Re-Dosing del Nido cardioplegia in adult cardiac surgery: Perfusion characteristics and outcomes--Is there an optimal redosing strategy?

OBJECTIVES: del Nido cardioplegia is utilized for myocardial protection in adult patients undergoing cardiac surgery; however, no standardized re-dosing protocol exists. We describe perfusion characteristics and clinical outcomes in adult cardiac surgery patients who were re-dosed with del Nido cardioplegia. METHODS: Chart review was performed for adult patients undergoing cardiac surgery (specific inclusion/exclusion criteria below) who received exactly two doses of del Nido cardioplegia from 2012 to 2019; n = 542 patients. The main outcome was a composite endpoint comprised of operative mortality, myocardial infarction, post-operative cardiac support device (CSD), and postoperative decrease in ejection fraction (EF), which was analyzed via multivariable logistic regression (MVLR). A secondary analysis evaluated postoperative vasoactive-inotropic scores (VIS) via gamma log link regression (GLLR) as a more physiologic indication of myocardial recovery. RESULTS: MVLR demonstrated that increased total cardiopulmonary bypass (CPB) time was associated with a positive composite outcome (p < .001), whereas time between doses (p = .237) and the volume of each dose was not (p = .626). GLLR also demonstrated that prolonged CBP, decreased EF, congestive heart failure at time of surgery, and low hematocrit at the start of the surgery were all associated with higher VIS. CONCLUSIONS: In this retrospective study, variations in re-dosing strategy for del Nido cardioplegia do not affect postoperative outcomes and increased CPB time is associated with increased operative mortality, myocardial infarction, need for post-operative CSDs, and reduced postoperative EF, and increased VIS, irrespective of the re-dosing strategy. Further studies are warranted to to identify additional patient and operative characteristics that predispose to complications.

Circulating and tissue matricellular RNA and protein expression in calcific aortic valve disease.

Aortic valve sclerosis is a highly prevalent, poorly characterized asymptomatic manifestation of calcific aortic valve disease and may represent a therapeutic target for disease mitigation. Human aortic valve cusps and blood were obtained from 333 patients undergoing cardiac surgery (n = 236 for severe aortic stenosis, n = 35 for asymptomatic aortic valve sclerosis, n = 62 for no valvular disease), and a multiplex assay was used to evaluate protein expression across the spectrum of calcific aortic valve disease. A subset of six valvular tissue samples (n = 3 for asymptomatic aortic valve sclerosis, n = 3 for severe aortic stenosis) was used to create RNA sequencing profiles, which were subsequently organized into clinically relevant gene modules. RNA sequencing identified 182 protein-encoding, differentially expressed genes in aortic valve sclerosis vs. aortic stenosis; 85% and 89% of expressed genes overlapped in aortic stenosis and aortic valve sclerosis, respectively, which decreased to 55% and 84% when we targeted highly expressed genes. Bioinformatic analyses identified six differentially expressed genes encoding key extracellular matrix regulators: TBHS2, SPARC, COL1A2, COL1A1, SPP1, and CTGF. Differential expression of key circulating biomarkers of extracellular matrix reorganization was observed in control vs. aortic valve sclerosis (osteopontin), control vs. aortic stenosis (osteoprotegerin), and aortic valve sclerosis vs. aortic stenosis groups (MMP-2), which corresponded to valvular mRNA expression. We demonstrate distinct mRNA and protein expression underlying aortic valve sclerosis and aortic stenosis. We anticipate that extracellular matrix regulators can serve as circulating biomarkers of early calcific aortic valve disease and as novel targets for early disease mitigation, pending prospective clinical investigations.

Direct access valve-in-valve implantation for management of complex valvulopathy.

The management of bioprosthetic structural valve degeneration requires complex surgical or transcatheter re-intervention for which many high-risk patients are not considered candidates. Here, we describe a technique for a direct surgical access valve-in-valve implantation in patients with complex bioprosthetic valvulopathy for whom standard surgical valve replacement and percutaneous interventions were high-risk and contraindicated, respectively.

Acute kidney injury following surgical aortic valve replacement.

BACKGROUND: Acute kidney injury (AKI) is a significant complication of surgical aortic valve replacement (SAVR). This study sought to describe AKI following SAVR, its risk factors, predictors and effect on long-term survival. METHODS: We retrospectively reviewed 2169 patients who underwent isolated SAVR between 2000 and 2012. The main end-points were occurrence of AKI, postoperative complications, and short- and long-term survival rates following SAVR. Patients were divided into two groups: AKI+ (n = 181) and AKI- (n = 1945). RESULTS: AKI occurred in 8.5% of patients, of which 3.9% (n = 7) needed dialysis. Predictors of AKI after SAVR were body mass index (BMI) and intraoperative packed red blood cells (PRBC) transfusion. AKI+ patients had a more complicated postoperative course and higher cumulative mortality (25% vs. 17%, p = 0.012) with a median follow-up of 4.1 years. AKI was not found to be an independent predictor of mortality. CONCLUSIONS: Predictors of AKI after SAVR are increased BMI and intraoperative PRBC transfusion. AKI conferred an increase in hospital length of stay and cumulative mortality while the need for postoperative dialysis was associated with the most complicated hospital stays and the highest in-hospital and cumulative mortalities; therefore careful recognition of patients at risk of AKI is warranted for a better preoperative renal optimization. However, incidence of AKI was lower than what is reported after both on-CPB cardiac surgeries and transcatheter aortic valve replacement, moreover AKI was not found to be an independent predictor of mortality.

In Vitro Proof of Concept of a First-Generation Growth-Accommodating Heart Valved Conduit for Pediatric Use.

Currently available heart valve prostheses have no growth potential, requiring children with heart valve diseases to endure multiple valve replacement surgeries with compounding risks. This study demonstrates the in vitro proof of concept of a biostable polymeric trileaflet valved conduit designed for surgical implantation and subsequent expansion via transcatheter balloon dilation to accommodate the growth of pediatric patients and delay or avoid repeated open-heart surgeries. The valved conduit is formed via dip molding using a polydimethylsiloxane-based polyurethane, a biocompatible material shown here to be capable of permanent stretching under mechanical loading. The valve leaflets are designed with an increased coaptation area to preserve valve competence at expanded diameters. Four 22 mm diameter valved conduits are tested in vitro for hydrodynamics, balloon dilated to new permanent diameters of 23.26 ± 0.38 mm, and then tested again. Upon further dilation, two valved conduits sustain leaflet tears, while the two surviving devices reach final diameters of 24.38 ± 0.19 mm. After each successful dilation, the valved conduits show increased effective orifice areas and decreased transvalvular pressure differentials while maintaining low regurgitation. These results demonstrate concept feasibility and motivate further development of a polymeric balloon-expandable device to replace valves in children and avoid reoperations.

Age-related enhanced degeneration of bioprosthetic valves due to leaflet calcification, tissue crosslinking, and structural changes.

AIMS: Bioprosthetic heart valves (BHVs), made from glutaraldehyde-fixed heterograft materials, are subject to more rapid structural valve degeneration (SVD) in paediatric and young adult patients. Differences in blood biochemistries and propensity for disease accelerate SVD in these patients, which results in multiple re-operations with compounding risks. The goal of this study is to investigate the mechanisms of BHV biomaterial degeneration and present models for studying SVD in young patients and juvenile animal models. METHODS AND RESULTS: We studied SVD in clinical BHV explants from paediatric and young adult patients, juvenile sheep implantation model, rat subcutaneous implants, and an ex vivo serum incubation model. BHV biomaterials were analysed for calcification, collagen microstructure (alignment and crimp), and crosslinking density. Serum markers of calcification and tissue crosslinking were compared between young and adult subjects. We demonstrated that immature subjects were more susceptible to calcification, microstructural changes, and advanced glycation end products formation. In vivo and ex vivo studies comparing immature and mature subjects mirrored SVD in clinical observations. The interaction between host serum and BHV biomaterials leads to significant structural and biochemical changes which impact their functions. CONCLUSIONS: There is an increased risk for accelerated SVD in younger subjects, both experimental animals and patients. Increased calcification, altered collagen microstructure with loss of alignment and increased crimp periods, and increased crosslinking are three main characteristics in BHV explants from young subjects leading to SVD. Together, our studies establish a basis for assessing the increased susceptibility of BHV biomaterials to accelerated SVD in young patients.

A biomimetic multilayered polymeric material designed for heart valve repair and replacement.

Materials currently used to repair or replace a heart valve are not durable. Their limited durability related to structural degeneration or thrombus formation is attributed to their inadequate mechanical properties and biocompatibility profiles. Our hypothesis is that a biostable material that mimics the structure, mechanical and biological properties of native tissue will improve the durability of these leaflets substitutes and in fine improve the patient outcome. Here, we report the development, optimization, and testing of a biomimetic, multilayered material (BMM), designed to replicate the native valve leaflets. Polycarbonate urethane and polycaprolactone have been processed as film, foam, and aligned fibers to replicate the leaflet's architecture and anisotropy, through solution casting, lyophilization, and electrospinning. Compared to the commercialized materials, our BMMs exhibited an anisotropic behavior and a closer mechanical performance to the aortic leaflets. The material exhibited superior biostability in an accelerated oxidization environment. It also displayed better resistance to protein adsorption and calcification in vitro and in vivo. These results will pave the way for a new class of advanced synthetic material with long-term durability for surgical valve repair or replacement.

Assessing sex-based differences in postsurgical clinical outcomes after use of del Nido cardioplegia.

OBJECTIVES: del Nido cardioplegia is used to pharmacologically arrest the heart during cardiac surgery and decrease reperfusion- and ischaemia-related myocardial injury. Studies have demonstrated the physiological differences between male and female hearts, potentially related to cardiac size or myocyte calcium handling; we aimed to assess for between-sex differences in clinical outcomes after receipt of del Nido cardioplegia. METHODS: Patients who underwent coronary artery bypass or coronary artery bypass graft/valve surgery at our institution using del Nido cardioplegia (January 2014 to December 2019) were included (n = 2118). Clinical data were collected retrospectively. After the creation of a propensity-matched cohort (n = 1252), multivariable logistic regression was used to analyse binary postoperative outcomes, and a Gamma model was used for a continuous postoperative outcome. Our primary end-point was a composite end-point comprised of 30-day mortality and/or need for a post-bypass mechanical support device. RESULTS: The final cohort included 459 females and 793 males (matched up to 1:2, all standardized mean differences <0.1). Multivariable logistic regression showed that biological sex was not associated with the composite primary end-point (odds ratio = 0.898, P = 0.779). A Gamma model indicated that there were no sex-related differences in vasoactive-inotropic scores reflecting vasopressor and inotrope usage at the time of patient operating room exit (exp[est] = 1.394, P = 0.189). CONCLUSIONS: Our findings showed no significant between-sex differences in clinical outcomes after receiving del Nido cardioplegia, suggesting adequate myocardial protection as currently administered. Further research is warranted to elicit if there are sex-based differences between cardioplegic solutions. IRB APPROVAL DATE (PROTOCOL NUMBER): 26 May 2021 (AAAR8359).

Re-dosing of del Nido cardioplegia in adult cardiac surgery requiring prolonged aortic cross-clamp.

OBJECTIVES: Few data exist on the use of del Nido cardioplegia in adults, specifically during operations requiring prolonged aortic cross-clamp. In this pilot study, we evaluate outcomes of patients undergoing surgery with cross-clamp time >3 h based on re-dosing strategy, using either full dose (FD; 1:4 blood to crystalloid ratio) or dilute (4:1 blood to crystalloid ratio) solution. METHODS: Consecutive adult patients (>18 years) undergoing cardiac surgery from 2012 to 2018 with cross-clamp time >3 h were reviewed. Patients were excluded if del Nido cardioplegia was not used. Patients were categorized into FD or dilute groups based on re-dosing solution. Propensity score matching was used to control for baseline differences between groups. The primary endpoint was in-hospital mortality. Other outcomes examined included: postoperative mechanical support, arrhythmia, stroke, dialysis and cardiac function. RESULTS: Included for analysis were 173 patients (115 male) with median age of 63.8 (interquartile range 53.9-73.1). Major comorbidities included diabetes (45), cerebrovascular disease (34), hypertension (131), atrial fibrillation (52) and previous cardiac surgery (83). There were 108 patients (62%) who received FD re-dosing, while 65 (38%) received dilute. A greater proportion of patients in the dilute group received retrograde delivery, for both induction (32/108 vs 39/65, P < 0.001) and re-dose (50/108 vs 53/65, P < 0.001). After propensity score matching, in-hospital mortality was not different between groups (6/48 vs 1/48, P = 0.131). There were no differences in rates of postoperative mechanical circulatory support, stroke, left ventricular ejection fraction or right ventricle dysfunction. CONCLUSIONS: Del Nido cardioplegia has been used in complex cardiac surgery requiring prolonged cross-clamp. Re-dosing can be performed with either FD or dilute del Nido solution with no statistical difference in outcomes.

Noncalcific Mechanisms of Bioprosthetic Structural Valve Degeneration.

Bioprosthetic heart valves (BHVs) largely circumvent the need for long-term anticoagulation compared with mechanical valves but are increasingly susceptible to deterioration and reduced durability with reoperation rates of ≈10% and 30% at 10 and 15 years, respectively. Structural valve degeneration is a common, unpreventable, and untreatable consequence of BHV implantation and is frequently characterized by leaflet calcification. However, 25% of BHV reoperations attributed to structural valve degeneration occur with minimal leaflet mineralization. This review discusses the noncalcific mechanisms of BHV structural valve degeneration, highlighting the putative roles and pathophysiological relationships between protein infiltration, glycation, oxidative and mechanical stress, and inflammation and the structural consequences for surgical and transcatheter BHVs.

Aortic Valve Regurgitation: Pathophysiology and Implications for Surgical Intervention in the Era of TAVR.

Aortic insufficiency (AI) or regurgitation is caused by the malcoaptation of the aortic valve (AV) cusps due to intrinsic abnormalities of the valve itself, a dilatation or geometric distortion of the aortic root, or by some combination thereof. In recent years, there has been an increase in the number of studies suggesting that AI is an active disease process caused by a combination of factors including but not limited to alteration of specific molecular pathways, genetic predisposition, and changes in the mechanotransductive properties of the AV apparatus. As the surgical management of AV disease continues to evolve, increasingly sophisticated surgical and percutaneous techniques for AV repair and replacement, including transcatheter aortic valve replacement (TAVR), have become more commonplace and will likely continue to expand as new devices are introduced. However, these techniques necessitate frequent reappraisal of the biological and mechanobiological mechanisms underlying AV regurgitation to better understand the risk factors for AI development and recurrence following surgical intervention as well as expand our limited knowledge on patient selection for such procedures. The aim of this review is to describe some of the putative mechanisms implicated in the development of AI, dissect some of the cross-talk among known and possible signaling pathways leading to valve remodeling, identify association between these pathways and pharmacological approaches, and discuss the implications for surgical and percutaneous approaches to AV repair in replacement in the TAVR era.

Aortic Root Replacement for a TAVR-Induced Aortic Root-to-Right Ventricular Fistula.

Aortic right ventricular fistulae have been thoroughly documented as a rare but potentially serious complication of surgical aortic valve replacement. The risk factors and pathogenesis contributing to this complication with respect to transcatheter aortic valve replacement (TAVR), however, remain far less characterized. We describe a post-TAVR aortic root-to-right ventricular fistula with associated pseudoaneurysm requiring surgical aortic root replacement.

Comparative pathology of human and canine myxomatous mitral valve degeneration: 5HT and TGF-ß mechanisms.

Myxomatous mitral valve degeneration (MMVD) is a leading cause of valve repair or replacement secondary to the production of mitral regurgitation, cardiac enlargement, systolic dysfunction, and heart failure. The pathophysiology of myxomatous mitral valve degeneration is complex and incompletely understood, but key features include activation and transformation of mitral valve (MV) valvular interstitial cells (VICs) into an active phenotype leading to remodeling of the extracellular matrix and compromise of the structural components of the mitral valve leaflets. Uncovering the mechanisms behind these events offers the potential for therapies to prevent, delay, or reverse myxomatous mitral valve degeneration. One such mechanism involves the neurotransmitter serotonin (5HT), which has been linked to development of valvulopathy in a variety of settings, including valvulopathy induced by serotonergic drugs, Serotonin-producing carcinoid tumors, and development of valvulopathy in laboratory animals exposed to high levels of serotonin. Similar to humans, the domestic dog also experiences naturally occurring myxomatous mitral valve degeneration, and in some breeds of dogs, the lifetime prevalence of myxomatous mitral valve degeneration reaches 100%. In dogs, myxomatous mitral valve degeneration has been associated with high serum serotonin, increased expression of serotonin-receptors, autocrine production of serotonin within the mitral valve leaflets, and downregulation of serotonin clearance mechanisms. One pathway closely associated with serotonin involves transforming growth factor beta (TGF-ß) and the two pathways share a common ability to activate mitral valve valvular interstitial cells in both humans and dogs. Understanding the role of serotonin and transforming growth factor beta in myxomatous mitral valve degeneration gives rise to potential therapies, such as 5HT receptor (5HT-R) antagonists. The main purposes of this review are to highlight the commonalities between myxomatous mitral valve degeneration in humans and dogs, with specific regards to serotonin and transforming growth factor beta, and to champion the dog as a relevant and particularly valuable model of human disease that can accelerate development of novel therapies.

Bringing prevost's sign into the third dimension: Artificial intelligence estimation of conjugate gaze adjusted length (CGAL) and correlation with acute ischemic stroke.

Conjugate gaze deviation is associated with acute ischemic stroke (AIS), although previously only measured on a 2D plane. The current study evaluates 3D imaging efficacy to assess conjugate gaze deviation and correlate direction and strength of deviation to neuro-clinical findings.A retrospective analysis of 519 patients who had CT scans for suspected AIS at our institution. Direction and angle of eye deviation were calculated based on 2D axial images. Volumetric reconstruction of CT scans allowed for calculation of 3D conjugate gaze adjusted length (CGAL). Angle, direction, and vector strength of both 2D and 3D scans were calculated by an artificial intelligence algorithm and tested for agreement with hemispheric ischemia location. CGAL measurements were correlated to NIHSS scores. Follow up MRI data was used to evaluate the sensitivity and specificity of CGAL in the identification of AIS.The final analysis included 122 patients. A strong agreement was found between 3D gaze direction and hemispheric ischemia location. CGAL measurements were highly correlated with NIHSS score (r = .72, P = .01). A CGAL >0.25, >0.28, and >0.35 exhibited a sensitivity of 91%, 86%, and 82% and specificity of 66%, 89%, and 89%, respectively, in AIS identification. A CGAL >0.28 has the best sensitivity-specificity balance in the identification of AIS. A CGAL >0.25 has the highest sensitivity.Given CED's correlation with NIHSS score a 1/4 deviation in the ipsilateral direction is a sensitive ancillary radiographic sign to assist radiologists in making a correct diagnosis even when not presented with full clinical data.

Glycation and Serum Albumin Infiltration Contribute to the Structural Degeneration of Bioprosthetic Heart Valves.

Valvular heart diseases are associated with significant cardiovascular morbidity and mortality, and often require surgical and/or percutaneous repair or replacement. Valve replacement is limited to mechanical and biological prostheses, the latter of which circumvent the need for lifelong anticoagulation but are subject to structural valve degeneration (SVD) and failure. Although calcification is heavily studied, noncalcific SVD, which represent roughly 30% of BHV failures, is relatively underinvestigated. This original work establishes 2 novel and interacting mechanisms-glycation and serum albumin incorporation-that occur in clinical valves and are sufficient to induce hallmarks of structural degeneration as well as functional deterioration.

Patents and heart valve surgery--I: mechanical valves.

Valvular heart disease, inherited or acquired, affects more than 5 million Americans yearly. Whereas medical treatment is beneficial in the initial stages of valvular heart disease, surgical correction provides symptomatic relief and long-term survival benefits. Surgical options include either repair or replacement using mechanical or bio-prosthetic valves. Patient age and the post-operative need for anticoagulation therapy are major determinants of the choice between use of mechanical or bio-prosthetic valves. Since the first mechanical valves were made available several decades ago, the incorporation of increasingly sophisticated materials and methodologies has led to substantial improvements in the valve design, and has catalyzed a parallel increase in the amount of patents issued for these emerging technologies. In this paper, we have chronologically reviewed such patents, briefly discussed various challenges that mechanical heart valve implementation is faced with and finally reviewed some of the strategies employed to overcome such obstacles. An ideal prosthetic heart valve would comprehensively mimic the natural hemodynamics and physiology of the native heart valve. Additionally, such a valve would be easily implantable, associated with a minimal risk of thrombosis and thus need for anti-coagulation, and with a proven long-term durability. With cutting edge technological advancements in the recent times, the ongoing innovative and collaborative efforts of physicians, scientists, and engineers will not seize until an ideal mechanical heart valve becomes a reality.

Patents and heart valve surgery - II: tissue valves.

Valvular heart disease affects millions of Americans yearly and currently requires surgical intervention to repair or replace the defective valves. Through a close-knit collaboration between physicians, scientists and biomedical engineers, a vast degree of research and development has been aimed towards the optimization of prosthetic heart valves. Although various methods have made fantastic strides in producing durable prostheses, the therapeutic efficacy of prosthetic valves is inherently limited by a dependency upon lifelong anticoagulant regimens for recipients - a difficult challenge for many in clinical setting. Thus, biological tissue valves have been developed to circumvent vascular and immunemediated complications by incorporating biological materials to mimic native valves while still maintaining a necessary level of structural integrity. Over the past decade, a multitude of patents pertaining to the refinement of designs as well as the advancement in methodologies and technologies associated with biological tissue valves have been issued. This review seeks to chronicle and characterize such patents in an effort to track the past, present, and future progress as well as project the trajectory of tissue valves in the years to come.

Bridging cardiogenic shock patients with short-term ventricular support at a community hospital to long-term ventricular support at a tertiary hospital.

BACKGROUND: Patients in cardiogenic shock require immediate circulatory support. Outcomes of patients who underwent short-term ventricular assist device (STVAD) implantation in a community hospital (CH) as a bridge to a long-term VAD (LTVAD) were compared with those who received both implants at the same tertiary hospital (TH). METHODS: Data were retrospectively reviewed for patients with a STVAD who were bridged to a LTVAD in a TH from 1997 to 2010. We studied outcomes and survival censored for cardiac transplantation. RESULTS: Thirty-seven patients (73% male) were identified. Mean age was 52 ± 16 years, 30% were diabetic, and 65% had intra-aortic balloon pump support. Reasons for STVAD implantation were an acute myocardial infarction, 38%; post-cardiotomy, 38%, decompensated chronic heart failure, 19%; and others, 5%. A STVAD was implanted in a CH in 20 patients (54%), and they had fewer cardiovascular risk factors than those whose STVAD was implanted at the TH. All patients at the CH were at Interagency Registry for Mechanically Assisted Circulatory Support 1 compared with 71% at the TH (p = 0.014). Patients from the CH tended to die sooner after LTVAD implant, although long-term survival was similar. At the 1-year follow-up, 65% from the CH were alive or had received a transplant vs 60% from the TH. CONCLUSION: Patients with cardiogenic shock in whom a STVAD was implanted in a CH and then were bridged to a LTVAD in a TH had similar long-term survival as those bridged to LTVAD at the TH.