Profibrotic VEGFR3-Dependent Lymphatic Vessel Growth in Autoimmune Valvular Carditis.

BACKGROUND: Rheumatic heart disease is the major cause of valvular heart disease in developing nations. Endothelial cells (ECs) are considered crucial contributors to rheumatic heart disease, but greater insight into their roles in disease progression is needed. METHODS: We used a Cdh5-driven EC lineage-tracing approach to identify and track ECs in the K/B.g7 model of autoimmune valvular carditis. Single-cell RNA sequencing was used to characterize the EC populations in control and inflamed mitral valves. Immunostaining and conventional histology were used to evaluate lineage tracing and validate single-cell RNA-sequencing findings. The effects of VEGFR3 (vascular endothelial growth factor receptor 3) and VEGF-C (vascular endothelial growth factor C) inhibitors were tested in vivo. The functional impact of mitral valve disease in the K/B.g7 mouse was evaluated using echocardiography. Finally, to translate our findings, we analyzed valves from human patients with rheumatic heart disease undergoing mitral valve replacements. RESULTS: Lineage tracing in K/B.g7 mice revealed new capillary lymphatic vessels arising from valve surface ECs during the progression of disease in K/B.g7 mice. Unsupervised clustering of mitral valve single-cell RNA-sequencing data revealed novel lymphatic valve ECs that express a transcriptional profile distinct from other valve EC populations including the recently identified PROX1 (Prospero homeobox protein 1)+ lymphatic valve ECs. During disease progression, these newly identified lymphatic valve ECs expand and upregulate a profibrotic transcriptional profile. Inhibiting VEGFR3 through multiple approaches prevented expansion of this mitral valve lymphatic network. Echocardiography demonstrated that K/B.g7 mice have left ventricular dysfunction and mitral valve stenosis. Valve lymphatic density increased with age in K/B.g7 mice and correlated with worsened ventricular dysfunction. Importantly, human rheumatic valves contained similar lymphatics in greater numbers than nonrheumatic controls. CONCLUSIONS: These studies reveal a novel mode of inflammation-associated, VEGFR3-dependent postnatal lymphangiogenesis in murine autoimmune valvular carditis, with similarities to human rheumatic heart disease.

Statistical shape representation of the thoracic aorta: accounting for major branches of the aortic arch.

Statistical shape modeling (SSM) is an emerging tool for risk assessment of thoracic aortic aneurysm. However, the head branches of the aortic arch are often excluded in SSM. We introduced an SSM strategy based on principal component analysis that accounts for aortic branches and applied it to a set of patient scans. Computational fluid dynamics were performed on the reconstructed geometries to identify the extent to which branch model accuracy affects the calculated wall shear stress (WSS) and pressure. Surface-averaged and location-specific values of pressure did not change significantly, but local WSS error was high near branches when inaccurately modeled.

New-onset postoperative atrial fibrillation after mitral valve surgery: Determinants and the effect on survival.

Objective: Mitral valve surgery (MVS) carries substantial risk of postoperative atrial fibrillation (PAF). Identifying patients who benefit from prophylactic left atrial appendage amputation (LAAA) or maze is ill-defined. To guide such interventions, we determined preoperative predictors of PAF and investigated 3-year survival of patients with PAF. Methods: We performed a retrospective analysis of patients undergoing isolated MVS (N = 670) between 2011 and 2021. Patients with preoperative atrial fibrillation, LAAA or pulmonary vein isolation were excluded. Patient characteristics were compared between those without PAF and those who developed transient or prolonged PAF. Predictors of any PAF and prolonged PAF were identified using multivariable regression analysis. Results: In total, 504 patients without preoperative atrial fibrillation underwent isolated MVS. Of them, 303 patients (60.2%) developed PAF; 138 (27.3%) developed transient and 165 (32.7%) developed prolonged (beyond 30 days) PAF. Patients with PAF were older (65.7 vs 54.3 years, P < .001), with larger left atria (4.8 vs 4.3 cm, P < .001), greater prevalence of hypertension (60% vs 47.8%, P < .05), and were New York Heart Association class III/IV (36% vs 8.5%, P < .001). Independent predictors of PAF included left atria volume index (odds ratio [OR], 1.02; P < .003), older age (OR, 1.04; P < .001), heart failure (OR, 6.73; P < .001), and sternotomy (OR, 2.19; P < .002). Age, heart failure, and sternotomy were independent predictors of prolonged PAF. Patients with PAF had greater mortality at 3 years compared with those without PAF (5.3% vs 0.5%, P < .005). On multivariable analysis, PAF was associated with increased mortality (hazard ratio, 7.81; P < .046). Conclusions: PAF is common after MVS and associated with late mortality. Older age, advanced heart failure, and sternotomy are associated with prolonged PAF. These factors may identify patients who would benefit from prophylactic LAAA or ablation during MVS.

CD47 Promotes Autoimmune Valvular Carditis by Impairing Macrophage Efferocytosis and Enhancing Cytokine Production.

Systemic autoantibody-mediated diseases accelerate chronic cardiovascular disease in humans. In the K/B.g7 mouse model of spontaneous autoantibody-mediated inflammatory arthritis, valvular carditis arises in part because of Fc receptor-mediated activation of macrophages, leading to production of pathogenic TNF and IL-6. In this study, we explored whether impaired efferocytosis mediated by the interaction of CD47-expressing apoptotic cells with signal regulatory protein α (SIRPα) on macrophages contributes to disease progression in this model. CD47-expressing apoptotic cells and SIRPα+ macrophages were abundant in inflamed/rheumatic cardiac valves from both mice and humans. In vivo anti-CD47 blockade both prevented and treated valvular carditis in K/B.g7 mice. Blocking CD47 enhanced macrophage efferocytosis and reduced macrophage production of TNF and IL-6. These studies highlight the CD47:SIRPα interaction as a key driver of chronic cardiac valve inflammation and suggest these molecules as potential therapeutic targets to reduce cardiovascular disease risk in autoantibody-driven inflammatory diseases.

Aortic valve repair for isolated right coronary leaflet prolapse.

Objectives: Isolated right coronary leaflet prolapse is a common cause of nonaneurysmal aortic insufficiency, but can rarely occur in patients with proximal aortic aneurysms. Standardized techniques for routine autologous repair of this disorder are presented. Methods: Most aortic valve leaflet prolapse is isolated to the right coronary leaflet, with hypertension and annular dilatation being contributory. Echocardiographically, a posteriorly eccentric aortic insufficiency jet together with "fracture" of the right leaflet tip are diagnostic. Primary repair includes internal geometric ring annuloplasty to downsize and reshape the annulus, together with central plication of the prolapsing leaflet. Thickened, scarred, or retracted noduli are released using an ultrasonic aspirator. The goal is to achieve equivalent coaptation heights of ≥8 mm for all 3 leaflets. Results: Three videos of 6 cases are provided to illustrate these techniques. In the first, 3 patients are shown with classic isolated right leaflet prolapse. In the second and third videos, alternative pathologies are presented for contrast. Applying the reconstructive approaches of geometric ring annuloplasty, leaflet plication, and ultrasonic nodular release, excellent early and late repair outcomes are obtainable in most patients. Conclusions: The combination of aortic ring annuloplasty, central leaflet plication, and ultrasonic nodular release allows routine and standardized repair of right coronary leaflet prolapse, either isolated or concomitant with aneurysm surgery.

First Dedicated Minimally Invasive Right Atrial Retractor.

INTRODUCTION: The importance of correcting tricuspid valve insufficiency in patients with left-sided valve disease is clear. In the United States, up to 30% of mitral valve operations are minimally invasive, while the data for isolated tricuspid valve is not known. A minimally invasive approach to the tricuspid valve provides faster recovery with lower transfusion rates and lower length of stay. MATERIALS AND METHODS: There are no dedicated right atrial (RA) retractors for minimally invasive tricuspid valve (TV) operations. TV exposure is different from mitral given the proximity of the tricuspid anterior annulus to the cut edge of the atrium. An RA retractor should be shallow while preventing slippage of the RA roof and should be quick to deploy and remove. We created a dedicated minimally invasive RA retractor to expose the TV and RA structures (fossa ovalis and coronary sinus). The retractor is a fenestrated shallow and wide retractor with bilateral articulating "wings" to expose left and right of the atrium. This retractor is compatible with the left atrial system by USB Medical Limited (Hatboro, Pennsylvania) and has tilting capability. A three-dimensional (3D)-printed prototype was modified after evaluation by two experienced minimally invasive surgeons (MCS and RKV). Once modifications were finalized, the retractor was then deployed in surgery. RESULTS: The RA retractor was used in isolated TV repairs, RA myxoma resection, RA clot removal, removal of RA migrated stents, select mitral valve operations, and closure of atrial septal defects. The retractor proved effective, safe, and fast to deploy and remove and allowed for full visualization of the tricuspid valve, interatrial septum, ostia of both vena cavas, and coronary sinus. The retractor was useful in mitral valve operations with existing aortic valve prosthesis and in the small left atria. CONCLUSION: The minimally invasive RA retractor affords excellent, stable exposure of the right atrial structures with fast deployment and removal.

Hemodynamic Characteristics and Outcomes of Pulmonary Hypertension in Patients Undergoing Tricuspid Valve Repair or Replacement.

BACKGROUND: The impact of pulmonary hypertension (PH) on outcomes after surgical tricuspid valve replacement (TVR) and repair (TVr) is unclear. We sought to characterize PH in patients undergoing TVR/TVr, based on invasive hemodynamics and evaluate the effect of PH on mortality. METHODS: We identified 86 consecutive patients who underwent TVR/TVr with invasive hemodynamic measurements within 3 months before surgery. We used Kaplan-Meier survival and restricted mean survival time (RMST) analyses to quantify the effects of PH on survival. RESULTS: The mean age was 63 ± 13 years, 59% were female, 45% had TVR, 55% had TVr, 39.5% had isolated TVR/TVr, and 60.5% had TVR/TVr concomitant with other cardiac surgeries). Eighty-six percent of these patients had PH with a mean pulmonary artery pressure of 30 ± 10 mm Hg, pulmonary vascular resistance (PVR) of 2.5 (interquartile range: 1.5-3.9) Wood units (WU), pulmonary arterial compliance of 2.3 (1.6-3.6) mL/mm Hg, and pulmonary arterial elastance of 0.8 (0.6-1.2) mm Hg/mL. Cardiac output was mildly reduced at 4.0 ± 1.4 L/min, with elevated right-atrial pressure (14 ± 12 mm Hg) and pulmonary capillary wedge pressure (19 ± 7 mm Hg). Over a median follow-up of 6.3 years, 22% of patients died. Patients with PVR ≥ 2.5 WU had lower RMST over 5 years compared with patients with PVR < 2.5 WU. CONCLUSION: PH is common in patients undergoing TVR/TVr, with combined pre- and postcapillary being the most common type. PVR ≥ 2.5 WU is associated with lower survival at 5-year follow-up.

CONTEXTE: On connaît mal les répercussions de l'hypertension pulmonaire (HP) chez les patients qui ont subi une intervention chirurgicale de remplacement de la valve tricuspide (RVT) ou de réparation de la valve tricuspide (rVT). Nous avons tenté de caractériser l'HP chez les patients ayant subi un RVT ou une rVT en fonction des paramètres de surveillance hémodynamique effractive et d'évaluer l'effet de l'HP sur la mortalité. MÉTHODOLOGIE: Nous avons relevé 86 patients consécutifs ayant subi un RVT ou une rVT qui avaient fait l'objet de mesures hémodynamiques effractives dans les trois mois précédant l'intervention chirurgicale. Pour quantifier les effets de l'HP sur la survie, nous avons analysé la survie au moyen de la méthode de Kaplan-Meier et de la survie moyenne restreinte. RÉSULTATS: Les patients avaient en moyenne 63 ± 13 ans; 59 % d'entre eux étaient des femmes; 45 % avaient subi un RVT et 55 %, une rVT; 39,5 % avaient subi seulement un RVT ou une rVT lors de l'intervention chirurgicale; 60,5 % avaient subi un RVT ou une rVT en même temps qu'une autre intervention cardiaque. Quatre-vingt-six pour cent de ces patients présentaient une HP avec une pression artérielle pulmonaire moyenne de 30 ± 10 mmHg, une résistance vasculaire pulmonaire (RVP) de 2,5 (intervalle interquartile : 1,5 à 3,9) unités de Wood (UW), une compliance artérielle pulmonaire de 2,3 (1,6 à 3,6) ml/mmHg et une élastance artérielle pulmonaire de 0,8 (0,6 à 1,2) mmHg/ml. On a observé une légère baisse du débit cardiaque à 4,0 ± 1,4 L/min, ainsi qu'une augmentation de la pression auriculaire droite (14 ± 12 mmHg) et de la pression artérielle pulmonaire d'occlusion (19 ± 7 mmHg). Sur une période médiane de suivi de 6,3 ans, 22 % des patients sont décédés. Le taux de survie moyenne restreinte à 5 ans était plus faible chez les patients présentant une RVP ≥ 2,5 UW que chez les patients présentant une RVP < 2,5 UW. CONCLUSION: L'HP est fréquente chez les patients subissant un RVT ou une rVT, le type le plus courant étant l'HP mixte (pré-capillaire et post-capillaire). Une RVP ≥ 2,5 UW est associée à un taux de survie à 5 ans plus faible.

Fifty Percent Reduction in Narcotic Use After Minimally Invasive Cardiac Surgery Using Liposomal Bupivacaine.

OBJECTIVE: Minimally invasive cardiac surgery via a right minithoracotomy (RMT) is a common approach to different valve pathologies, tumor resection, and atrial septal defect (ASD) closure. We studied intraoperative field block using liposomal bupivacaine (LB) in these operations. METHODS: Consecutive 171 minimally invasive RMTs (fourth intercostal space) were studied, and patients in cardiogenic or septic shock, intravenous drug abuse, and those re-explored were excluded (n = 12). An early cohort was treated with standard postoperative analgesia while another underwent intraoperative field block with LB immediately after incision. We compared postoperative pain level, narcotic utilization (morphine milligram equivalent), and intensive care unit (ICU) and hospital length of stay. RESULTS: The procedures included 48 isolated mitral valve replacements (MVR); 2 MVR with other procedures; 93 mitral valve repairs (MVRr); 9 MVRr with other procedures; 4 isolated tricuspid valve repairs; 2 myxoma resections; 1 ASD closure. There were 13 patients in the non-LB group and 146 patients in the LB group. Use of LB decreased mean postoperative narcotic utilization by 50% (P = 0.003). The LB group had lower pain levels on postoperative day 1 (P = 0.039), which continued through postoperative day 5 (P = 0.030). We found no difference in ICU or hospital length of stay between groups. There were no complications from LB field block. CONCLUSIONS: LB field block decreases postoperative pain and narcotic utilization after cardiac surgery via a RMT, but it does not reduce length of stay. The technique is safe and should be considered in all patients undergoing RMT cardiac surgery.

Neurological complications associated with left ventricular assist device therapy.

INTRODUCTION: Associated with significant morbidity and mortality, neurological complications in adult patients with left ventricular assist devices (LVAD) approaches a prevalence as high as 25%. As the number of individuals using LVAD support grows, it is increasingly important for providers to understand the hematologic and hemodynamic changes associated with LVAD implantation, the risk factors for neurological complications and their mitigation strategies. Areas covered: PubMed searches were completed using the terms 'Left ventricular assist device and stroke' (994 results) then 'Left ventricular assist device and stroke risk factors' (199 results). Results were filtered by 'humans' (178 results). The manuscript focuses on the risk factors and mitigation strategies for stroke identified in the literature following LVAD implantation and managing this complication. Expert commentary: There is little consensus on how to accurately predict stroke risk in the LVAD population. While some recent large-scale clinical trials identified a limited number of risk factors, further research is warranted to generate reliable predictive models and treatment protocols for these patients. This should include developing novel agents and monitoring techniques to individualize anticoagulation therapy while safely balancing the risk of bleeding, thrombosis and stroke. A multi-specialty commitment is necessary to further standardize the management of these patients.

A Simple Porcine Model of Inducible Sustained Atrial Fibrillation.

The surgical management of atrial fibrillation (AF) is an evolving field with a history of testing various lesion sets and ablation technologies. Previous animal models of AF require a chronic intervention to make AF reliably inducible. Our objective was to create an acute, reliable, and reproducible porcine model of sustained AF. To accomplish this, 21 adult domestic pigs underwent median sternotomy. Methods to induce AF were then performed sequentially: manual stimulation, rapid pacing (200 beats per minute), and then rapid pacing of 8 beats with a cycle length of 300 milliseconds, followed by an extra stimulus at decreasing cycle lengths. If AF was not induced, burst pacing was performed at a cycle length of 90 milliseconds for 30 seconds. If AF was still not induced, intravenous neostigmine was administered, and the process was repeated. Atrial fibrillation was considered sustained after 1 minute. Attempts at AF induction were successful in 18 (86%) of 21. Atrial fibrillation was induced during manual stimulation in four (19%), during rapid pacing in five (24%), during burst pacing in five (24%), and after the administration of neostigmine in four (19%). Mean (SD) duration of AF was 3.6 (2.6) minutes. Of the 18, 14 (78%) reverted to sinus rhythm spontaneously and 4 (22%) required an antiarrhythmic. This technique of inducing AF can easily be used to evaluate new technologies and lesion sets without the need for creating a chronic animal model.

Quantification of the functional consequences of atrial fibrillation and surgical ablation on the left atrium using cardiac magnetic resonance imaging.

OBJECTIVES: The effect of atrial fibrillation (AF) on left atrial (LA) function has not been well defined and has been largely based on limited echocardiographic evaluation. This study examined the effect of AF and a subsequent Cox-Maze IV (CMIV) procedure on atrial function. METHODS: Cardiac magnetic resonance imaging (cMRI) was performed in 20 healthy volunteers, 8 patients with paroxysmal atrial fibrillation (PAF) and 7 patients with persistent or long-standing persistent atrial fibrillation (LSP AF). Six of the PAF patients underwent surgical ablation with the CMIV procedure and 5 underwent both pre- and postoperative cMRIs. The persistent or LSP AF patients underwent only postoperative cMRIs because all scans were performed with patients in normal sinus rhythm. Volume-time curves throughout the cardiac cycle and regional wall shortening were evaluated using the cine images and compared across groups. RESULTS: Compared with normal volunteers, patients with PAF had significantly decreased reservoir contribution to left ventricular (LV) filling (P = 0.0010), an increased conduit function contribution (P = 0.04) and preserved booster pump function (P = 0.14). Following the CMIV procedure, significant reductions were noted with respect to reservoir and booster pump function, with corresponding increases in conduit function. These differences were more drastic in patients with persistent/LSP AF. Regional wall motion was significantly reduced by PAF in all wall segments (P < 0.05), but was not further reduced by the CMIV. Despite changes in LA function, LV function was preserved following surgery. CONCLUSIONS: PAF significantly altered LA function and has a detrimental effect on regional wall motion. Surgical intervention further altered LA function, but the reasons for this are likely multifactorial and not entirely related to the lesion set itself.

Aortic Root Replacement for Pseudoaneurysm Arising from Freestyle Aortic Bioprosthesis.

A 70-year-old female presented with a new systolic murmur and shortness of breath three years after undergoing aortic root replacement using a 27-mm Medtronic Freestyle® stentless full root bioprosthesis (Medtronic, Inc., Fridley, Minnesota, USA). A large complex aortic root pseudoaneurysm was identified on contrasted computed tomography of the chest and transesophageal echocardiogram. We describe the redo aortic root replacement using a customized Dacron tube/valve composite graft with a proximal "skirt" and a modified Cabrol technique.

Trends in the indications and survival in pediatric heart transplants: a 24-year single-center experience in 307 patients.

BACKGROUND: Heart transplantation is the only viable treatment for children with end-stage heart failure due to congenital heart disease (CHD) or cardiomyopathy. This study reviewed the trends in the indications for transplant and survival after transplant during the past 24 years. METHODS: A retrospective review was performed of the 307 heart transplants performed at our center since 1986. To analyze the trends in the indications for transplant as well as operative death and late-survival, the data were divided into three periods in 8-year increments: 1986 to 1993 (50 patients), 1994 to 2001 (116 patients), and 2002 to 2009 (141 patients). RESULTS: The indications for transplantation were 39% cardiomyopathy, 57% CHD, and 4% retransplant. Of the 173 with CHD, 139 (80%) had single-ventricle (SV) anomalies. In the CHD group, transplantation for failed SV palliation, including Fontan procedure, became the predominant indication in the last 8-year interval of our program. Survival after transplant was the best in patients with cardiomyopathy and the worst in patients with failed palliations for SV anomalies, including failed Fontan procedures. CONCLUSIONS: Transplantation for heart failure related to failed SV palliation has become the most common indication for patients with CHD. The high-risk nature of these transplants will have significant implications for heart transplant programs as more infants with SV anomalies survive palliative procedures performed during infancy.

Differential modulation of right ventricular strain and right atrial mechanics in mild vs. severe pressure overload.

Increased right atrial (RA) and ventricular (RV) chamber volumes are a late maladaptive response to chronic pulmonary hypertension. The purpose of the current investigation was to characterize the early compensatory changes that occur in the right heart during chronic RV pressure overload before the development of chamber dilation. Magnetic resonance imaging with radiofrequency tissue tagging was performed on dogs at baseline and after 10 wk of pulmonary artery banding to yield either mild RV pressure overload (36% rise in RV pressure; n = 5) or severe overload (250% rise in RV pressure; n = 4). The RV free wall was divided into three segments within a midventricular plane, and circumferential myocardial strain was calculated for each segment, the septum, and the left ventricle. Chamber volumes were calculated from stacked MRI images, and RA mechanics were characterized by calculating the RA reservoir, conduit, and pump contribution to RV filling. With mild RV overload, there were no changes in RV strain or RA function. With severe RV overload, RV circumferential strain diminished by 62% anterior (P = 0.04), 42% inferior (P = 0.03), and 50% in the septum (P = 0.02), with no change in the left ventricle (P = 0.12). RV filling became more dependent on RA conduit function, which increased from 30 ± 9 to 43 ± 13% (P = 0.01), than on RA reservoir function, which decreased from 47 ± 6 to 33 ± 4% (P = 0.04), with no change in RA pump function (P = 0.94). RA and RV volumes and RV ejection fraction were unchanged from baseline during either mild (P > 0.10) or severe RV pressure overload (P > 0.53). In response to severe RV pressure overload, RV myocardial strain is segmentally diminished and RV filling becomes more dependent on RA conduit rather than reservoir function. These compensatory mechanisms of the right heart occur early in chronic RV pressure overload before chamber dilation develops.

Performance of a novel dual-electrode bipolar radiofrequency ablation device: a chronic porcine study.

OBJECTIVE: : Over recent years, a variety of energy sources, including bipolar radiofrequency, have been used to replace the traditional incisions of the Cox-Maze procedure for the surgical treatment of atrial fibrillation (AF). The purpose of this study was to evaluate the safety and efficacy of a novel dual-electrode bipolar radiofrequency ablation device Synergy (Atricure, Inc., Cincinnati, OH USA) for AF in a chronic porcine model. METHODS: : Six domestic pigs underwent a modified Cox-Maze IV procedure without cardiopulmonary bypass using the Synergy device. Animals survived for 30 days. Each pig then underwent induction of AF and was killed to remove the heart en bloc for histologic assessment. Each ablation line was dissected perpendicularly at 5-mm intervals to assess the lesion width, depth, and transmurality. RESULTS: : All animals survived the operation. Electrical isolation of the left atrial appendage and the pulmonary veins were documented by pacing acutely and at 30 days after the operation in all six animals. All animals failed to be induced in AF at 30 days. There was no gross evidence of intra-atrial thrombus formation or stricture of the pulmonary veins. All ablations (n = 209) examined were discrete, linear, and transmural, with a mean lesion width of 3.0 ± 0.7 mm and a mean lesion depth of 5.4 ± 3.3 mm. The mean ablation time was 16.3 ± 4.4 seconds, with a mean total energy delivery of 238 ± 170 J. CONCLUSIONS: : The Atricure Synergy was able to create reliable chronic transmural lesions of the modified Cox-Maze IV procedure on a porcine beating heart without cardiopulmonary bypass. The ablation lines were significantly wider when compared with its predecessor, the Isolator II.