Complex Cardiovascular Disease Research Articles

Mitochondrial Dysfunction Associated with mtDNA Mutation: Mitochondrial Genome Editing in Atherosclerosis Research.

Atherosclerosis is a complex cardiovascular disease often associated with mitochondrial dysfunction, which can lead to various cellular and metabolic abnormalities. Within the mitochondrial genome, specific mutations have been implicated in contributing to mitochondrial dysfunction. Atherosclerosis-associated m.15059G>A mutation has been of particular interest due to its potential role in altering mitochondrial function and cellular health. This study aims to investigate the role of the atherosclerosis-associated m.15059G>A mutation in the development of mitochondrial dysfunction in monocyte-- like cells. Monocyte-like cytoplasmic hybrid cell line TC-HSMAM1, which contains the m.15059G>A mutation in mtDNA, was used. The MitoCas9 vector was utilized to eliminate mtDNA copies carrying the m.15059G>A mutation from TC-HSMAM1 cybrids. Mitochondrial membrane potential, generation of reactive oxygen species, and lipid peroxidation levels were assessed using flow cytometry. Cellular reduced glutathione levels were assessed using the confocal microscopy. The oxygen consumption rate was measured using polarographic oxygen respirometry. The elimination of the m.15059G>A mutation resulted in a significant increase in mitochondrial membrane potential and improved mitochondrial efficiency while also causing a decrease in the generation of reactive oxygen species, lipid peroxidation, as well as cellular bioenergetic parameters, such as proton leak and non-mitochondrial oxygen consumption. At the same time, no changes were found in the intracellular antioxidant system after the mitochondrial genome editing. The presence of the m.15059G>A mutation contributes to mitochondrial dysfunction by reducing mitochondrial membrane potential, increasing the generation of reactive oxygen species and lipid peroxidation, and altering mitochondrial bioenergetics. Elimination of the mtDNA containing atherogenic mutation leads to an improvement in mitochondrial function.

DAJLENet: A neural network based on dual attention and joint learning for explainable heart failure adverse event prediction

Heart Failure (HF) is a common, high-risk, complex cardiovascular disease that is often accompanied by other diseases and has a high mortality rate. The use of electronic health records (EHRs) to predict the risk of adverse events, such as death, intensive care units (ICU) transfer, and readmission, in patients with HF is an important topic in the field of personalized treatment and prognosis. However, the heterogeneity and diversity of patient EHRs make it difficult for traditional machine learning models to adequately mine the hidden features and well train patient representations. In addition, significant sample imbalance and lack of labeled data can limit model performance. To address the above issues, this study proposes a neural network called DAJLENet for predicting adverse events in heart failure with explainability. The model obtains feature-level and visit-level patient representations through feature mining, feature embedding, and dual attention mechanisms. Based on the patient representation, a joint training method of classification task and contrastive learning task is used to learn shared representations to alleviate the sample imbalance problem and improve the model performance. Experimental results on four heart failure prediction tasks show that DAJLENet has an improvement of 1%–3% on various metrics compared to the most advanced models, and an improvement of more than 5% on unbalanced datasets.

Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023).

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.

Precision medicine enhances personalized medicine in cardiology

Personalized medicine and precision medicine, frequently used synonymously, shall be clearly differentiated. Accordingly, personalization in cardiac medicine is based on the clinical presentation of apatient, as well as his/her cardiovascular risk factors and comorbidities, electrocardiography, imaging, and biomarkers for myocardial load and ischemia. Personalization is based on large clinical trials with detailed subgroup analyses and is practiced on the basis of guidelines. Further in depth personalization is achieved by precision medicine, which is based on innovative imaging for myocardial structure, coronary morphology, and electrophysiology. From the clinical perspective, genome analyses are relevant for comparatively rare monogenetic cardiovascular diseases. While these as well as transcriptome and metabolome analyses play asignificant role in cardiovascular research with great translation potential, they have not yet been broadly introduced in the diagnosis, prevention, and treatment of complex cardiovascular diseases. Furthermore, digital technologies have considerable potential in cardiovascular precision medicine. On the one hand, this is based on the frequency of the diseases with the availability of Big Data and, on the other hand, on the availability of bio-signals and sensors of those signals in cardiovascular diseases.

Deep Learning-Based Prediction of Stress and Strain Maps in Arterial Walls for Improved Cardiovascular Risk Assessment

Conducting computational stress-strain analysis using finite element methods (FEM) is a common approach when dealing with the complex geometries of atherosclerosis, which is a leading cause of global mortality and complex cardiovascular disease. The considerable expense linked to FEM analysis encourages the substitution of FEM with a considerably faster data-driven machine learning (ML) approach. This study investigated the potential of end-to-end deep learning tools as a more effective substitute for FEM in predicting stress-strain fields within 2D cross sections of arterial walls. We first proposed a U-Net-based fully convolutional neural network (CNN) to predict the von Mises stress and strain distribution based on the spatial arrangement of calcification within arterial wall cross-sections. Further, we developed a conditional generative adversarial network (cGAN) to enhance, particularly from the perceptual perspective, the prediction accuracy of stress and strain field maps for arterial walls with various calcification quantities and spatial configurations. On top of U-Net and cGAN, we also proposed their ensemble approaches to improve the prediction accuracy of field maps further. Our dataset, consisting of input and output images, was generated by implementing boundary conditions and extracting stress-strain field maps. The trained U-Net models can accurately predict von Mises stress and strain fields, with structural similarity index scores (SSIM) of 0.854 and 0.830 and mean squared errors of 0.017 and 0.018 for stress and strain, respectively, on a reserved test set. Meanwhile, the cGAN models in a combination of ensemble and transfer learning techniques demonstrate high accuracy in predicting von Mises stress and strain fields, as evidenced by SSIM scores of 0.890 for stress and 0.803 for strain. Additionally, mean squared errors of 0.008 for stress and 0.017 for strain further support the model’s performance on a designated test set. Overall, this study developed a surrogate model for finite element analysis, which can accurately and efficiently predict stress-strain fields of arterial walls regardless of complex geometries and boundary conditions.

APELIN AS A POTENTIAL DOWNSTREAM MEDIATOR OF THE IGF-1 CARDIOPROTECTIVE PATHWAY IN THE HYPERTROPHIED MYOCARDIUM OF SPONTANEOUSLY HYPERTENSIVE RATS

Objective: Hypertension is a complex cardiovascular disease and contributes to worldwide morbidity and mortality associated to the development of hypertensive cardiac hypertrophy and the progression of heart failure. Hypertensive myocardium is characterized by mitochondrial dysfunction and redox disbalance. On the other hand, aerobic exercise upregulates several humoral factors such as insulin like growth factor-1 (IGF-1) and apelin, involved in cardioprotective effects. Particularly, whether apelin mediates IGF-1 cardioprotective effects by an autocrine paracrine mechanism is not clear yet. Objective. To determine the acute effects of IGF-1/apelin on oxidative stress and mitochondrial status, as well as the possible crosstalk between the signaling pathways triggered by them in spontaneously hypertensive rats (SHR) myocardium. Design and method: Adult SHR isolated hearts or cardiomyocytes were perfused during 10 min in the presence or absence of IGF-1 or apelin, and the specific antagonist of their receptors (AG1024 and ML221 for IGF1R and APJ, respectively). We explored reactive oxygen species (ROS) production, SOD activity, APJ cellular distribution, mitochondrial membrane potential (↖ ⇘) and permeability transition pore opening through the calcium retention capacity (CRC). Results: IGF-1 exerted an antioxidant effect evidenced by an increase in SOD activity (U/mg, IGF-1: 59.8±5.2, vs Control: 41.6±3) and decrease in ROS production (%, IGF-1: 66±12, vs Control: 100±8). In mitochondria, IGF-1 prevented loss induced by H2O2 (IGF-1: 0.934±0.016, vs Control: 0.827±0.027) and increased CRC (IGF-1: 251±34, vs Control: 135±23). Interestingly, IGF-1 upregulated APJ expression (IGF-1: 175.8±27.7 vs Control: 100±16 % mRNA) while favoring its translocation to the sarcolemma (Pearson coefficient: IGF-1: 0.880±0.011 vs Control: 0.758±0.031) in isolated cardiomyocytes. Moreover, exogenous apelin was able to emulate IGF-1 antioxidant and mitochondrial actions (SOD: 64±5.3 U/mg; ROS: 64± 7 %; ↖ ⇘ loss induced by H2O2: 0.981±0.025 and CRC 264±31). These effects were prevented by inhibition of APJ (Apelin+ML221: SOD: 33±4.4, CRC: 84±17, 0.808±0.042) but not by AG1024 (Apelin+AG: 0.985±0.068, CRC: 245±47). Conclusions: In conclusion, our data suggest that IGF-1 by sequentially activating its own receptor and the apelin/APJ pathway is responsible for cardioprotection. Therefore, apelin emerges as a downstream effector of the cardiac IGF-1 signaling pathway.

GPU accelerated digital twins of the human heart open new routes for cardiovascular research

The recruitment of patients for rare or complex cardiovascular diseases is a bottleneck for clinical trials and digital twins of the human heart have recently been proposed as a viable alternative. In this paper we present an unprecedented cardiovascular computer model which, relying on the latest GPU-acceleration technologies, replicates the full multi-physics dynamics of the human heart within a few hours per heartbeat. This opens the way to extensive simulation campaigns to study the response of synthetic cohorts of patients to cardiovascular disorders, novel prosthetic devices or surgical procedures. As a proof-of-concept we show the results obtained for left bundle branch block disorder and the subsequent cardiac resynchronization obtained by pacemaker implantation. The in-silico results closely match those obtained in clinical practice, confirming the reliability of the method. This innovative approach makes possible a systematic use of digital twins in cardiovascular research, thus reducing the need of real patients with their economical and ethical implications. This study is a major step towards in-silico clinical trials in the era of digital medicine.

Cardiac Surgeons Highlight the Need for Innovation Stewardship: Noteworthy in 2022.

Modern cardiac surgery has rapidly evolved to treat complex cardiovascular disease. This past year boasted noteworthy advances in xenotransplantation, prosthetic cardiac valves, and endovascular thoracic aortic repair. Newer devices often offer incremental design changes while demanding significant cost increases that leave surgeons to decide if the benefit to patients justifies the increased cost. As innovations are introduced, surgeons must continuously aim to harmonize short- and long-term benefits with financial costs). We must also ensure quality patient outcomes while embracing innovations that will advance equitable cardiovascular care.

Chinese expert consensus on clinical application of percutaneous mechanical circulatory support devices in interventional therapy for patients with complex cardiovascular disease.

Chinese expert consensus on clinical application of percutaneous mechanical circulatory support devices in interventional therapy for patients with complex cardiovascular disease.

ESC guidelines 2022 on cardiovascular assessment and management of patients undergoing non-cardiac surgery : What is new?

The new European Society of Cardiology (ESC) guidelines on the cardiovascular assessment and management of patients undergoing non-cardiac surgery were published in August 2022. In the preparation of the new document the previous guidelines published in 2014 were completely revised and the recommendations for action were adapted or renewed. Furthermore, the guidelines have been supplemented with some new chapters. The new and revised recommendations result in significant changes for the clinical practice. This particularly applies to the preoperative risk stratification, the perioperative risk management and the detection and management approaches in cases of perioperative and postoperative complications. Cardiovascular biomarkers play aspecial role in both the preoperative risk stratification and the detection of postoperative complications in combination with appropriate algorithms for action. The perioperative management of antithrombotic treatment (antiplatelet therapy or oral anticoagulation) is becoming increasingly individualized depending on the risk of ischemia or bleeding of the planned surgery. Particular attention is paid to the early detection of perioperative or postoperative myocardial infarctions based on determination of high-sensitivity (hs) cardiac troponin, not least because its association with high risk of morbidity and mortality. In patients with complex cardiovascular diseases, such as severe coronary artery disease, valvular heart diseases or those with ventricular support systems, the decision in an interdisciplinary team is highly recommended.

Abstract 13488: Strain versus Right Heart Catheterization in Decompensated Heart Failure With Preserved Ejection Fraction

Background: Heart Failure (HF) is a complex cardiovascular (CV) disease with half of patients having preserved ejection fraction (HFpEF). Right heart catheterization (RHC) is often used to prognosticate and guide therapy in decompensated HFpEF while strain echocardiography is increasingly being used as an alternative modality. Purpose: To evaluate the prognostic impact of strain imaging compared to RHC in hospitalized patients with decompensated HFpEF. Methods: This was a retrospective cross-sectional study with patients hospitalized for acute HFpEF exacerbation with echo and RHC data available during index admission. Strain analysis was performed using 2D strain imaging software. Demographic and clinical parameters were obtained with mortality data via National Death Index. The outcomes of interest were 6 month, 1 year and 5 year all cause mortality and a composite of CV death with HF readmissions. Separate models incorporating all variables were done using survival analysis by multivariable Cox regression after adjusting for age, gender and race. Results: A total sample of 178 patients was included in the analysis. The mean age±SD was 69.4±13.5. Majority were African American (50%) and female (62%). Half(53%) had diabetes while 88% had hypertension. The 5 year all cause mortality rate was 45% with CV death at 18% and overall readmission rate was 29%. Only mean pulmonary artery pressure (mPAP) was significantly predictive of 6 month all cause mortality HR 2.01; 95% CI (1.07-3.78) p=0.031 and 5 year all cause mortality 1.91; 95% CI (1.46-2.51) p<0.001. For the composite outcome of combined CV death and HF readmissions, right atrial reservoir strain was significant at the 6 month and 1 year time periods with HR 0.65; 95% CI (0.44-0.96) p=0.03 and HR 0.60; 95% CI (0.41-0.89) p=0.01 respectively. Conclusions: RHC and strain variables may be predictive of different outcomes in decompensated HFpEF.

Chinese expert consensus on clinical application of percutaneous mechanical circulatory support devices in interventional therapy for patients with complex cardiovascular disease

经皮机械循环辅助（percutaneous mechanical circulatory support，pMCS）是一种主要应用于心血管急危重症救治的生命支持技术。近年来，随着复杂、高危心血管疾病介入治疗的开展，pMCS在心血管疾病介入治疗中的应用也逐渐受到重视。为指导pMCS技术的应用，中华医学会心血管病学分会组织国内相关专家，汇总国内外循证医学证据，并结合我国实际情况，制定了《经皮机械循环辅助在复杂心血管疾病介入治疗应用中国专家共识》。该共识对pMCS装置，pMCS在复杂、高危冠状动脉疾病、心律失常、瓣膜性心脏病介入治疗中的应用，pMCS的管理，并发症及处理，撤离等进行了全面的介绍，并给出了建议。共识的颁布和实施对规范pMCS的临床应用有重要意义。.

Epigenetic and phenotypic characterization of iPSCs-derived smooth muscle cells: Towards a cellular model for complex arterial diseases

Smooth muscle cells (SMCs) capacity to switch between proliferative (synthetic) and quiescent (contractile) phenotypes is a widely studied mechanism in cardiovascular disease. Primary SMCs tend to lose many physiological features in culture, which makes the study of their contractile function challenging. Recently, an optimized protocol of induced pluripotent stem cells (iPSCs) differentiation into contractile SMCs was described. We aimed at obtaining a deep phenotyping of SMCs derived from iPSCs and evaluating these cellular models in the context of complex cardiovascular diseases. We differentiated 3 human iPSCs lines towards SMC phenotypes using two alternative 24-day protocols, involving either RepSox (R-SMCs) or TGF-β/PDGF-BB (TP-SMCs) during late differentiation. We analyzed gene expression and open chromatin profiles at 6 time points of differentiation and compared them to primary human SMCs and artery tissue. We used CRISPR-Cas9 system to induce mutations at LRP1 cardiovascular disease locus. Both differentiation protocols provided SMCs with abundant expression of typical SMC markers. TP-SMCs exhibited greater capacity of proliferation, migration and lower calcium release in response to contractile signals compared to R-SMCs. RNA-Seq results showed that most genes involved in the contractile function of arteries were highly expressed in R-SMCs, while TP-SMCs were more similar to cultured primary human SMCs. Open chromatin regions of R-SMCs were highly enriched for variants associated with vascular diseases such as hypertension and intracranial aneurysm, whereas TP-SMCs were more enriched for variants associated to peripheral artery disease and aortic aneurysm. Deletion of a cardiovascular disease associated enhancer region led to a dysregulation of LRP1 expression in TP-SMCs, but not in R-SMCs. LRP1 inactivation in TP-SMCs led to a major decrease in SMC proliferation, migration, and deregulation of multiple genes involved in SMC function and extracellular matrix maintenance. Differentiation of SMCs from iPSCs using two complementary protocols provides cellular models suitable for the study of a variety of vascular diseases. We confirmed LRP1 as a regulatory target gene of a common variant associated to multiple cardiovascular diseases and identified multiple genes involved in SMC function downstream of LRP1.

Clinical Phenotypes of Cardiovascular and Heart Failure Diseases Can Be Reversed? The Holistic Principle of Systems Biology in Multifaceted Heart Diseases

Recent advances in cardiology and biological sciences have improved quality of life in patients with complex cardiovascular diseases (CVDs) or heart failure (HF). Regardless of medical progress, complex cardiac diseases continue to have a prolonged clinical course with high morbidity and mortality. Interventional coronary techniques together with drug therapy improve quality and future prospects of life, but do not reverse the course of the atherosclerotic process that remains relentlessly progressive. The probability of CVDs and HF phenotypes to reverse can be supported by the advances made on the medical holistic principle of systems biology (SB) and on artificial intelligence (AI). Studies on clinical phenotypes reversal should be based on the research performed in large populations of patients following gathering and analyzing large amounts of relative data that embrace the concept of complexity. To decipher the complexity conundrum, a multiomics approach is needed with network analysis of the biological data. Only by understanding the complexity of chronic heart diseases and explaining the interrelationship between different interconnected biological networks can the probability for clinical phenotypes reversal be increased.

Screening for Mitochondrial tRNA Mutations in 318 Patients with Dilated Cardiomyopathy

Objectives: Dilated cardiomyopathy (DCM) is a complex cardiovascular disease with unknown etiology. Although nuclear genes play active roles in DCM, mitochondrial dysfunction was believed to be involved in the pathogenesis of DCM. The objective of this study was to analyze the association between mitochondrial tRNA (mt-tRNA) mutations and DCM. Materials and Methods: We performed a mutational analysis of mt-tRNA genes in a cohort of 318 patients with DCM and 200 age- and gender-matched control subjects. To further assess their pathogenicity, phylogenetic analysis and mitochondrial functions including mtDNA copy number, ATP, and ROS were analyzed. Results: Seven possible pathogenic mutations, i.e., MT-TL1 3302A>G, MT-TI 4295A>G, MT-TM 4435A>G, MT-TA 5655T>C, MT-TH 12201T>C, MT-TE 14692A>G, and MT-TT 15927G>A, were identified in the DCM group but were absent in controls. These mutations occurred at extremely conserved nucleotides of corresponding tRNAs and led to the failure in tRNAs metabolism. Moreover, a significant reduction in ATP and mtDNA copy number and a marked increase in ROS level were observed in polymononuclear leukocytes (PMNs) derived from the DCM patients carrying these mt-tRNA mutations, suggesting that these mutations may cause mitochondrial dysfunction that was responsible for DCM. Conclusions: Our data indicated that mt-tRNA mutations may be the molecular basis for DCM, which provides novel insights into the pathophysiology of DCM that manifested as mitochondrial dysfunction.

Probiotici i prebiotici kod arterijske hipertenzije

There is growing evidence that a disturbed microbiota, a complex ecosystem, is associated with the development of numerous diseases, including arterial hypertension. This complex cardiovascular disease is the result of not sufficiently clear role that genetic and environmental factors play in it. Not only does the treatment of hypertension include a drug therapy, but also it includes a variety of non-pharmacological measures based on dietary intervention. Probiotics and prebiotics are besides the nutrition the most commonly used substances that are aimed at maintaining a healthy microbiome or restoring the balance in case of disturbed bacterial homeostasis in disease. Although many studies have confirmed the effects of an imbalance in the gut microbiota (dysbiosis) in the last decade, the benefits of dietary intervention with probiotics in people with hypertension need to be supported by stronger evidence and further clinical trials in order to be ultimately confirmed.

Применение оригинального L-орнитина-L-аспартата у больных с комплексной кардиоваскулярной патологией и сахарным диабетом 2-го типа

Статья посвящена вопросам лечения неалкогольной жировой болезни печени как осложнения у пациентов с комплексной кардиоваскулярной патологией и сахарным диабетом 2-го типа. Приведены данные исследования влияния препарата Гепа-Мерц® на функциональное состояние печени, эндотелия, реологические свойства крови, состояние капиллярного кровотока, маркеры эндотоксикоза и клиническое состояние у данной категории пациентов. Полученные результаты подтверждают возможность влияния препарата Гепа-Мерц® на функциональные нарушения работы печени у пациентов с комплексной кардиоваскулярной патологией и сахарным диабетом 2-го типа.

AFM investigation of APAC (antiplatelet and anticoagulant heparin proteoglycan)

Antiplatelet and anticoagulant drugs are classified antithrombotic agents with the purpose to reduce blood clot formation. For a successful treatment of many known complex cardiovascular diseases driven by platelet and/or coagulation activity, the need of more than one antithrombotic agent is inevitable. However, combining drugs with different mechanisms of action enhances risk of bleeding. Dual anticoagulant and antiplatelet (APAC), a novel semisynthetic antithrombotic molecule, provides both anticoagulant and antiplatelet properties in preclinical studies. APAC is entering clinical studies with this new exciting approach to manage cardiovascular diseases. For a better understanding of the biological function of APAC, comprehensive knowledge of its structure is essential. In this study, atomic force microscopy (AFM) was used to characterize APAC according to its structure and to investigate the molecular interaction of APAC with von Willebrand factor (VWF), since specific binding of APAC to VWF could reduce platelet accumulation at vascular injury sites. By the optimization of drop-casting experiments, we were able to determine the volume of an individual APAC molecule at around 600 nm3, and confirm that APAC forms multimers, especially dimers and trimers under the experimental conditions. By studying the drop-casting behavior of APAC and VWF individually, we depictured their interaction by using an indirect approach. Moreover, in vitro and in vivo conducted experiments in pigs supported the AFM results further. Finally, the successful adsorption of APAC to a flat gold surface was confirmed by using photothermal-induced resonance, whereby attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) served as a reference method.Graphical abstract

3D Printing-A Cutting Edge Technology for Treating Post-Infarction Patients.

The increasing complexity of cardiovascular interventions requires advanced peri-procedural imaging and tailored treatment. Three-dimensional printing technology represents one of the most significant advances in the field of cardiac imaging, interventional cardiology or cardiovascular surgery. Patient-specific models may provide substantial information on intervention planning in complex cardiovascular diseases, and volumetric medical imaging from CT or MRI can be translated into patient-specific 3D models using advanced post-processing applications. 3D printing and additive manufacturing have a great variety of clinical applications targeting anatomy, implants and devices, assisting optimal interventional treatment and post-interventional evaluation. Although the 3D printing technology still lacks scientific evidence, its benefits have been shown in structural heart diseases as well as for treatment of complex arrhythmias and corrective surgery interventions. Recent development has enabled transformation of conventional 3D printing into complex 3D functional living tissues contributing to regenerative medicine through engineered bionic materials such hydrogels, cell suspensions or matrix components. This review aims to present the most recent clinical applications of 3D printing in cardiovascular medicine, highlighting also the potential for future development of this revolutionary technology in the medical field.

A 3D Bioprinted In Vitro Model of Pulmonary Artery Atresia to Evaluate Endothelial Cell Response to Microenvironment.

Vascular atresia are often treated via transcatheter recanalization or surgical vascular anastomosis due to congenital malformations or coronary occlusions. The cellular response to vascular anastomosis or recanalization is, however, largely unknown and current techniques rely on restoration rather than optimization of flow into the atretic arteries. An improved understanding of cellular response post anastomosis may result in reduced restenosis. Here, an in vitro platform is used to model anastomosis in pulmonary arteries (PAs) and for procedural planning to reduce vascular restenosis. Bifurcated PAs are bioprinted within 3D hydrogel constructs to simulate a reestablished intervascular connection. The PA models are seeded with human endothelial cells and perfused at physiological flow rate to form endothelium. Particle image velocimetry and computational fluid dynamics modeling show close agreement in quantifying flow velocity and wall shear stress within the bioprinted arteries. These data are used to identify regions with greatest levels of shear stress alterations, prone to stenosis. Vascular geometry and flow hemodynamics significantly affect endothelial cell viability, proliferation, alignment, microcapillary formation, and metabolic bioprofiles. These integrated in vitro-in silico methods establish a unique platform to study complex cardiovascular diseases and can lead to direct clinical improvements in surgical planning for diseases of disturbed flow.