Understanding the next circulation: lymphatics and what the future holds.

PURPOSE OF REVIEW: The lymphatic system was previously considered the forgotten circulation because of an absence of adequate options for imaging and intervention. However, recent advances over the last decade have improved management strategies for patients with lymphatic disease, including chylothorax, plastic bronchitis, ascites, and protein-losing enteropathy. RECENT FINDINGS: New imaging modalities have enabled detailed visualization of lymphatic vessels to allow for a better understanding of the cause of lymphatic dysfunction in a variety of patient subsets. This sparked the development of multiple transcatheter and surgery-based techniques tailored to each patient based on imaging findings. In addition, the new field of precision lymphology has added medical management options for patients with genetic syndromes, who have global lymphatic dysfunction and typically do not respond as well to the more standard lymphatic interventions. SUMMARY: Recent developments in lymphatic imaging have given insight into disease processes and changed the way patients are managed. Medical management has been enhanced and new procedures have given patients more options, leading to better long-term results.

Large aneurysms and pseudoaneurysms of surgically reconstructed right ventricular outflow tracts.

Aneurysm and pseudoaneurysm development is a known, albeit uncommon, complication after right ventricular outflow tract surgical reconstruction. Large right ventricular outflow tract aneurysms and pseudoaneurysms have not been extensively described in recent literature and we report our experience with this unusual complication in five patients at our institution over the last 8 years. Although uncommon, this complication has potentially important clinical implications. Thus, clinicians should be aware of its potential, particularly in certain anatomic conditions.

Incidence and fate of device-related left pulmonary artery stenosis and aortic coarctation in small infants undergoing transcatheter patent ductus arteriosus closure.

OBJECTIVES: To evaluate short- and middle-term outcomes after transcatheter patent ductus arteriosus (TC-PDA) closure in small infants, specifically device-related left pulmonary artery (LPA) stenosis and aortic coarctation, risk factors, and changes over time. BACKGROUND: Recent studies have demonstrated successful transcatheter PDA (TC-PDA) closure in small infants. LPA stenosis and aortic coarctation have been seen after TC-PDA, but it is not clear whether device-related LPA/aortic obstruction persists. METHODS: A single-center retrospective study of infants ≤4 kg who underwent TC-PDA closure from February 1, 2007 to September 1, 2018 was performed, evaluating the incidence and risk factors for LPA stenosis and coarctation. RESULTS: Forty-four patients underwent successful TC-PDA with Amplatzer Vascular Plug II (AVPII; n = 30), Amplatzer Duct Occluder II-Additional Sizes (n = 10), Amplatzer Duct Occluder I (n = 3), and coil-filled AVPI (n = 1) devices, all via an antegrade approach. Median birthweight and procedural weight were 890 g (range: 490-3,250) and 2.8 kg (range: 1.2-4.0), respectively. Median follow-up was 0.7 years (range: 2 days-7 years). Thirty-eight patients had post-procedure echocardiograms assessing LPA/aortic obstruction. Of those, 17 had LPA flow acceleration/stenosis (≥1.5 m/s), which improved or resolved in all patients with available follow-up; 3 developed mild coarctation (>2 m/s), which improved in the two with more than short-term follow-up; 4 developed mild flow acceleration (1.5-2 m/s) in the descending aorta, which resolved in three and increased in one (2.4 m/s). Flow acceleration in the LPA was associated with younger procedural age, larger PDA minimal diameter, and placement of a device other than the AVPII. There was no device-related mortality or need for reintervention. CONCLUSION: TC-PDA in small infants is effective, without significant complications. Device-related LPA/aortic obstruction can improve with time/growth.

Large Patent Ductus Arteriosus Masked by High Altitude Hypoxia Until Descent to Sea Level.

We present a 41-year-old female with progressive shortness of breath immediately after moving to sea level from high altitude. The patient was found to have a large PDA with systemic RV and PA pressures and pulmonary hypertension, which resolved following PDA closure.

Lymphatic Disorders and Management in Patients With Congenital Heart Disease.

Congenital heart disease can lead to notable lymphatic complications such as chylothorax, plastic bronchitis, protein-losing enteropathy, and ascites. Recent improvements in lymphatic imaging and the development of new lymphatic procedures can help alleviate symptoms and improve outcomes.

Current strategies for myocardial gene delivery.

Existing methods of cardiac gene delivery can be classified by the site of injection, interventional approach and type of cardiac circulation at the time of transfer. General criteria to assess the efficacy of a given delivery method include: global versus regional myocardial transduction, technical complexity and the pathophysiological effects associated with its use, delivery-related collateral expression and the delivery-associated inflammatory and immune response. Direct gene delivery (intramyocardial, endocardial, epicardial) may be useful for therapeutic angiogenesis and for focal arrhythmia therapy but with gene expression which is primarily limited to regions in close proximity to the injection site. An often unappreciated limitation of these techniques is that they are frequently associated with substantial systemic vector delivery. Percutaneous infusion of vector into the coronary arteries is minimally invasive and allows for transgene delivery to the whole myocardium. Unfortunately, efficiency of intracoronary delivery is highly variable and the short residence time of vector within the coronary circulation and significant collateral organ expression limit its clinical potential. Surgical techniques, including the incorporation of cardiopulmonary bypass with isolated cardiac recirculation, represent novel delivery strategies that may potentially overcome these limitations; yet, these techniques are complex with inherent morbidity that must be thoroughly evaluated before safe translation into clinical practice. Characteristics of the optimal technique for gene delivery include low morbidity, increased myocardial transcapillary gradient, extended vector residence time in the coronary circulation and exclusion of residual vector from the systemic circulation after delivery to minimize extracardiac expression and to mitigate a cellular immune response. This article is part of a Special Section entitled "Special Section: Cardiovascular Gene Therapy".

Model-specific selection of molecular targets for heart failure gene therapy.

Heart failure (HF) is a complex multifaceted problem of abnormal ventricular function and structure. In recent years, new information has been accumulated allowing for a more detailed understanding of the cellular and molecular alterations that are the underpinnings of diverse causes of HF, including myocardial ischemia, pressure-overload, volume-overload or intrinsic cardiomyopathy. Modern pharmacological approaches to treat HF have had a significant impact on the course of the disease, although they do not reverse the underlying pathological state of the heart. Therefore gene-based therapy holds a great potential as a targeted treatment for cardiovascular diseases. Here, we survey the relative therapeutic efficacy of genetic modulation of ß-adrenergic receptor signaling, Ca(2+) handling proteins and angiogenesis in the most common extrinsic models of HF.

MCARD-mediated gene transfer of GRK2 inhibitor in ovine model of acute myocardial infarction.

ß-Adrenergic receptor (ßAR) dysfunction in acute myocardial infarction (MI) is associated with elevated levels of the G-protein-coupled receptor kinase-2 (GRK2), which plays a key role in heart failure progression. Inhibition of GRK2 via expression of a peptide ßARKct transferred by molecular cardiac surgery with recirculating delivery (MCARD) may be a promising intervention. Five sheep underwent scAAV6-mediated MCARD delivery of ßARKct, and five received no treatment (control). After a 3-week period, the branch of the circumflex artery (OM1) was ligated. Quantitative PCR data showed intense ßARKct expression in the left ventricle (LV). Circumferential fractional shortening was 23.4 ± 7.1 % (baseline) vs. -2.9 ± 5.2 % (p < 0.05) in the control at 10 weeks. In the MCARD-ßARKct group, this parameter was close to baseline. The same trend was observed with LV wall thickening. Cardiac index fully recovered in the MCARD-ßARKct group. LV end-diastolic volume and LV end-diastolic pressure did not differ in both groups. MCARD-mediated ßARKct gene expression results in preservation of regional and global systolic function after acute MI without arresting progressive ventricular remodeling.

AAV6-ßARKct gene delivery mediated by molecular cardiac surgery with recirculating delivery (MCARD) in sheep results in robust gene expression and increased adrenergic reserve.

OBJECTIVE: Genetic modulation of heart function is a novel therapeutic strategy. We investigated the effect of molecular cardiac surgery with recirculating delivery (MCARD)-mediated carboxyl-terminus of the ß-adrenergic receptor kinase (ßARKct) gene transfer on cardiac mechanoenergetics and ß-adrenoreceptor (ßAR) signaling. METHODS: After baseline measurements, sheep underwent MCARD-mediated delivery of 10(14) genome copies of self-complimentary adeno-associated virus (scAAV6)-ßARKct. Four and 8 weeks after MCARD, mechanoenergetic studies using magnetic resonance imaging were performed. Tissues were analyzed with real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting. ßAR density, cyclic adenosine monophosphate levels, and physiologic parameters were evaluated. RESULTS: There was a significant increase in dP/dt(max) at 4 weeks: 1384 ± 76 versus 1772 ± 182 mm Hg/s; and the increase persisted at 8 weeks in response to isoproterenol (P < .05). Similarly, the magnitude of dP/dt(min) increased at both 4 weeks and 8 weeks with isoproterenol stimulation (P < .05). At 8 weeks, potential energy was conserved, whereas in controls there was a decrease in potential energy (P < .05) in response to isoproterenol. RT-qPCR confirmed robustness of ßARKct expression throughout the left ventricle and undetectable expression in extracardiac tissues. Quantitative Western blot data confirmed higher expression of ßARKct in the left ventricle: 0.46 ± 0.05 versus 0.00 in lung and liver (P < .05). Survival was 100% and laboratory parameters of major organ function were within normal limits. CONCLUSIONS: MCARD-mediated ßARKct delivery is safe, results in robust cardiac-specific gene expression, enhances cardiac contractility and lusitropy, increases adrenergic reserve, and improves energy utilization efficiency in a preclinical large animal model.