Mechanical pump complication after HeartMate 3 implantation.

BACKGROUND: With the improvement in postoperative complications and long-term survival post LVAD, continuing to improve clinical outcomes will require efforts to decrease long-term complications. The purpose of this study is to describe the incidence of mechanical pump failure requiring surgery, which we define as pump failure secondary to either outflow graft compression, outflow graft obstruction, or pump thrombosis requiring surgical intervention. METHODS: 141 consecutive adult patients who underwent HeartMate3 Implantation using the "cut-then-sew" implantation technique between September 2015 and September 2021 were included in our study. The primary outcome measure was mechanical pump complication (outflow graft obstruction and or pump thrombosis) requiring surgical intervention. Secondary outcome measures included incidence of bleeding, stroke, renal failure, length of stay, and overall survival. Median follow up was 27.3 months. RESULTS: Eleven (7.8%) of patients developed mechanical pump complications. Six patients developed outflow graft obstruction. Five patients developed acute pump thrombosis. Median time to a mechanical complication was 828 days. Of the 11 patients who underwent surgery, 10 patients (90%) survived to discharge. Overall survival at 1, 3, and 5 years was 82.9%, 69.1% and 55.2% respectively for the entire cohort. CONCLUSION: The mechanical pump complication rate of 7.8% which is quite high may be related to duration of follow up, as the median time to mechanical complication was 828 days. This study highlights an important late complication that occurs post LVAD implantation.

Unilateral versus bilateral anterograde cerebral perfusion in acute type A aortic dissection repair: A systematic review and meta-analysis.

OBJECTIVES: The aim of the study is to compare the safety and efficacy of unilateral anterograde cerebral perfusion (UACP) and bilateral anterograde cerebral perfusion (BACP) for acute type A aortic dissection (ATAAD). METHODS: A systematic review of the MEDLINE (PubMed), Scopus, and Cochrane Library databases (last search: August 7th, 2021) was performed according to the PRISMA statement. Studies directly comparing UACP versus BACP for ATAAD were included. Random-effects meta-analyses were performed. RESULTS: Eight retrospective cohort studies were identified, incorporating 2416 patients (UACP: 843, BACP: 1573). No statistically significant difference was observed regarding in-hospital mortality (odds ratio [OR]:1.05 [95% Confidence Interval (95% CI):0.70-1.57]), permanent neurological deficit (PND) (OR: 0.94 [95% CI: 0.52-1.70]), transient neurological deficit (TND) (OR: 1.37 [95% CI: 0.98-1.92]), renal failure (OR: 0.96 [95% CI: 0.70-1.32]), and re-exploration for bleeding (OR: 0.77 [95% CI: 0.48-1.22]). Meta-regression analysis revealed that PND and TND were not influenced by differences in rates of total arch repair, Bentall procedure, and concomitant CABG in UACP and BACP groups. Cardiopulmonary bypass time (Standard Mean Difference [SMD]: -0.11 [95% CI: -0.22, 0.44]), Cross clamp time (SMD: -0.04 [95% CI: -0.38, 0.29]), and hypothermic circulatory arrest time (SMD: -0.12 [95% CI: -0.55, 0.30]) were comparable between UACP and BACP. Intensive care unit stay was shorter in BACP arm (SMD:0.16 [95% CI: 0.01, 0.31]); however, length of hospital stay was shorter in UACP arm (SMD: -0.25 [95% CI: -0.45, -0.06]). CONCLUSIONS: UACP and BACP had similar results in terms of in-hospital mortality, PND, TND, renal failure, and re-exploration for bleeding rate in patients with ATAAD. ICU stay was shorter in the BACP arm while LOS was shorter in the UACP arm.

Connective Tissue Disorders and Cardiovascular Complications: The Indomitable Role of Transforming Growth Factor-ß Signaling.

Marfan Syndrome (MFS) and Loeys-Dietz Syndrome (LDS) represent heritable connective tissue disorders that segregate with a similar pattern of cardiovascular defects (thoracic aortic aneurysm, mitral valve prolapse/regurgitation, and aortic dilatation with regurgitation). This pattern of cardiovascular defects appears to be expressed along a spectrum of severity in many heritable connective tissue disorders and raises suspicion of a relationship between the normal development of connective tissues and the cardiovascular system. With overwhelming evidence of the involvement of aberrant Transforming Growth Factor-beta (TGF-ß) signaling in MFS and LDS, this signaling pathway may represent the common link in the relationship between connective tissue disorders and their associated cardiovascular complications. To further explore this hypothetical link, this chapter will review the TGF-ß signaling pathway, the heritable connective tissue syndromes related to aberrant TGF-ß signaling, and will discuss the pathogenic contribution of TGF-ß to these syndromes with a primary focus on the cardiovascular system.

Elevated Wall Tension Initiates Interleukin-6 Expression and Abdominal Aortic Dilation.

BACKGROUND: Hypertension (HTN) has long been associated with abdominal aortic aneurysm (AAA) development, and these cardiovascular pathologies are biochemically characterized by elevated plasma levels of angiotensin II (AngII) as well as interleukin-6 (IL-6). A biologic relationship between HTN and AAA has not been established, however. Accordingly, the objective of this study was to evaluate whether elevated tension may initiate IL-6 production to accumulate monocyte/macrophages and promote dilation of the abdominal aorta (AA). METHODS: An IL-6 infusion model (4.36 µg/kg/day) was created utilizing an osmotic infusion pump, and after 4 weeks, AA diameter was measured by digital microscopy. The AA was then excised for CD68 immunostaining and flow cytometric analysis with CD11b and F4/80 to identify macrophages. Aortic segments from wild-type mice were suspended on parallel wires in an ex vivo tissue myograph at experimentally derived optimal tension (1.2 g) and in the presence of elevated tension (ET, 1.7 g) for 3 hr, and expression of IL-6 and monocyte chemoattractant protein-1 (MCP-1) was evaluated by quantitative polymerase chain reaction (QPCR). Isolated aortic vascular smooth muscle cells (VSMCs) were subjected to 12% biaxial cyclic stretch or held static (control) for 3 hr (n = 7), and IL-6 and MCP-1 expressions were evaluated by QPCR. RESULTS: Four-week IL-6 infusion resulted in an AA outer diameter that was 72.5 ± 5.6% (P < 0.05) greater than that of control mice, and aortic dilation was accompanied by an accumulation of macrophages in the AA medial layer as defined by an increase in CD68 + staining as well as an increase by flow cytometric quantification of CD11b+/F4/80+ cells. Wild-type AA segments did not respond to ex vivo application of ET but cyclic stretch of isolated VSMCs increased IL-6 (2.03 ± 0.3 fold) and MCP-1 (1.51 ± 0.11 fold) expression compared to static control (P < 0.05). Pretreatment with the selective STAT3 inhibitor WP1066 blunted the response in both cases. Interestingly, AngII did not stimulate expression of IL-6 and MCP-1 above that initiated by tension and again, the response was inhibited by WP1066, supporting an integral role of STAT3 in this pathway. CONCLUSIONS: An IL-6 infusion model can initiate macrophage accumulation as well as aortic dilation, and under conditions of elevated tension, this proinflammatory cytokine can be produced by aortic VSMCs. By activation of STAT3, MCP-1 is expressed to increase media macrophage abundance and create an environment susceptible to dilation. This biomechanical association between HTN and aortic dilation may allow for the identification of novel therapeutic strategies.

Differential hypertensive protease expression in the thoracic versus abdominal aorta.

BACKGROUND: Hypertension (HTN), which is a major risk factor for cardiovascular morbidity and mortality, can drive pathologic remodeling of the macro- and microcirculation. Patterns of aortic pathology differ, however, suggesting regional heterogeneity of the pressure-sensitive protease systems triggering extracellular matrix remodeling in the thoracic (TA) and abdominal aortas (AA). This study tested the hypothesis that the expression of two major protease systems (matrix metalloproteinases [MMPs] and cathepsins) in the TA and AA would be differentially affected with HTN. METHODS: Normotensive (BPN3) mice at 14-16 weeks of age underwent implantation of osmotic infusion pumps for 28-day angiotensin II (AngII) delivery (1.46 mg/kg/day; BPN3+AngII; n = 8) to induce HTN. The TA and AA were harvested to determine levels of MMP-2, MMP-9, and membrane type 1-MMP, and cathepsins S, K, and L were evaluated in age-matched BPN3 (n = 8) control and BPH2 spontaneously hypertensive mice (non-AngII pathway; n = 7). Blood pressure was monitored via CODA tail cuff plethysmography (Kent Scientific Corporation, Torrington, Conn). Quantitative real-time polymerase chain reaction and immunoblotting/zymography were used to measure MMP and cathepsin messenger RNA expression and protein abundance, respectively. Target protease values were compared within each aortic region via analysis of variance. RESULTS: Following 28 days infusion, the BPN3+AngII mice had a 17% increase in systolic blood pressure, matching that of the BPH2 spontaneously hypertensive mice (both P < .05 vs BPN3). MMP-2 gene expression demonstrated an AngII-dependent increase in the TA (P < .05), but MMP-9 was not altered with HTN. Expression of tissue inhibitor of metalloproteinases-1 was markedly increased in TA of BPN3+AngII mice, but tissue inhibitor of metalloproteinases-2 demonstrated decreased expression in the AA of both hypertensive groups (P < .05). Only cathepsin K responded to AngII-induced HTN with significant elevation in the TA of those mice, but expression of cathepsin L and cystatin C was inhibited in AA of both hypertensive groups (P < .05). Apoptotic markers were not significantly elevated in any experimental group. CONCLUSIONS: By using two different models of HTN, this study has identified pressure-dependent as well as AngII-dependent regional alterations in aortic gene expression of MMPs and cathepsins that may lead to differential remodeling responses in each of the aortic regions. Further studies will delineate mechanisms and may provide targeted therapies to attenuate down-stream aortic pathology based on demonstrated regional heterogeneity.

Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin.

BACKGROUND: The purpose of this study was to determine whether patients with heart failure and a preserved ejection fraction (HFpEF) have an increase in passive myocardial stiffness and the extent to which discovered changes depend on changes in extracellular matrix fibrillar collagen and cardiomyocyte titin. METHODS AND RESULTS: Seventy patients undergoing coronary artery bypass grafting underwent an echocardiogram, plasma biomarker determination, and intraoperative left ventricular epicardial anterior wall biopsy. Patients were divided into 3 groups: referent control (n=17, no hypertension or diabetes mellitus), hypertension (HTN) without (-) HFpEF (n=31), and HTN with (+) HFpEF (n=22). One or more of the following studies were performed on the biopsies: passive stiffness measurements to determine total, collagen-dependent and titin-dependent stiffness (differential extraction assay), collagen assays (biochemistry or histology), or titin isoform and phosphorylation assays. In comparison with controls, patients with HTN(-)HFpEF had no change in left ventricular end-diastolic pressure, myocardial passive stiffness, collagen, or titin phosphorylation but had an increase in biomarkers of inflammation (C-reactive protein, soluble ST2, tissue inhibitor of metalloproteinase 1). In comparison with both control and HTN(-)HFpEF, patients with HTN(+)HFpEF had increased left ventricular end-diastolic pressure, left atrial volume, N-terminal propeptide of brain natriuretic peptide, total, collagen-dependent, and titin-dependent stiffness, insoluble collagen, increased titin phosphorylation on PEVK S11878(S26), reduced phosphorylation on N2B S4185(S469), and increased biomarkers of inflammation. CONCLUSIONS: Hypertension in the absence of HFpEF did not alter passive myocardial stiffness. Patients with HTN(+)HFpEF had a significant increase in passive myocardial stiffness; collagen-dependent and titin-dependent stiffness were increased. These data suggest that the development of HFpEF depends on changes in both collagen and titin homeostasis.

Multidimensional Contribution of Matrix Metalloproteinases to Atherosclerotic Plaque Vulnerability: Multiple Mechanisms of Inhibition to Promote Stability.

The prevalence of atherosclerotic disease continues to increase, and despite significant reductions in major cardiovascular events with current medical interventions, an additional therapeutic window exists. Atherosclerotic plaque growth is a complex integration of cholesterol penetration, inflammatory cell infiltration, vascular smooth muscle cell (VSMC) migration, and neovascular invasion. A family of matrix-degrading proteases, the matrix metalloproteinases (MMPs), contributes to all phases of vascular remodeling. The contribution of specific MMPs to endothelial cell integrity and VSMC migration in atherosclerotic lesion initiation and progression has been confirmed by the increased expression of these proteases in plasma and plaque specimens. Endogenous blockade of MMPs by the tissue inhibitors of metalloproteinases (TIMPs) may attenuate proteolysis in some regions, but the progression of matrix degeneration suggests that MMPs predominate in atherosclerotic plaque, precipitating vulnerability. Plaque neovascularization also contributes to instability and, coupling the known role of MMPs in angiogenesis to that of atherosclerotic plaque growth, interest in targeting MMPs to facilitate plaque stabilization continues to accumulate. This article aims to review the contributions of MMPs and TIMPs to atherosclerotic plaque expansion, neovascularization, and rupture vulnerability with an interest in promoting targeted therapies to improve plaque stabilization and decrease the risk of major cardiovascular events.

The prevalence of attention-deficit/hyperactivity disorder following neonatal aortic arch repair.

OBJECTIVE: We sought to determine the prevalence of attention-deficit/hyperactivity disorder in a population of children who underwent neonatal heart surgery involving repair of the aortic arch for Norwood Stage I, interrupted aortic arch, and combined repair of aortic coarctation with ventricular septal defect. METHODS: Children between the ages of 5 and 16 were surveyed using the ADHD-IV and the Child Heath Questionnaire-50. Classification as attention-deficit/hyperactivity disorder was defined for this study as either a parent-reported diagnosis of attention-deficit/hyperactivity disorder or ADHD-IV inattention score of ⩾93 percentile. RESULTS: Of the 134 surveys, 57 (43%) were returned completed. A total of 25 (44%) children either had a diagnosis of attention-deficit/hyperactivity disorder and/or ADHD-IV inattention score ⩾93 percentile. Eleven of the 13 (85%) children with interrupted aortic arch, 3 of the 7 (42.9%) children with combined coarctation/ventricular septal defect repair, and 9 of the 33 (27.3%) children with hypoplastic left-heart syndrome were classified as having attention-deficit/hyperactivity disorder. Only 7 of the 25 (28%) children received medical treatment for this condition. Quality of life indicators in the Child Heath Questionnaire-50 Questionnaire were highly correlated with the ADHD-IV scores. CONCLUSION: The risks for the development of attention-deficit/hyperactivity disorder are multifactorial but are significantly increased in this post-surgical population. This study revealed a low treatment rate for attention-deficit/hyperactivity disorder, and a significant impact on the quality of life in these children.

Reproducible porcine model of thoracic aortic aneurysm.

BACKGROUND: Thoracic aortic aneurysms (TAAs) develop secondary to abnormal aortic extracellular matrix remodeling, resulting in a weakened and dilated aortic wall that progressed to rupture if left unattended. Currently, no diagnostic/prognostic tests are available for the detection of TAA disease. This is largely driven by the lack of a large animal model, which would permit longitudinal/mechanistic studies. Accordingly, the objective of the present study was to establish a reproducible porcine model of aortic dilatation, which recapitulates the structural and biochemical changes observed during human TAA development. METHODS AND RESULTS: Descending TAAs were induced in Yorkshire pigs (20-25 kg; n=7) through intra-adventitial injections of collagenase (5 mL, 0.35 mg/mL) and periadventitial application of crystalline CaCl2 (0.5 g). Three weeks after TAA induction, aortas were harvested and tissue was collected for biochemical and histological measurements. A subset of animals underwent MRI preoperatively and at terminal surgery. Results were compared with sham-operated controls (n=6). Three weeks after TAA induction, aortic luminal area increased by 38 ± 13% (P=0.018 versus control). Aortic structural changes included elastic lamellar degradation and decreased collagen content. The protein abundance of matrix metalloproteinases 3, 8, 9, and 12 increased in TAA tissue homogenates, whereas tissue inhibitors of metalloproteinases 1 and 4 decreased. CONCLUSIONS: These data demonstrate aortic dilatation, aortic medial degeneration, and alterations in matrix metalloproteinase/tissue inhibitors of metalloproteinase abundance, consistent with TAA formation. This study establishes for the first time a large animal model of TAA that recapitulates the hallmarks of human disease and provides a reproducible test bed for examining diagnostic, prognostic, and therapeutic strategies.

Connective tissue disorders and cardiovascular complications: the indomitable role of transforming growth factor-beta signaling.

Marfan Syndrome (MFS) and Loeys-Dietz Syndrome (LDS) represent heritable connective tissue disorders that cosegregate with a similar pattern of cardiovascular defects (thoracic aortic aneurysm, mitral valve prolapse/regurgitation, and aortic root dilatation with regurgitation). This pattern of cardiovascular defects appears to be expressed along a spectrum of severity in many heritable connective tissue disorders and raises suspicion of a relationship between the normal development of connective tissues and the cardiovascular system. Given the evidence of increased transforming growth factor-beta (TGF-ß) signaling in MFS and LDS, this signaling pathway may represent the common link in this relationship. To further explore this hypothetical link, this chapter will review the TGF-ß signaling pathway, heritable connective tissue syndromes related to TGF-ß receptor (TGFBR) mutations, and discuss the pathogenic contribution of TGF-ß to these syndromes with a primary focus on the cardiovascular system.

New Directions in Diagnostics for Aortic Aneurysms: Biomarkers and Machine Learning.

This review article presents an appraisal of pioneering technologies poised to revolutionize the diagnosis and management of aortic aneurysm disease, with a primary focus on the thoracic aorta while encompassing insights into abdominal manifestations. Our comprehensive analysis is rooted in an exhaustive survey of contemporary and historical research, delving into the realms of machine learning (ML) and computer-assisted diagnostics. This overview draws heavily upon relevant studies, including Siemens' published field report and many peer-reviewed publications. At the core of our survey lies an in-depth examination of ML-driven diagnostic advancements, dissecting an array of algorithmic suites to unveil the foundational concepts anchoring computer-assisted diagnostics and medical image processing. Our review extends to a discussion of circulating biomarkers, synthesizing insights gleaned from our prior research endeavors alongside contemporary studies gathered from the PubMed Central database. We elucidate the prevalent challenges and envisage the potential fusion of AI-guided aortic measurements and sophisticated ML frameworks with the computational analyses of pertinent biomarkers. By framing current scientific insights, we contemplate the transformative prospect of translating fundamental research into practical diagnostic tools. This narrative not only illuminates present strides, but also forecasts promising trajectories in the clinical evaluation and therapeutic management of aortic aneurysm disease.

Late Outcomes of Surgery Versus Medical Therapy in Patients With Type A Aortic Intramural Hematoma: Meta-Analysis of Reconstructed Time-to-Event Data.

The effect of an initial surgical approach (in comparison with initial medical therapy) in acute type A intramural hematoma remains insufficiently explored. We designed a pooled analysis of Kaplan-Meier-derived individual patient data from studies with follow-up for overall survival (all-cause death). Restricted mean survival time was calculated to evaluate lifetime gain or loss. The Risk of Bias in Non-Randomized Studies of Interventions tool (ROBINS-I) was used to assess risk of bias. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) was applied to assess certainty of evidence. Eight studies met our eligibility criteria, including a total of 654 patients (311 patients treated with surgery and 343 patients treated with medical therapy alone). All the studies were non-randomized and observational. The median follow-up was 4.6 years (interquartile range 1.0 to 7.7). Patients who underwent surgery had a significantly lower risk of mortality compared with patients receiving medical therapy alone (hazard ratio 0.51, 95% confidence interval 0.35 to 0.74, p <0.001). The restricted mean survival time was overall 1.1 years greater with surgery compared with medical therapy, and this difference was statistically significant (p <0.001), which means that surgery is associated with lifetime gain. The overall risk of bias (ROBINS-I) was considered moderate-to-serious and the certainty of evidence (GRADE) was deemed to be low. In conclusion, in the overall follow-up, surgery as the initial approach was associated with better late survival and lifetime gain in comparison with medical therapy alone in the setting of acute type A aortic intramural hematoma; however, high-quality randomized trials are warranted to establish the efficacy of the surgical strategy.

Paradoxical Changes: EMMPRIN Tissue and Plasma Levels in Marfan Syndrome-Related Thoracic Aortic Aneurysms.

Background: Thoracic aortic aneurysms (TAAs) associated with Marfan syndrome (MFS) are unique in that extracellular matrix metalloproteinase inducer (EMMPRIN) levels do not behave the way they do in other cardiovascular pathologies. EMMPRIN is shed into the circulation through the secretion of extracellular vesicles. This has been demonstrated to be dependent upon the Membrane Type-1 MMP (MT1-MMP). We investigated this relationship in MFS TAA tissue and plasma to discern why unique profiles may exist. Methods: Protein targets were measured in aortic tissue and plasma from MFS patients with TAAs and were compared to healthy controls. The abundance and location of MT1-MMP was modified in aortic fibroblasts and secreted EMMPRIN was measured in conditioned culture media. Results: EMMPRIN levels were elevated in MFS TAA tissue but reduced in plasma, compared to the controls. Tissue EMMPRIN elevation did not induce MMP-3, MMP-8, or TIMP-1 expression, while MT1-MMP and TIMP-2 were elevated. MMP-2 and MMP-9 were reduced in TAA tissue but increased in plasma. In aortic fibroblasts, EMMPRIN secretion required the internalization of MT1-MMP. Conclusions: In MFS, impaired EMMPRIN secretion likely contributes to higher tissue levels, influenced by MT1-MMP cellular localization. Low EMMPRIN levels, in conjunction with other MMP analytes, distinguished MFS TAAs from controls, suggesting diagnostic potential.

Long-Term Outcomes of Patients Undergoing Aortic Root Replacement With Mechanical Versus Bioprosthetic Valves: Meta-Analysis of Reconstructed Time-to-Event Data.

Background An aspect not so clear in the scenario of aortic surgery is how patients fare after composite aortic valve graft replacement (CAVGR) depending on the type of valve (bioprosthetic versus mechanical). We performed a study to evaluate the long-term outcomes of both strategies comparatively. Methods and Results Pooled meta-analysis of Kaplan-Meier-derived time-to-event data from studies with follow-up for overall survival (all-cause death), event-free survival (composite end point of cardiac death, valve-related complications, stroke, bleeding, embolic events, and/or endocarditis), and freedom from reintervention. Twenty-three studies met our eligibility criteria, including 11 428 patients (3786 patients with mechanical valves and 7642 patients with bioprosthetic valve). The overall population was mostly composed of men (mean age, 45.5-75.6 years). In comparison with patients who underwent CAVGR with bioprosthetic valves, patients undergoing CAVGR with mechanical valves presented no statistically significant difference in the risk of all-cause death in the first 30 days after the procedure (hazard ratio [HR], 1.24 [95% CI, 0.95-1.60]; P=0.109), but they had a significantly lower risk of all-cause mortality after the 30-day time point (HR, 0.89 [95% CI, 0.81-0.99]; P=0.039) and lower risk of reintervention (HR, 0.33 [95% CI, 0.24-0.45]; P<0.001). Despite its increased risk for the composite end point in the first 6 years of follow-up (HR, 1.41 [95% CI, 1.09-1.82]; P=0.009), CAVGR with mechanical valves is associated with a lower risk for the composite end point after the 6-year time point (HR, 0.46 [95% CI, 0.31-0.67]; P<0.001). Conclusions CAVGR with mechanical valves is associated with better long-term outcomes in comparison with CAVGR with bioprosthetic valves.

A standardized method for plasma extracellular vesicle isolation and size distribution analysis.

The following protocol describes our workflow for isolation and quantification of plasma extracellular vesicles (EVs). It requires limited sample volume so that the scientific value of specimens is maximized. These steps include isolation of vesicles by automated size exclusion chromatography and quantification by tunable resistive pulse sensing. This workflow optimizes reproducibility by minimizing variations in processing, handling, and storage of EVs. EVs have significant diagnostic and therapeutic potential, but clinical application is limited by disparate methods of data collection. This standardized protocol is scalable and ensures efficient recovery of physiologically intact EVs that may be used in a variety of downstream biochemical and functional analyses. Simultaneous measurement quantifies EV concentration and size distribution absolutely. Absolute quantification corrects for variations in EV number and size, offering a novel method of standardization in downstream applications.