CAR T therapy beyond cancer: the evolution of a living drug.

Engineering a patient's own T cells to selectively target and eliminate tumour cells has cured patients with untreatable haematologic cancers. These results have energized the field to apply chimaeric antigen receptor (CAR) T therapy throughout oncology. However, evidence from clinical and preclinical studies underscores the potential of CAR T therapy beyond oncology in treating autoimmunity, chronic infections, cardiac fibrosis, senescence-associated disease and other conditions. Concurrently, the deployment of new technologies and platforms provides further opportunity for the application of CAR T therapy to noncancerous pathologies. Here we review the rationale behind CAR T therapy, current challenges faced in oncology, a synopsis of preliminary reports in noncancerous diseases, and a discussion of relevant emerging technologies. We examine potential applications for this therapy in a wide range of contexts. Last, we highlight concerns regarding specificity and safety and outline the path forward for CAR T therapy beyond cancer.

The Emerging Field of Cardioimmunology: Past, Present and Foreseeable Future.

Over the past 30 years, the field of cardioimmunology has moved from being dismissed as a field that was chasing an epiphenomenon of little biological consequence to a scientific discipline that is providing important new insights into the immunologic basis for hypertension, atherosclerosis, myocarditis, pericarditis, autoimmune heart disease, and heart failure. In this article, we will review the conceptual insights and technical breakthroughs that have allowed the field to move forward, as well as the clinical trials in the cardioimmunology space, to provide a historical context for the articles that will appear in the compendium that is focused on the interface between cardioimmunology, myocardial function, and disease.

Modeling Heart Diseases on a Chip: Advantages and Future Opportunities.

Heart disease is a significant burden on global health care systems and is a leading cause of death each year. To improve our understanding of heart disease, high quality disease models are needed. These will facilitate the discovery and development of new treatments for heart disease. Traditionally, researchers have relied on 2D monolayer systems or animal models of heart disease to elucidate pathophysiology and drug responses. Heart-on-a-chip (HOC) technology is an emerging field where cardiomyocytes among other cell types in the heart can be used to generate functional, beating cardiac microtissues that recapitulate many features of the human heart. HOC models are showing great promise as disease modeling platforms and are poised to serve as important tools in the drug development pipeline. By leveraging advances in human pluripotent stem cell-derived cardiomyocyte biology and microfabrication technology, diseased HOCs are highly tuneable and can be generated via different approaches such as: using cells with defined genetic backgrounds (patient-derived cells), adding small molecules, modifying the cells' environment, altering cell ratio/composition of microtissues, among others. HOCs have been used to faithfully model aspects of arrhythmia, fibrosis, infection, cardiomyopathies, and ischemia, to name a few. In this review, we highlight recent advances in disease modeling using HOC systems, describing instances where these models outperformed other models in terms of reproducing disease phenotypes and/or led to drug development.

Role of the Lymphatics in Cardiac Disease.

Cardiovascular diseases remain the largest cause of death worldwide with recent evidence increasingly attributing the development and progression of these diseases to an exacerbated inflammatory response. As a result, significant research is now focused on modifying the immune environment to prevent the disease progression. This in turn has highlighted the lymphatic system in the pathophysiology of cardiovascular diseases owing, in part, to its established function in immune cell surveillance and trafficking. In this review, we highlight the role of the cardiac lymphatic system and its potential as an immunomodulatory therapeutic target in selected cardiovascular diseases.

In vivo reprogramming as a new approach to cardiac regenerative therapy.

Cardiovascular diseases are a common cause of death worldwide. Adult cardiomyocytes have limited regenerative capacity after injury, and there is growing interest in cardiac regeneration as a new therapeutic strategy. There are several limitations of induced pluripotent stem cell-based transplantation therapy with respect to efficiency and risks of tumorigenesis. Direct reprogramming enables the conversion of terminally differentiated cells into target cell types using defined factors. In most cardiac diseases, activated fibroblasts proliferate in the damaged heart and contribute to the progression of heart failure. In vivo cardiac reprogramming, in which resident cardiac fibroblasts are converted into cardiomyocytes in situ, is expected to become a new cardiac regenerative therapy. Indeed, we and other groups have demonstrated that in vivo reprogramming improves cardiac function and reduces fibrosis after myocardial infarction. In this review, we summarize recent discoveries and developments related to in vivo reprogramming. In addition, issues that need to be resolved for clinical application are described.

Anesthetic Care of the Pregnant Patient With Cardiovascular Disease: A Scientific Statement From the American Heart Association.

The pregnancy-related mortality rate in the United States is excessively high. The American Heart Association is dedicated to fighting heart disease and recognizes that cardiovascular disease, preexisting or acquired during pregnancy, is the leading cause of maternal mortality in the United States. Comprehensive scientific statements from cardiology and obstetrics experts guide the treatment of cardio-obstetric patients before, during, and after pregnancy. This scientific statement aims to highlight the role of specialized cardio-obstetric anesthesiology care, presenting a systematic approach to the care of these patients from the anesthesiology perspective. The anesthesiologist is a critical part of the pregnancy heart team as the perioperative physician who is trained to prevent or promptly recognize and treat patients with peripartum cardiovascular decompensation. Maternal morbidity is attenuated with expert anesthesiology peripartum care, which includes the management of neuraxial anesthesia, inotrope and vasopressor support, transthoracic echocardiography, optimization of delivery location, and consideration of advanced critical care and mechanical support when needed. Standardizing the anesthesiology approach to patients with high peripartum cardiovascular risk and ensuring that cardio-obstetrics patients have access to the appropriate care team, facilities, and advanced cardiovascular therapies will contribute to improving peripartum morbidity and mortality.

Mesenchymal stem cells arouse myocardial NAD+ metabolism to alleviate microgravity-induced cardiac dysfunction.

After prolonged space operations, astronauts showed maladaptive atrophy within mostly left-ventricular myocardium, resulting in cardiac dysfunction. However, the mechanism of cardiac dysfunction under microgravity conditions is unclear, and the relevant prevention and treatment measures also need to be explored. Through simulating the microgravity environment with a tail suspension (TS) model, we found that long-term exposure to microgravity promotes aging of mouse hearts, which is closely related to cardiac dysfunction. The intravenous administration of adipose-derived mesenchymal stem cells (ADSCs) emerged preventive and therapeutic effect against myocardial senescence and the decline in cardiac function. Plasma metabolomics analysis suggests the loss of NAD+ in TS mice and motivated myocardial NAD + metabolism and utilization in ADSCs-treated mice, likely accounting for ADSCs' function. Oral administration of nicotinamide mononucleotide (NMN, a NAD + precursor) showed similar therapeutic effect to ADSCs treatment. Collectively, these data implicate the effect of ADSCs in microgravity-induced cardiac dysfunction and provide new therapeutic ideas for aging-related maladaptive cardiac remodeling.

The development of inherited cardiac conditions services: current position and future perspectives.

BACKGROUND: Over the last two decades, inherited cardiac conditions (ICC) centres have emerged with the aim of improving outcomes for patients and their families, through early diagnosis, genetic testing, risk assessment and specialist treatment. SOURCES OF DATA: A literature search was performed using PubMed (https://pubmed.ncbi.nlm.nih.gov/). Commissioned ICC service reviews from NHS England, NHS Improvement and PHG Foundation were evaluated. AREAS OF AGREEMENT: ICC patient management requires a multi-disciplinary approach. ICC services are predominantly based within tertiary centres. Despite expansion, provision of care remains inadequate to meet rising demands. Access to services is inconsistent, partly due to geographic variation and lack of standardized pathways. AREAS OF CONTROVERSY: The optimal ICC care model remains undecided, although there is growing interest in 'hub-and-spoke' networks, which could aid secondary and tertiary service integration and repatriation of care. GROWING POINTS: Genetic mainstreaming is a priority for the Genomic Medicine Service Alliance. The benefits of telehealth and virtual clinics have been validated by their use during the COVID-19 pandemic. Other innovations to improve resource efficiency, such as clinical scientist-led and nurse-led clinics, show promise. AREAS TIMELY FOR DEVELOPING RESEARCH: An update for the NHS ICC service specifications is planned that appears well timed given the rapid evolution of the ICC landscape in the decade since last review. This has the potential to address needs including national audit, standardized pathways and ICC networks to improve governance and equity of care. Delegation of commissioning for specialist services to integrated care systems may also provide opportunity for increased regional direction.

Zebrafish Models of Cardiac Disease: From Fortuitous Mutants to Precision Medicine.

Heart disease is the leading cause of death worldwide. Despite decades of research, most heart pathologies have limited treatments, and often the only curative approach is heart transplantation. Thus, there is an urgent need to develop new therapeutic approaches for treating cardiac diseases. Animal models that reproduce the human pathophysiology are essential to uncovering the biology of diseases and discovering therapies. Traditionally, mammals have been used as models of cardiac disease, but the cost of generating and maintaining new models is exorbitant, and the studies have very low throughput. In the last decade, the zebrafish has emerged as a tractable model for cardiac diseases, owing to several characteristics that made this animal popular among developmental biologists. Zebrafish fertilization and development are external; embryos can be obtained in high numbers, are cheap and easy to maintain, and can be manipulated to create new genetic models. Moreover, zebrafish exhibit an exceptional ability to regenerate their heart after injury. This review summarizes 25 years of research using the zebrafish to study the heart, from the classical forward screenings to the contemporary methods to model mutations found in patients with cardiac disease. We discuss the advantages and limitations of this model organism and introduce the experimental approaches exploited in zebrafish, including forward and reverse genetics and chemical screenings. Last, we review the models used to induce cardiac injury and essential ideas derived from studying natural regeneration. Studies using zebrafish have the potential to accelerate the discovery of new strategies to treat cardiac diseases.

Enteral Access Outcomes in Patients Hospitalized With Cardiac Disease: A Retrospective Cohort Study.

INTRODUCTION: Patients admitted with principal cardiac diagnosis (PCD) can encounter difficult inpatient stays that are often marked by malnutrition. In this setting, enteral feeding may improve nutritional status. This study examined the association of PCD with perioperative outcomes after elective enteral access procedures. METHODS: Adult patients who underwent enteral access procedures between 2018 and 2020 at a tertiary care institution were reviewed retrospectively. Differences in baseline characteristics between patients with and without PCD were adjusted using entropy balancing. Multivariable logistic and linear regressions were subsequently developed to evaluate the association between PCD and nutritional outcomes, perioperative morbidity and mortality, length of stay, and nonelective readmission after enteral access. RESULTS: 912 patients with enteral access met inclusion criteria, of whom 84 (9.2%) had a diagnosis code indicating PCD. Compared to non-PCD, patients with PCD more commonly received percutaneous endoscopic gastrostomy by general surgery and had a higher burden of comorbidities as measured by the Charlson comorbidity index. Multivariable risk adjustment generated a strongly balanced distribution of baseline covariates between patient groups (standardized differences ranged from -2.45 × 10-8 to 3.18 × 108). After adjustment, despite no significant association with in-hospital mortality, percentage change prealbumin, length of stay, or readmission, PCD was associated with an approximately 2.25-day reduction in time to meet goal feeds (95% CI -3.76 to -0.74, P = 0.004) as well as decreased odds of reoperation (adjusted odds ratio 0.28, 95% CI 0.09-0.86, P = 0.026) and acute kidney injury (adjusted odds ratio 0.24, 95% CI 0.06-0.91, P = 0.035). CONCLUSIONS: Despite having more comorbidities than non-PCD, adult enteral access patients with PCD experienced favorable nutritional and perioperative outcomes.

SCMR expert consensus statement for cardiovascular magnetic resonance of patients with a cardiac implantable electronic device.

Cardiovascular magnetic resonance (CMR) is a proven imaging modality for informing diagnosis and prognosis, guiding therapeutic decisions, and risk stratifying surgical intervention. Patients with a cardiac implantable electronic device (CIED) would be expected to derive particular benefit from CMR given high prevalence of cardiomyopathy and arrhythmia. While several guidelines have been published over the last 16 years, it is important to recognize that both the CIED and CMR technologies, as well as our knowledge in MR safety, have evolved rapidly during that period. Given increasing utilization of CIED over the past decades, there is an unmet need to establish a consensus statement that integrates latest evidence concerning MR safety and CIED and CMR technologies. While experienced centers currently perform CMR in CIED patients, broad availability of CMR in this population is lacking, partially due to limited availability of resources for programming devices and appropriate monitoring, but also related to knowledge gaps regarding the risk-benefit ratio of CMR in this growing population. To address the knowledge gaps, this SCMR Expert Consensus Statement integrates consensus guidelines, primary data, and opinions from experts across disparate fields towards the shared goal of informing evidenced-based decision-making regarding the risk-benefit ratio of CMR for patients with CIEDs.

Stem cell therapy for cardiac regeneration: past, present, and future.

Cardiac disorders remain the leading cause of mortality worldwide. Current clinical strategies, including drug therapy, surgical interventions, and organ transplantation offer limited benefits to patients without regenerating the damaged myocardium. Over the past decade, stem cell therapy has generated a keen interest owing to its unique self-renewal and immune privileged characteristics. Furthermore, the ability of stem cells to differentiate into specialized cell types, has made them a popular therapeutic tool against various diseases. This comprehensive review provides an overview of therapeutic potential of different types of stem cells in reference to cardiovascular diseases. Furthermore, it sheds light on the advantages and limitations associated with each cell type. An in-depth analysis of the challenges associated with stem cell research and the hurdles for its clinical translation and their possible solutions have also been elaborated upon. It examines the controversies surrounding embryonic stem cells and the emergence of alternative approaches, such as the use of induced pluripotent stem cells for cardiac therapeutic applications. Overall, this review serves as a valuable resource for researchers, clinicians, and policymakers involved in the field of regenerative medicine, guiding the development of safe and effective stem cell-based therapies to revolutionize patient care.

Psychological interventions targeting mental health and stress among females with cardiac disease: a scoping review.

Interventions that target mental health symptoms and stress among those with established cardiac disease have included predominately male samples despite female patients reporting greater severity of these symptoms. The aim of this scoping review was to synthesize the published literature on psychological interventions for females with cardiac disease. We conducted a systematic search of peer-reviewed randomized clinical trials (RCTs) published in the English language from 2003 to 2023, in three databases: Medline (Ovid), PsycInfo (Ovid), and CINAHL (EBSCO). Articles that included female samples, a control or comparison group, implemented psychological interventions, and measured depression, anxiety, or stress as an outcome were included in the review. Nine articles describing eight RCTs of psychological interventions, with a total of 1587 female patients with cardiac disease, were included. Interventions were most successful at reducing stress (75% of studies measuring stress reported efficacy), while symptoms of depression and anxiety were less responsive to intervention (∼30% of studies targeting these symptoms reported improvements) in comparison to a control condition. This scoping review highlights that further advancement in knowledge is required to better address the needs of females with cardiac disease and distress, particularly depression and anxiety.

Survival With Favorable Neurologic Outcome and Quality of Cardiopulmonary Resuscitation Following In-Hospital Cardiac Arrest in Children With Cardiac Disease Compared With Noncardiac Disease.

OBJECTIVES: To assess associations between outcome and cardiopulmonary resuscitation (CPR) quality for in-hospital cardiac arrest (IHCA) in children with medical cardiac, surgical cardiac, or noncardiac disease. DESIGN: Secondary analysis of a multicenter cluster randomized trial, the ICU-RESUScitation Project (NCT02837497, 2016-2021). SETTING: Eighteen PICUs. PATIENTS: Children less than or equal to 18 years old and greater than or equal to 37 weeks postconceptual age receiving chest compressions (CC) of any duration during the study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1,100 children with IHCA, there were 273 medical cardiac (25%), 383 surgical cardiac (35%), and 444 noncardiac (40%) cases. Favorable neurologic outcome was defined as no more than moderate disability or no worsening from baseline Pediatric Cerebral Performance Category at discharge. The medical cardiac group had lower odds of survival with favorable neurologic outcomes compared with the noncardiac group (48% vs 55%; adjusted odds ratio [aOR] [95% CI], aOR 0.59 [95% CI, 0.39-0.87], p = 0.008) and surgical cardiac group (48% vs 58%; aOR 0.64 [95% CI, 0.45-0.9], p = 0.01). We failed to identify a difference in favorable outcomes between surgical cardiac and noncardiac groups. We also failed to identify differences in CC rate, CC fraction, ventilation rate, intra-arrest average target diastolic or systolic blood pressure between medical cardiac versus noncardiac, and surgical cardiac versus noncardiac groups. The surgical cardiac group had lower odds of achieving target CC depth compared to the noncardiac group (OR 0.15 [95% CI, 0.02-0.52], p = 0.001). We failed to identify a difference in the percentage of patients achieving target CC depth when comparing medical cardiac versus noncardiac groups. CONCLUSIONS: In pediatric IHCA, medical cardiac patients had lower odds of survival with favorable neurologic outcomes compared with noncardiac and surgical cardiac patients. We failed to find differences in CPR quality between medical cardiac and noncardiac patients, but there were lower odds of achieving target CC depth in surgical cardiac compared to noncardiac patients.

Extracorporeal Cardiopulmonary Resuscitation Use Among Children With Cardiac Disease in the ICU: A Meta-Analysis and Meta-Regression of Data Through March 2024.

OBJECTIVE: Epidemiologic data on extracorporeal cardiopulmonary resuscitation (ECPR) use in children with cardiac disease after in-hospital cardiac arrest (IHCA) are lacking. We aimed to investigate trends in ECPR use over time in critically ill children with cardiac disease. DATA SOURCES: We performed a secondary analysis of a recent systematic review (PROSPERO CRD42020156247) to investigate trends in ECPR use in children with cardiac disease. PubMed, Web of Science, Embase, and Cumulative Index to Nursing and Allied Health Literature were screened (inception to September 2021). For completeness of this secondary analysis, PubMed was also rescreened (September 2021 to March 2024). STUDY SELECTION: Observational studies including epidemiologic data on ECPR use in children with cardiac disease admitted to an ICU. DATA EXTRACTION: Data were extracted by two independent investigators. The risk of bias was assessed using the National Heart Lung and Blood Institutes Quality Assessment Tools. Random-effects meta-analysis was used to compute a pooled proportion of subjects undergoing ECPR; meta-regression was used to assess trends in ECPR use over time. DATA SYNTHESIS: Of the 2664 studies identified, 9 (17,669 patients) included data on ECPR use in children with cardiac disease. Eight were cohort studies, 1 was a case-control, 8 were retrospective, 1 was prospective, 6 were single-center, and 3 were multicenter. Seven studies were included in the meta-analysis; all were judged of good quality. By meta-analysis, we found that a pooled proportion of 21% (95% CI, 15-29%) of pediatric patients with cardiac disease experiencing IHCA were supported with ECPR. By meta-regression adjusted for category of patients (surgical vs. general cardiac), we found that the use of ECPR in critically ill children with cardiac disease significantly increased over time ( p = 0 .026). CONCLUSIONS: About one-fifth of critically ill pediatric cardiac patients experiencing IHCA were supported with ECPR, and its use significantly increased over time. This may partially explain the increased trends in survival demonstrated for this population.

Young Spouses' Experiences of Having a Partner With Heart Disease and Adolescents Living at Home.

AIM: To describe the life situation of spouses having a partner with heart disease and adolescents living at home. DESIGN: Qualitative inductive design. METHOD: Participants (n = 22) were included from three Scandinavian countries. Semi-structured interviews were analysed using thematic analysis with an inductive and latent approach. RESULTS: Three themes were derived. 'Being in spousal and parental role transition' described how daily life had been affected and parental responsibilities had been doubled due to their partner's heart disease. 'Living with unpredictability and insecurity' included how the unpredictable illness trajectory caused worries and affected the well-being of the family. 'Managing a challenging life situation' highlights how spouses coped with their partners' heart disease and adapted to a new life situation. CONCLUSION: Young spouses' life situation was greatly affected by their partner's heart disease, resulting in increased responsibilities and double parenthood. Having a positive attitude and mindset towards life was used as a strategy to cope with the changed life situation and find a new way of life. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: All family members are affected by heart disease. Spouses needed additional professional support and guidance on how to involve the children when a parent is ill. IMPACTS: This study highlights how young spouses, with adolescents living at home, experience their life situation. The life situation is unpredictable due to the partner's heart disease, as they must handle both caring for their partner and taking on double parenthood. Research involving family members can improve person- and family-centred care and treatment outcomes in health care and society. REPORTING METHOD: COREQ checklist was used preparing the manuscript. PATIENT OR PUBLIC CONTRIBUTION: Data collection included interviews with spouse. WHAT DOES THIS PAPER CONTRIBUTE TO THE WIDER GLOBAL CLINICAL COMMUNITY?: By highlighting the spouses changed life situation due to heart disease and the importance of including them in health care.

Age-Related Quality of Life in Cardiac Surgical Patients with Extracorporeal Life Support.

BACKGROUND: The rationale of the study was to analyze the impact of age on quality of life (QoL) in patients who had undergone cardiac surgery with consecutive extracorporeal life support (ECLS) treatment. METHODS: The study population consisted of 200 patients, operated upon between August 2006 and December 2018. The patient cohort was divided into two groups following an arbitrary cutoff age of 70 years. Comparative outcome analysis was calculated utilizing the European Quality of Life-5-Dimensions-5-Level Version (EQ-5D-5L). RESULTS: A total of 113 patients were 70 years or less old (group young), whereas 87 patients were older than 70 years (group old). In 45.7% of cases, the ECLS system was established during cardiogenic shock and external cardiac massage. The overall survival-to-discharge was 31.5% (n = 63), with a significantly better survival in the younger patient group (young = 38.9%; old = 21.8%, p = 0.01). Forty-two patients (66%) responded to the QoL survey after a median follow-up of 4.3 years. Older patients reported more problems with mobility (y = 52%; o = 88%, p = 0.02) and self-care (y = 24%; o = 76%, p = 0.01). However, the patients' self-rated health status utilizing the Visual Analogue Scale revealed no differences (y = 70% [50-80%]; o = 70% [60-80%], p = 0.38). Likewise, the comparison with an age-adjusted German reference population revealed similar QoL indices. There were no statistically significant differences in the EQ-5D-5L index values related to sex, number of comorbidities, and emergency procedures. CONCLUSION: Despite the limited sample size due to the high mortality rate especially in elderly, the present study suggests that QoL of elderly patients surviving ECLS treatment is almost comparable to younger patients.

Cardiac disease-induced trauma and stress-related disorders.

OBJECTIVE: This review aims to present an updated overview of cardiac disease-induced trauma and stress-related disorders such as acute stress disorder (ASD), adjustment disorder (AjD), and posttraumatic stress disorder (PTSD). First, the prevalence of these disorders, their diagnostic criteria, and their differences from other trauma-related disorders are described. Special challenges in diagnosis and treatment are identified, with various screening tools being evaluated for symptom assessment. Additionally, the risk factors studied so far for the development of symptoms of cardiac-induced posttraumatic stress disorder and the bidirectional relationship between posttraumatic stress disorder and cardiovascular diseases are summarized. Various therapeutic interventions, including pharmacological approaches, are also discussed. Finally, various areas for future research are outlined. BACKGROUND: Experiencing a cardiovascular disease, particularly a life-threatening cardiac event, can potentially lead to stress-related disorders such as ASD, AjD, and cardiac disease-induced PTSD (CDI-PTSD). If left untreated, these disorders are associated with a worsening cardiac prognosis and higher mortality rates. Approaching treatment through a trauma-focused lens may be beneficial for managing CDI-PTSD and stress-related disorders. CONCLUSION: Future research should explore treatment options for both the patients and the caregivers as well as investigate the long-term effects of trauma-focused interventions on physical and mental health outcomes.

Current Research for Heart Disease Biology and Therapeutics.

Cardiac and vascular diseases are the leading cause of death globally [...].

The Relevance of the Endothelium in Cardiopulmonary Disorders.

The endothelium is a cell monolayer that lines vessels and separates tissues from blood flow. Endothelial cells (ECs) have a multitude of functions, including regulating blood flow and systemic perfusion through changes in vessel diameter. When an injury occurs, the endothelium is affected by altering its functions and structure, which leads to endothelial dysfunction, a characteristic of many vascular diseases. Understanding the role that the endothelium plays in pulmonary vascular and cardiopulmonary diseases, and exploring new therapeutic strategies is of utmost importance to advance clinically. Currently, there are several treatments able to improve patients' quality of life, however, none are effective nor curative. This review examines the critical role of the endothelium in the pulmonary vasculature, investigating the alterations that occur in ECs and their consequences for blood vessels and potential molecular targets to regulate its alterations. Additionally, we delve into promising non-pharmacological therapeutic strategies, such as exercise and diet. The significance of the endothelium in cardiopulmonary disorders is increasingly being recognized, making ECs a relevant target for novel therapies aimed at preserving their functional and structural integrity.