Patient-Specific Modeling of Hemodynamics: Supporting Surgical Planning in a Fontan Circulation Correction

Computational fluid dynamics (CFD) is a modeling technique that enables calculation of the behavior of fluid flows in complex geometries. In cardiovascular medicine, CFD methods are being used to calculate patient-specific hemodynamics for a variety of applications, such as disease research, noninvasive diagnostics, medical device evaluation, and surgical planning. This paper provides a concise overview of the methods to perform patient-specific computational analyses using clinical data, followed by a case study where CFD-supported surgical planning is presented in a patient with Fontan circulation complicated by unilateral pulmonary arteriovenous malformations. In closing, the challenges for implementation and adoption of CFD modeling in clinical practice are discussed.     

Exercise Training for People Living With Fontan Circulation: An Underutilized Intervention

Surgical repair for children born with single-ventricle congenital heart disease, culminating in the Fontan operation, has resulted in dramatic improvements in survival; children born with these lesions are now typically expected to survive well into adulthood. Most, but not all, patients with Fontan circulation have reduced exercise capacity compared with the general population that, in turn, is associated with increased cardiovascular morbidity and mortality. The cause of reduced exercise capacity is multifactorial. A significant contributor is the absence of a subpulmonary ventricular pump, which limits preload and appropriate cardiac output augmentation to meet the increased metabolic demands that occur with exercise. Although in its infancy relative to adults with acquired heart disease, the evidence to date suggests that exercise interventions to improve exercise capacity and Fontan physiology in children and adults with Fontan circulation are safe, effective, and well tolerated. However, many knowledge gaps remain, including a detailed understanding of the unique physiological adaptations that occur, the optimal approach to exercise in this population, and the effectiveness of home-based interventions using telemedicine and remote physiological monitoring technologies. Furthermore, the long-term impact of such interventions on the Fontan-cardiovascular system, physical activity levels, health-related quality of life, and late cardiovascular morbidity and mortality are not well characterized. In this review, we outline the factors associated with reduced exercise capacity in persons with Fontan circulation, review the experience to date of dedicated interventions to improve exercise capacity, and highlight the current knowledge gaps in the field and priorities for further study.     

The Safety and Effects of Bosentan in Patients with a Fontan Circulation

Objective. Adult patients with a Fontan circulation tend to have diminished exercise capacity. The principal objective of this study was to investigate the safety of the endothelin receptor antagonist bosentan in Fontan patients, and, secondarily, to assess effects on cardiovascular performance, New York Heart Association functional classification (NYHA FC), and ventricular function. Design. A 6‐month prospective, single‐center, pilot, safety study of bosentan in Fontan patients. Setting. Adult Congenital Heart Disease referral center. Patients. All patients ≥18 years old with a Fontan circulation and in NYHA FC ≥II were invited to enroll. Interventions. Patients started on 62.5 mg bid of bosentan, uptitrating to 125 mg bid after 2 weeks. Outcome Measures. Safety was assessed by the incidence of anticipated and unanticipated adverse events during the 6‐month study period; specifically those relating to hepatic, renal, or hematological dysfunction as measured by monthly blood tests. Other outcome measures included cardiopulmonary exercise test, 6‐minute walk distance test, Borg dyspnea index, NYHA FC, and ventricular function parameters using transthoracic echocardiography. Results. Of the eight patients enrolled, six completed the study. Two patients withdrew from the study (one for non–trial related reasons, one due to adverse events). No clinically significant adverse events relating to bosentan therapy occurred during this study and, in particular, no significant abnormalities in hepatic function tests were observed. Three patients reported transient adverse events. Improvements in NYHA FC and systolic ventricular function were observed after 6 months of bosentan treatment. Conclusions. The small number of patients with a Fontan circulation in our study was able to tolerate bosentan for 6 months. The safety and tolerability of bosentan in a larger patient population remains unknown. The results presented here justify further investigation in larger studies.     

The Need for Combination Drug Therapies in Patients with Complex Dyslipidemia

The accurate quantification of mitral regurgitation (MR) using 2D imaging tools is difficult due to its structural complexity; however, it is crucially important in clinical medicine as MR severity has prognostic consequences. Novel 3-dimensional (3D) echocardiography and 3-dimensional (3D) color Doppler methods can provide quantitative and qualitative classification of MR including measurement of the vena contracta area, regurgitant volume, regurgitant fraction, and effective regurgitant orifice area (EROA). Nevertheless, with so many conventional and developing techniques it can be difficult to decide which technique to use for selected patients. We suggest using an approach that is focused not only on the techniques and measurements but also combines imaging portability, availability, clinical efficiency, and accurate and reproducible assessments. In this review we discuss the established and emerging applications of 3D color Doppler for the quantification of MR severity.     

Plastic Bronchitis and Protein-Losing Enteropathy in the Fontan Patient: Evolving Understanding and Emerging Therapies

Plastic bronchitis (PB) and protein-losing enteropathy (PLE) are rare but potentially devastating complications of the Fontan circulation. PB occurs in ～4% of Fontan patients, typically presents within 2 to 3 years of Fontan completion with chronic cough, wheezing, fever, or acute asphyxiation, and is characterised by proteinaceous airway casts that are expectorated or found on bronchoscopy. PLE develops in 4% to 13% of patients, usually within 5 to 10 years post Fontan, and manifests with edema, ascites, hypoalbuminemia, lymphopenia, hypogammaglobulinemia, and elevated fecal alpha-1 antitrypsin 1. These disorders have similar pathophysiology involving disruption of the lymphatic system resulting from elevated central venous pressure combined with elevated lymphatic production and inflammation, resulting in lymphatic drainage into low-pressure circuits such as the airways (PB) and duodenum (PLE). Our understanding of these disorders has greatly improved over the past decade as a result of advances in imaging of the lymphatic system through magnetic resonance lymphangiography and early success with lymphatic interventions including lymphatic embolisation, thoracic duct embolisation, and percutaneous thoracic duct decompression. Both PB and PLE require a multidisciplinary approach that addresses and optimises residual hemodynamic lesions through catheter-based intervention, lowers central venous pressure through medical therapy, minimises symptoms, and targets abnormal lymphatic perfusion when symptoms persist. This review summarises the pathophysiology of these disorders and the current evidence base regarding management, proposes treatment algorithms, and identifies future research opportunities. Key considerations regarding the development of a lymphatic intervention program are also highlighted.     

Heart Failure in Adult Congenital Heart Disease: From Advanced Therapies to End-of-Life Care

There is mounting recognition that some of the most urgent problems of adult congenital heart disease (ACHD) are the prevention, diagnosis, and management of heart failure (HF). Recent expert consensus and position statements not only emphasize a specific and pressing need to tackle HF in ACHD (ACHD-HF) but also highlight the difficulty of doing so given a current sparsity of data. Some of the challenges will be addressed by this review. The authors are from 3 different centres; each centre has an established subspeciality ACHD-HF clinic and is able to provide heart transplant, multiorgan transplant, and mechanical support for patients with ACHD. Appropriate care of this complex population requires multidisciplinary ACHD-HF teams evaluate all possible treatment options. The risks and benefits of nontransplant ACHD surgery, percutaneous structural and electrophysiological intervention, and ongoing conservative management must be considered alongside those of transplant strategies. In our approach, advanced care planning and palliative care coexist with the consideration of advanced therapies. An ethos of shared decision making, guided by the patient’s values and preferences, strengthens clinical care, but requires investment of time as well as skilled communication. In this review, we aim to offer practical real-world advice for managing these patients, supported by scientific data where it exists.     

Developing Therapies for Depression in Drug Dependence: Results of a Stage 1 Therapy Study

Objective: This Stage 1b controlled trial sought a preliminary test of the relative efficacy of Behavioral Therapy for Depression in Drug Dependence (BTDD) against a structured relaxation intervention (REL) for treating DSM-IV depressive disorders and substance abuse. Method: Thirty-eight methadone maintained opiate dependent participants, who met criteria for a DSM-IV depressive disorder, were randomized to one of two, 24-week treatment conditions (BTDD or REL). Results: Depression response, defined as at least a 50% reduction in Hamilton Depression Scale score from baseline to the end of study, was high and similar in both BTDD (61%) and REL (65%). Rates of drug use were low overall, both at baseline and at the end of study, and did not differ between treatment groups at study endpoint. Conclusions: The findings suggest that both behavioral- and relaxation-based approaches show promise for treating comorbid depression in drug dependent populations. Future work should examine combining or modifying these interventions to target substance use more directly and include values based methods for increasing more adaptive behavioral patterns.     

Contemporary Provider Management Practices and Attitudes Toward Referral for Advanced Heart Failure Therapies in Fontan Patients Across North America

Background: To date, no reports have described clinicians’ management practices for patients with Fontan circulatory failure or their understanding of risk factors for mortality and transplant outcomes in these patients.Methods and Results: A cross-sectional survey of caregivers across North America was conducted from February to September 2020. Responses were compared by primary specialty (heart failure/transplant vs non-heart failure/transplant), years of experience (early, mid, and late career), and Fontan center volume (low, medium, and high). Of 400 responses, the majority were from general cardiologists (111, 28%) followed by heart failure/transplant specialists (93, 23%). Although most agreed that patients with Fontan physiology will have signs/symptoms of heart failure (369 [93%]) and eventuate in heart transplant (286 [72%]), many disagreed (180 [45%]) that routine evaluation by a transplant cardiologist is needed without symptoms. Transplant providers were more likely than non-transplant providers to suggest referral for manifestations of Fontan circulatory failure such as protein-losing enteropathy, plastic bronchitis, liver fibrosis/cirrhosis, and worsening valve regurgitation. Non-transplant providers were more likely to suggest that protein-losing enteropathy, plastic bronchitis, and Fontan-associated liver disease lead to inferior outcomes after transplantation. Early career and transplant providers more favorably viewed ventricular assist device use for Fontan patients failing traditional heart failure therapy (P < .05 for all).Conclusions: There is significant variation in the management of Fontan patients, including heterogeneous timing of referral of such patients to the heart failure/transplant team, which may have implications for future outcomes.     

Carbon Nanotubes: Current Perspectives on Diverse Applications in Targeted Drug Delivery and Therapies

Current discoveries as well as research findings on various types of carbon nanostructures have inspired research into their utilization in a number of fields. These carbon nanostructures offer uses in pharmacy, medicine and different therapies. One such unique carbon nanostructure includes carbon nanotubes (CNTs), which are one-dimensional allotropes of carbon nanostructure that can have a length-to-diameter ratio greater than 1,000,000. After their discovery, CNTs have drawn extensive research attention due to their excellent material properties. Their physical, chemical and electronic properties are excellent and their composites provide great possibilities for enormous nanometer applications. The current study provides a systematic review based on prior literature review and data gathered from various sources. The various research studies from many research labs and organizations were systematically retrieved, collected, compiled and written. The entire collection and compilation of this review concluded the use of CNT approaches and their efficacy and safety for the treatment of various diseases such as brain tumors or cancer via nanotechnology-based drug delivery, phototherapy, gene therapy, antiviral therapy, antifungal therapy, antibacterial therapy and other biomedical applications. The current review covers diverse applications of CNTs in designing a range of targeted drug delivery systems and application for various therapies. It concludes with a discussion on how CNTs based medicines can expand in the future.