Familial Associations of Prevalence and Cause-Specific Mortality for Thoracic Aortic Disease and Bicuspid Aortic Valve in a Large-Population Database.

BACKGROUND: Thoracic aortic disease and bicuspid aortic valve (BAV) likely have a heritable component, but large population-based studies are lacking. This study characterizes familial associations of thoracic aortic disease and BAV, as well as cardiovascular and aortic-specific mortality, among relatives of these individuals in a large-population database. METHODS: In this observational case-control study of the Utah Population Database, we identified probands with a diagnosis of BAV, thoracic aortic aneurysm, or thoracic aortic dissection. Age- and sex-matched controls (10:1 ratio) were identified for each proband. First-degree relatives, second-degree relatives, and first cousins of probands and controls were identified through linked genealogical information. Cox proportional hazard models were used to quantify the familial associations for each diagnosis. We used a competing-risk model to determine the risk of cardiovascular-specific and aortic-specific mortality for relatives of probands. RESULTS: The study population included 3 812 588 unique individuals. Familial hazard risk of a concordant diagnosis was elevated in the following populations compared with controls: first-degree relatives of patients with BAV (hazard ratio [HR], 6.88 [95% CI, 5.62-8.43]); first-degree relatives of patients with thoracic aortic aneurysm (HR, 5.09 [95% CI, 3.80-6.82]); and first-degree relatives of patients with thoracic aortic dissection (HR, 4.15 [95% CI, 3.25-5.31]). In addition, the risk of aortic dissection was higher in first-degree relatives of patients with BAV (HR, 3.63 [95% CI, 2.68-4.91]) and in first-degree relatives of patients with thoracic aneurysm (HR, 3.89 [95% CI, 2.93-5.18]) compared with controls. Dissection risk was highest in first-degree relatives of patients who carried a diagnosis of both BAV and aneurysm (HR, 6.13 [95% CI, 2.82-13.33]). First-degree relatives of patients with BAV, thoracic aneurysm, or aortic dissection had a higher risk of aortic-specific mortality (HR, 2.83 [95% CI, 2.44-3.29]) compared with controls. CONCLUSIONS: Our results indicate that BAV and thoracic aortic disease carry a significant familial association for concordant disease and aortic dissection. The pattern of familiality is consistent with a genetic cause of disease. Furthermore, we observed higher risk of aortic-specific mortality in relatives of individuals with these diagnoses. This study provides supportive evidence for screening in relatives of patients with BAV, thoracic aneurysm, or dissection.

Predictors of Adherence to Anti-Impulse Therapy among Patients Treated for Acute Type-B Aortic Dissections.

BACKGROUND: Medical management remains the mainstay of treatment for patients who present with acute Type-B aortic dissections (TBAD). However, it is unclear whether patients maintain adherence to their anti-impulse therapy medication regimen following hospital discharge. This study was designed to evaluate rates and predictors of medication adherence among insured patients treated for acute TBAD. METHODS: We used the Truven MarketScan database to identify US patients who presented with an acute TBAD between 2008 to 2017. Patients with continuous health insurance (Commercial or Medicare Part C) for at least 12 months after TBAD diagnosis were stratified by whether they underwent open surgical repair (OPEN), thoracic endovascular aortic repair (TEVAR), or only medication management (MED). Prescriptions for anti-impulse therapy medications were captured and adherence was defined by the medication possession ratio as > 80% fill rate over the follow-up period. Mixed-effects logistic regression models were used to identify predictors for medication adherence. RESULTS: A total of 6,702 patients were identified that underwent treatment for TBAD (3% TEVAR, 9% OPEN, & 74% MED), whereas 14% received no intervention. The overall mean (±SD) rate of adherence to anti-impulse therapy was 72.6% ( ± 26), and varied based on type of TBAD intervention (73.4% TEVAR, 74.4% OPEN, & 72.4% MED). The majority of patients across all treatment groups were prescribed ≥ 2 agents, with beta-blockers and diuretics being the most common medication classes. The odds of adherence to anti-impulse therapy were significantly lower for patients who were female (OR: 0.93; 95%CI:0.85-0.99; P = 0.03), aged < 45 years (OR: 0.81; 95%CI:0.69-0.96; P < 0.001), nonadherent on preexisting therapy (OR: 0.81; 95%CI: 0.73-0.89; P < 0.001), and when medications were obtained in less than a 90 days supply from retail pharmacies. CONCLUSIONS: Nearly a quarter of patients were nonadherent with anti-impulse therapy prescribed following an acute TBAD, which was more likely among younger female patients not adherent before their event. Adherence was improved among patients who received their medications by mail and when a > 90 days supply was prescribed. These findings may be used by quality improvement initiatives to improve medication adherence following TBAD and help prevent further complications.

Premature atrial stimulation accentuates conduction abnormalities in cardiac surgery patients that develop postoperative atrial fibrillation.

BACKGROUND: postoperative atrial fibrillation (POAF) is a common cardiac surgery complication that is associated with increased complications and negative outcomes, but the association between presurgical atrial conduction abnormalities and POAF has not been investigated clinically during premature atrial S1S2 stimulation. This clinical study sought to examine whether intraoperative premature atrial stimulation reveals increased areas of slowed and/or blocked conduction in patients that develop POAF. METHODS: High-density intraoperative epicardial left atrial mapping was conducted in 20 cardiac surgery patients with no prior history of atrial fibrillation (AF). In 20 patients, 6 (30%) developed POAF. A flexible-array of 240-electrodes was placed on the posterior left atrial wall in between the pulmonary veins. Activation maps were generated for sinus and premature atrial S1S2 stimulated beats. The area of conduction block (CB), conduction delay (CD) and the combination of both (CDCB) for conduction velocity < 0.1, 0.1 ≤ x < 0.2 and < 0.2 m/s, respectively were quantified. RESULTS: For a premature atrial S2 beat with shortest cycle length captured, conduction velocity maps revealed a significantly higher area for CD (13.19 ± 6.59 versus 6.06 ± 4.22 mm2, p = 0.028) and CDCB (17.36 ± 8.75 versus 7.41 ± 6.39 mm2, p = 0.034), and a trend toward a larger area for CB (4.17 ± 3.66 versus 1.34 ± 2.86 mm2, p = 0.063) in patients who developed POAF in comparison to those that remained in the sinus. Sinus and S1 paced beats did not show substantial differences in abnormal conduction areas between patients with and without POAF. CONCLUSION: In comparison to sinus and S1 beats, premature atrial S2 beats accentuate conduction abnormalities in the posterior left atrial wall of cardiac surgery patients that developed POAF.

Rapid-deployment aortic valve replacement after aortic root replacement: A safe alternative to redo root replacement.

Reoperative aortic root replacement, following prior biologic or mechanical valved conduit aortic root prosthesis, presents a technical challenge. The rapid-deployment aortic valve prosthesis is an approved alternative to traditional bioprosthetic aortic valve replacement. We present three clinical cases in which rapid-deployment aortic valve prostheses were utilized in lieu of reoperative full aortic root replacement. All three patients recovered uneventfully. The rapid-deployment valve insertion in a prior surgical aortic root prosthesis is a safe option to avoid reoperative full aortic root replacement.

Is timing everything? Bioprosthetic valve fracture in valve-in-valve TAVR.

We present a challenging case of early bioprosthetic valve degeneration following valve-in-valve transcatheter aortic valve replacement and bioprosthetic valve fracture.

Transesophageal echocardiography identification of aortic dissection during cardiac arrest and cessation of ECMO initiation.

Cardiac arrest is a challenging clinical presentation that emergency medicine providers often encounter. Aortic dissection is an uncommon etiology in all-comers presenting in cardiac arrest. The use of bedside point of care echocardiography to aid in resuscitative efforts is expanding, particularly with the increasing use of transesophageal echocardiography (TEE) by emergency medicine providers. Additionally, emergency department initiation of extracorporeal membrane oxygenation (ECMO) is a relatively newer development in emergency department practice. We report the case of a 64-year old male presenting to the emergency department in cardiac arrest with TEE identification of aortic dissection as the etiology resulting in discontinuation of ECMO initiation attempts.

Repair of ascending aortic aneurysms following cardiac transplantation.

Ascending aortic aneurysms arising from the native aorta following cardiac transplantation are rare. We report two patients who developed aneurysms of the native ascending aorta requiring surgical repair post-transplantation. Both patients underwent ascending and hemi-arch replacement and recovered uneventfully. Heart transplant patients with pre-existing aortic dilation/ectasia may display more rapid aneurysmal growth compared to non-transplant patients. Therefore close observation is warranted in these patients.

Tracking the elusive fibrocyte: identification and characterization of collagen-producing hematopoietic lineage cells during murine wound healing.

Fibrocytes are a unique population of circulating cells reported to exhibit characteristics of both hematopoietic and mesenchymal cells, and play an important role in wound healing. However, putative fibrocytes have been found to lose expression of hematopoietic surface markers such as CD45 during differentiation, making it difficult to track these cells in vivo with conventional methodologies. In this study, to distinguish hematopoietic and nonhematopoietic cells without surface markers, we took advantage of the gene vav 1, which is expressed solely on hematopoietic cells but not on other cell types, and established a novel transgenic mouse, in which hematopoietic cells are irreversibly labeled with green fluorescent protein and nonhematopoietic cells with red fluorescent protein. Use of single-cell transcriptional analysis in this mouse model revealed two discrete types of collagen I (Col I) expressing cells of hematopoietic lineage recruited into excisional skin wounds. We confirmed this finding on a protein level, with one subset of these Col I synthesizing cells being CD45+ and CD11b+, consistent with the traditional definition of a fibrocyte, while another was CD45- and Cd11b-, representing a previously unidentified population. Both cell types were found to initially peak, then reduce posthealing, consistent with a disappearance from the wound site and not a loss of identifying surface marker expression. Taken together, we have unambiguously identified two cells of hematopoietic origin that are recruited to the wound site and deposit collagen, definitively confirming the existence and natural time course of fibrocytes in cutaneous healing.

Paracrine mechanism of angiogenesis in adipose-derived stem cell transplantation.

INTRODUCTION: Adipose-derived stem cells (ASCs) have shown potential for cell-based therapy in the field of plastic surgery. However, the fate of ASCs after transplantation and the mechanism(s) of their biologic capabilities remain unclear. METHODS: We isolated and cultured ASCs from transgenic mice that express both luciferase and green fluorescent protein and injected the cells into the inguinal fat pads of wild-type mice. We tested 4 experimental groups, namely, ischemic fat pads with/without ASCs and control fat pads with/without ASCs. RESULTS: Transplanted ASCs were tracked with bioluminescence imaging. The luminescence gradually decreased over 28 days, indicating cell death after transplantation. More ASCs were retained in ischemic fat pads on day 7 compared to control fat pads. On day 14, adipose tissue vascular density was higher in the ASC transplantation groups compared to those without ASCs. On day 28, there was decreased atrophy of adipose tissue in ASC-treated ischemic fat pads. Transplanted ASCs were detected as nonproliferating green fluorescent protein-positive cells, whereas native endothelial cells adjacent to the transplanted ASCs were proliferative. Protein analysis demonstrated higher expression of hepatocyte growth factor and vascular endothelial growth factor in the ASC transplantation groups, suggesting a paracrine mechanism, which was confirmed by in vitro experiments with conditioned media from ASCs. CONCLUSIONS: Transplanted ASCs are preferentially retained in ischemic adipose tissue, although most of the cells eventually undergo cell death. They exert an angiogenic effect on adipose tissue mainly through a paracrine mechanism. Increased understanding of these effects will help develop ASCs as a tool for cell-based therapy.

Transcatheter Aortic Valve Replacement Improves Quality of Life and Ventricular Function With Low-Flow/Low-Gradient Aortic Stenosis.

Background: D2 aortic stenosis (AS) is the highest risk AS subtype with worse operative and mortality outcomes. This study aimed to investigate the quality of life (QoL) and left ventricular ejection fraction (LVEF) in patients with classic (D2 subtype) low-flow/low-gradient AS who underwent transcatheter aortic valve replacement (TAVR). Methods: In total, 634 patients with severe AS underwent TAVR at our institution from 2014 to 2020, of whom 76 met criteria for classic D2 AS with reduced LVEF. Echocardiographic and clinical outcomes including mortality, stroke, pacemaker placement (PPM), and readmission at baseline were compared with those at 30 days and 1 year. QoL data were extracted from the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Results: The average baseline Society of Thoracic Surgeons risk score for patients with D2 AS was 7.66 ± 6.76. Patients with D2 AS reported improved QoL post-TAVR. The average baseline KCCQ-12 score was 39.5 ± 20, with improvement to 68.9 ± 20.6 at 30 days (P < .01) and 74.9 ± 17.5 at 1 year (P < .01). Mortality was 0% at 30 days and 18.4% at 1 year. The average baseline LVEF was 36.1 ± 9.4. Left ventricular function improved to 43.5 ± 12.9 (P <.001) at 30 days and 46.3 ± 11.2 (P = .03) at 1 year. Complications post-TAVR at 30 days included stroke (1.3%) and PPM (11.8%). Patients with D2 AS exhibited higher baseline conduction defects including atrial fibrillation and higher postoperative PPM than those with other subtypes. Conclusions: Patients with D2 AS had significantly improved LVEF and QoL following TAVR at 30 days and 1 year. Postoperative rates of new PPM were higher than other subtypes, while stroke, dialysis, and mortality were lower than expected, supporting the benefit of TAVR in this high-risk group.

CD105 protein depletion enhances human adipose-derived stromal cell osteogenesis through reduction of transforming growth factor ß1 (TGF-ß1) signaling.

Clinically available sources of bone for repair and reconstruction are limited by the accessibility of autologous grafts, infectious risks of cadaveric materials, and durability of synthetic substitutes. Cell-based approaches for skeletal regeneration can potentially fill this need, and adipose tissue represents a promising source for development of such therapies. Here, we enriched for an osteogenic subpopulation of cells derived from human subcutaneous adipose tissue utilizing microfluidic-based single cell transcriptional analysis and fluorescence-activated cell sorting (FACS). Statistical analysis of single cell transcriptional profiles demonstrated that low expression of endoglin (CD105) correlated with a subgroup of adipose-derived cells with increased osteogenic gene expression. FACS-sorted CD105(low) cells demonstrated significantly enhanced in vitro osteogenic differentiation and in vivo bone regeneration when compared with either CD105(high) or unsorted cells. Evaluation of the endoglin pathway suggested that enhanced osteogenesis among CD105(low) adipose-derived cells is likely due to identification of a subpopulation with lower TGF-ß1/Smad2 signaling. These findings thus highlight a potential avenue to promote osteogenesis in adipose-derived mesenchymal cells for skeletal regeneration.

Dura mater stimulates human adipose-derived stromal cells to undergo bone formation in mouse calvarial defects.

Human adipose-derived stromal cells (hASCs) have a proven capacity to aid in osseous repair of calvarial defects. However, the bone defect microenvironment necessary for osseous healing is not fully understood. In this study, we postulated that the cell-cell interaction between engrafted ASCs and host dura mater (DM) cells is critical for the healing of calvarial defects. hASCs were engrafted into critical sized calvarial mouse defects. The DM-hASC interaction was manipulated surgically by DM removal or by insertion of a semipermeable or nonpermeable membrane between DM and hASCs. Radiographic, histologic, and gene expression analyses were performed. Next, the hASC-DM interaction is assessed by conditioned media (CM) and coculture assays. Finally, bone morphogenetic protein (BMP) signaling from DM was investigated in vivo using novel BMP-2 and anti-BMP-2/4 slow releasing scaffolds. With intact DM, osseous healing occurs both from host DM and engrafted hASCs. Interference with the DM-hASC interaction dramatically reduced calvarial healing with abrogated BMP-2-Smad-1/5 signaling. Using CM and coculture assays, mouse DM cells stimulated hASC osteogenesis via BMP signaling. Through in vivo manipulation of the BMP-2 pathway, we found that BMP-2 plays an important role in DM stimulation of hASC osteogenesis in the context of calvarial bone healing. BMP-2 supplementation to a defect with disrupted DM allowed for bone formation in a nonhealing defect. DM is an osteogenic cell type that both participates in and stimulates osseous healing in a hASC-engrafted calvarial defect. Furthermore, DM-derived BMP-2 paracrine stimulation appears to play a key role for hASC mediated repair.

Mechanical force prolongs acute inflammation via T-cell-dependent pathways during scar formation.

Mechanical force significantly modulates both inflammation and fibrosis, yet the fundamental mechanisms that regulate these interactions remain poorly understood. Here we performed microarray analysis to compare gene expression in mechanically loaded wounds vs. unloaded control wounds in an established murine hypertrophic scar (HTS) model. We identified 853 mechanically regulated genes (false discovery rate <2) at d 14 postinjury, a subset of which were enriched for T-cell-regulated pathways. To substantiate the role of T cells in scar mechanotransduction, we applied the HTS model to T-cell-deficient mice and wild-type mice. We found that scar formation in T-cell-deficient mice was reduced by almost 9-fold (P < 0.001) with attenuated epidermal (by 2.6-fold, P < 0.01) and dermal (3.9-fold, P < 0.05) proliferation. Mechanical stimulation was highly associated with sustained T-cell-dependent Th2 cytokine (IL-4 and IL-13) and chemokine (MCP-1) signaling. Further, T-cell-deficient mice failed to recruit systemic inflammatory cells such as macrophages or monocytic fibroblast precursors in response to mechanical loading. These findings indicate that T-cell-regulated fibrogenic pathways are highly mechanoresponsive and suggest that mechanical forces induce a chronic-like inflammatory state through immune-dependent activation of both local and systemic cell populations.

Minimally Invasive versus Full Sternotomy SAVR in the Era of TAVR: An Institutional Review.

In the era of advancing transcatheter aortic valve replacement (TAVR) technology, traditional open surgery remains a valuable intervention for patients who are not TAVR candidates. We sought to compare perioperative variables and postoperative outcomes of minimally invasive and full sternotomy surgical aortic valve replacement (SAVR) at a single institution. A retrospective analysis of 113 patients who underwent isolated SAVR via full sternotomy or upper hemi-sternotomy between January 2015 and December 2019 at the University of Utah Hospital was performed. Preoperative comorbidities and demographic information were not different among groups, with the exception of diabetes, which was significantly more common in the full sternotomy group (p = 0.01). Median procedure length was numerically shorter in the minimally invasive group but was not significant following the Bonferroni correction (p = 0.047). Other perioperative variables were not significantly different. The two groups showed no difference in the incidence of postoperative adverse events (p = 0.879). As such, minimally invasive SAVR via hemi-sternotomy remains a safe and effective alternative to full sternotomy for patients who meet the criteria for aortic valve replacement.

Surgical approaches to create murine models of human wound healing.

Wound repair is a complex biologic process which becomes abnormal in numerous disease states. Although in vitro models have been important in identifying critical repair pathways in specific cell populations, in vivo models are necessary to obtain a more comprehensive and pertinent understanding of human wound healing. The laboratory mouse has long been the most common animal research tool and numerous transgenic strains and models have been developed to help researchers study the molecular pathways involved in wound repair and regeneration. This paper aims to highlight common surgical mouse models of cutaneous disease and to provide investigators with a better understanding of the benefits and limitations of these models for translational applications.

Akt-mediated mechanotransduction in murine fibroblasts during hypertrophic scar formation.

Although numerous factors are implicated in skin fibrosis, the exact pathophysiology of hypertrophic scarring remains unknown. We recently demonstrated that mechanical force initiates hypertrophic scar formation in a murine model, potentially enhancing cellular survival through Akt. Here, we specifically examined Akt-mediated mechanotransduction in fibroblasts using both strain culture systems and our murine scar model. In vitro, static strain increased fibroblast motility, an effect blocked by wortmannin (a phosphoinositide-3-kinase/Akt inhibitor). We also demonstrated that high-frequency cyclic strain was more effective at inducing Akt phosphorylation than low frequency or static strain. In vivo, Akt phosphorylation was induced by mechanical loading of dermal fibroblasts in both unwounded and wounded murine skin. Mechanically loaded scars also exhibited strong expression of α-smooth muscle actin, a putative marker of pathologic scar formation. In vivo inhibition of Akt increased apoptosis but did not significantly abrogate hypertrophic scar development. These data suggest that although Akt signaling is activated in fibroblasts during mechanical loading of skin, this is not the critical pathway in hypertrophic scar formation. Future studies are needed to fully elucidate the critical mechanotransduction components and pathways which activate skin fibrosis.

Evaluating Quality in Adult Cardiac Surgery.

National and institutional quality initiatives provide benchmarks for evaluating the effectiveness of medical care. However, the dramatic growth in the number and type of medical and organizational quality-improvement standards creates a challenge to identify and understand those that most accurately determine quality in cardiac surgery. It is important that surgeons have knowledge and insight into valid, useful indicators for comparison and improvement. We therefore reviewed the medical literature and have identified improvement initiatives focused on cardiac surgery. We discuss the benefits and drawbacks of existing methodologies, such as comprehensive regional and national databases that aid self-evaluation and feedback, volume-based standards as structural indicators, process measurements arising from evidence-based research, and risk-adjusted outcomes. In addition, we discuss the potential of newer methods, such as patient-reported outcomes and composite measurements that combine data from multiple sources.

Preventing or Minimizing Acute Kidney Injury in Patients Undergoing Transcatheter Aortic Valve Replacement.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is now routinely performed in patients with aortic stenosis with low mortality and complication rates. Although periprocedural risks have been substantially minimized, procedure- and contrast-induced acute kidney injury (AKI) remains a major concern. AKI remains a frequent complication of contrast-guided interventional procedures and is associated with a significantly adverse prognosis. We review the currently available clinical data related to AKI, with emphasis on contrast-induced nephropathy (CIN), and discuss a novel, integrated approach aiming to minimize AKI risk in high-risk patients. A stepwise algorithm is also proposed for the management of these complex patients.

Surgical explantation of atrial septal closure devices for refractory nickel allergy symptoms.

OBJECTIVES: Systemic allergic reactions to nickel alloys in percutaneous atrial septal defect occlusion devices have a poorly defined natural history. We describe our experience of surgical removal of the offending device in a series of patients with nickel allergy and refractory symptoms. METHODS: Patients with atrial septal defect device explants for nickel allergy were reviewed. Administered questionnaires focused on symptoms, quality of life, and satisfaction along with the 36-Item Short Form Health Survey to measure physical and mental health postsurgery. RESULTS: Atrial septal defect devices were removed for nickel allergy in 58 patients during the past 10 years. The median age was 42 years (range, 24-71 years) and 95% were women. Explantation occurred at a median of 8 years (range, 6 months-18 years) after insertion. Symptoms included fatigue (82%), chest pain (78%), headache (73%), and palpitation (58%). Surveys were available for 45 patients: 58% rated their quality of life as poor and 69% were not at all satisfied with their device. Postexplant, all patients reported improvement in their symptoms, with 18 patients (42%) noting complete resolution. In 12 patients prospectively studied, the preoperative scores in physical and mental health domains were lower than the validation group, indicating significant disability. Similarly, there was marked improvement in each domain postremoval. CONCLUSIONS: Patients with nickel allergy and severe refractory symptoms after atrial septal defect device implantation experience profound resolution of symptoms and improved quality of life after removal. Nickel allergy should be considered before device insertion, and a low threshold should exist for surgical removal for refractory symptoms.