 weeks. After sacrifice, valves were macroscopically evaluated and thrombus weight was documented. RESULTS: The median weight of the 9 animals was 64.3 kg, range 52.5-70.9. In the low-dose group (2 animals), both valves showed manifest, chronic thrombosis with blocked hinges. In the intermediary-dose group, a normal functioning valve without thrombosis was seen in 2/4 animals. In the high-dose group (3 pigs), there was no valve thrombosis. No bleeding events occurred. In all animals, apixaban plasma levels were low compared to clinical target levels. CONCLUSIONS: The pulmonary position seems to be an aggressive model for mechanical valve thrombosis in pigs. Apixaban has the potential to prevent valve thrombosis, even in these thrombogenic conditions. Detailed pharmacokinetic studies are needed to determine the ideal apixaban dosage for future experiments and to enable extrapolation to the clinical situation.

Total endoscopic left ventricle lipoma removal.

BACKGROUND: Left ventricle (LV) lipoma is a very rare, benign cardiac tumor. Due to its rarity, LV lipoma is often misdiagnosed. Aspecific symptoms such as murmurs, arrhythmias, memory loss and palpitation may occur due to the mass effect. CASE PRESENTATION: We report a case report of a 42 year old woman who was found to have left ventricle mass after check-up for arrhytmia. By a fully endoscopic approach, the mass was successfully resected from the left ventricle without the need for sternotomy. CONCLUSION: Total endoscopic removal of left ventricle lipoma's can be done safely and has several advantages to conventional sternotomy. Larger studies are needed to confirm this hypothesis.

Juvenile Papillomatosis: A Case Report.

Juvenile papillomatosis of the breast, also known as Swiss cheese disease, is a rare and benign proliferative disorder affecting young women. These patients tend to have a strong family history of cancer. The lesion typically presents as a localized mass without sharp borders. Clinical presentation resembles that of a precancerous lesion. For this reason, JP is often misdiagnosed in the preoperative period. However postoperative histopathological examination reveals distinct microscopic features, such as duct papillomatosis, cysts and sclerosing adenosis, which confirm the diagnosis of juvenile papillomatosis. We report two cases of juvenile papillomatosis. Both cases were preoperatively diagnosed as benign proliferative lesions with fibrocystic changes. However, after surgical excision, histopathological examination showed juvenile papillomatosis. Interestingly, both patients had a strong family history of breast cancer in both the paternal and maternal line. More research is needed to assess the correlation between a family history of breast cancer and the juvenile papillomatosis.