Normative healthy reference values for global and segmental 3D principal and geometry dependent strain from cine cardiac magnetic resonance imaging.

3-Dimensional (3D) myocardial deformation analysis (3D-MDA) enables novel descriptions of geometry-independent principal strain (PS). Applied to routine 2D cine cardiovascular magnetic resonance (CMR), this provides unique measures of myocardial biomechanics for disease diagnosis and prognostication. However, healthy reference values remain undefined. This study describes age- and sex-stratified reference values from CMR-based 3D-MDA, including 3D PS. One hundred healthy volunteers were prospectively recruited following institutional ethics approval and underwent CMR imaging. 3D-MDA was performed using validated software. Age- and sex-stratified global and segmental strain measures were derived for conventional geometry-dependent [circumferential (CS), longitudinal (LS), and radial (RS)] and geometry-independent [minimum (minPS) and maximum principal (maxPS)] directions of deformation. Layer-specific contraction angle interactions were determined using local minPS vectors. The average age was 43 ± 15 years and 55% were women. Strain measures were higher in women versus men. 3D PS-based assessment of maximum tissue shortening (minPS) and maximum tissue thickening (maxPS) were greater than corresponding geometry-dependent markers of LS and RS, consistent with improved representation of local tissue deformations. Global maxPS amplitude best discriminated both age and sex. Segmental analyses showed greater strain amplitudes in apical segments. Transmural PS contraction angles were higher in females and showed a heterogeneous distribution across segments. In this study we provided age and sex-based reference values for 3D strain from CMR imaging, demonstrating improved capacity for 3D PS to document maximal local tissue deformations and to discriminate age and sex phenotypes. Novel markers of layer-specific strain angles from 3D PS were also described.

Elastin integrity in bicuspid valve-associated aortopathy is associated with altered biomechanical properties and influenced by age.

Background: Aortic wall remodelling in bicuspid aortic valve (BAV) patients is heterogeneous and characterized by elastin fiber breakdown alongside impaired biomechanics. However, the relationship between aortic histopathological changes and biomechanics are incompletely understood. We clarify the influence of elastin fiber integrity on ex vivo aortic wall mechanical properties in BAV patients, and explore the influence of patient age. Methods: Aortic tissue samples (N=66) from 19 BAV patients undergoing prophylactic ascending aortic resection surgery were analyzed. Semi-quantitative histopathological analysis was conducted to assess elastin fiber integrity including elastin content and elastic fiber fragmentation. Ex vivo biaxial mechanical testing generated stress-strain curves from which physiological [low-strain tangential modulus (LTM), transition zone onset stress (TZo)] and supraphysiological [transition zone end stress (TZe) and high-strain tangential modulus (HTM)] mechanical properties were obtained. Relationships between histopathology and mechanical properties were determined using a linear mixed effect model. BAV patients were subdivided according to 'younger' and 'older' age groups (i.e., 51-60 and 61-70 years old, respectively). Results: No statistically significant differences in elastin content were observed between younger and older BAV patients. Older patients showed greater elastin fiber fragmentation compared to their younger cohort (74% versus 61%). Elastin fiber histopathology was associated with differences in physiological mechanical properties: elastin fragmentation corresponded with lower LTM (P=0.005) and TZo (P=0.044) in younger BAV patients and higher LTM (P=0.049) and TZo (P=0.001) in older BAV patients. Histopathology changes were significantly associated with supraphysiological mechanical properties only in older BAV patients: decreased elastin integrity was associated with increased TZe (P=0.049) and HTM (P<0.001). Conclusions: Elastin histopathologic changes in BAV aortopathy correspond with differences in mechanical properties and this relationship is influenced by patient age. These novel findings provide additional mechanistic insights into aortic wall remodeling and support a more nuanced stratification of BAV patients by age.

Effect of Active Cancer on the Cardiac Phenotype: A Cardiac Magnetic Resonance Imaging-Based Study of Myocardial Tissue Health and Deformation in Patients With Chemotherapy-Naïve Cancer.

Background The overlap between cancer and cardiovascular care continues to expand, with intersections emerging before, during, and following cancer therapies. To date, emphasis has been placed on how cancer therapeutics influence downstream cardiac health. However, whether active malignancy itself influences chamber volumes, function, or overall myocardial tissue health remains uncertain. We sought to perform a comprehensive cardiovascular magnetic resonance-based evaluation of cardiac health in patients with chemotherapy-naïve cancer with comparison with a healthy volunteer population. Methods and Results Three-hundred and eighty-one patients with active breast cancer or lymphoma before cardiotoxic chemotherapy exposure were recruited in addition to 102 healthy volunteers. Both cohorts underwent standardized cardiovascular magnetic resonance imaging with quantification of chamber volumes, ejection fraction, and native myocardial T1. Left ventricular mechanics were incrementally assessed using three-dimensional myocardial deformation analysis, providing global longitudinal, circumferential, radial, and principal peak-systolic strain amplitude and systolic strain rate. The mean age of patients with cancer was 53.8±13.4 years; 79% being women. Despite similar left ventricular ejection fraction, patients with cancer showed smaller chambers, increased strain amplitude, and systolic strain rate in both conventional and principal directions, and elevated native T1 versus sex-matched healthy volunteers. Adjusting for age, sex, hypertension, and diabetes mellitus, the presence of cancer remained associated with these cardiovascular magnetic resonance parameters. Conclusions The presence of cancer is independently associated with alterations in cardiac chamber size, function, and objective markers of tissue health. Dedicated research is warranted to elucidate pathophysiologic mechanisms underlying these findings and to explore their relevance to the management of patients with cancer referred for cardiotoxic therapies.

Fluoroquinolone-Associated Type A Aortic Dissection in Alpha-1 Anti-Trypsin Deficiency.

Fluroquinolone antibiotics have come under increased scrutiny given their recent association with aortic events. Although judicious use has been urged in select patient populations, such as those with Marfan and Ehlers-Danlos syndromes, that have a known predisposition for aortopathy, other at-risk patient populations may remain. We describe the atypical delayed-presentation of a type A aortic dissection in a patient with alpha-1 anti-trypsin (A1AT) deficiency and longstanding FQ exposure. This case suggests that caution in prescribing fluroquinolone antibiotics should be extended to include those with A1AT deficiency.

Acellular bioscaffolds redirect cardiac fibroblasts and promote functional tissue repair in rodents and humans with myocardial injury.

Coronary heart disease is a leading cause of death. Tissue remodeling and fibrosis results in cardiac pump dysfunction and ischemic heart failure. Cardiac fibroblasts may rebuild damaged tissues when prompted by suitable environmental cues. Here, we use acellular biologic extracellular matrix scaffolds (bioscaffolds) to stimulate pathways of muscle repair and restore tissue function. We show that acellular bioscaffolds with bioinductive properties can redirect cardiac fibroblasts to rebuild microvascular networks and avoid tissue fibrosis. Specifically, when human cardiac fibroblasts are combined with bioactive scaffolds, gene expression is upregulated and paracrine mediators are released that promote vasculogenesis and prevent scarring. We assess these properties in rodents with myocardial infarction and observe bioscaffolds to redirect fibroblasts, reduce tissue fibrosis and prevent maladaptive structural remodeling. Our preclinical data confirms that acellular bioscaffold therapy provides an appropriate microenvironment to stimulate pathways of functional repair. We translate our observations to patients with coronary heart disease by conducting a first-in-human observational cohort study. We show that bioscaffold therapy is associated with improved perfusion of infarcted myocardium, reduced myocardial scar burden, and reverse structural remodeling. We establish that clinical use of acellular bioscaffolds is feasible and offers a new frontier to enhance surgical revascularization of ischemic heart muscle.

The science of BAV aortopathy.

The aortopathy associated with bicuspid aortic valve (BAV) is an epidemiologically relevant source of chronic and acute aortic disease (aneurysm and dissection). However, its pathogenesis is still the object of scientific uncertainties and debates. Indeed, the mechanisms determining the diseases of the ascending aorta in BAV patients are most likely complex and multifactorial, i.e. resulting from variable modes of interplay between genetic and hemodynamic factors. Although few scientific studies have so far taken into adequate account this complexity, leaving the precise sequence of pathogenetic events still undiscovered, the accumulated evidence from previous research approaches have at least brought about important insights. While genetic studies have so far identified variants relevant to either valve malformation or aortic complications (including those in the genes NOTCH1, TGFBR2, ACTA2, GATA5, NKX2.5, SMAD6, ROBO4), however each explaining not more than 5% of the study population, other investigations have thoroughly described both the flow features, with consequent forces acting on the arterial wall (including skewed flow jet direction, rotational flow, wall shear stress), and the main changes in the molecular and cellular wall structure (including extracellular matrix degradation, smooth muscle cell changes, oxidative stress, unbalance of TGF-ß signaling, aberrant endothelial-to-mesenchymal transition). All of this evidence, together with the recognition of the diverse phenotypes that the aortopathy can assume in BAV patients, holding possible prognostic significance, is reviewed in this chapter. The complex and multifaceted body of knowledge resulting from clinical and basic science studies on BAV aortopathy has the potential to importantly influence modes of clinical management of this disease in the near future.

Applications of a Specialty Bicuspid Aortic Valve Program: Clinical Continuity and Translational Collaboration.

Bicuspid aortic valve (BAV) is a common congenital heart diagnosis and is associated with aortopathy. Current guidelines for aortic resection have been validated but are based on aortic diameter, which is insufficient to predict acute aortic events. Clinical and translational collaboration is necessary to identify biomarkers that can individualize the timing of prophylactic surgery for BAV aortopathy. We describe our multidisciplinary BAV program, including research protocols aimed at biomarker discovery and results from our longitudinal clinical registry. From 2012-2018, 887 patients enrolled in our clinical BAV registry with the option to undergo four dimensional flow cardiovascular magnetic resonance imaging (4D flow CMR) and donate serum plasma or tissue samples. Of 887 patients, 388 (44%) had an elective BAV-related procedure after initial presentation, while 499 (56%) continued with medical management. Of medical patients, 44 (9%) had elective surgery after 2.3 ± 1.4 years. Surgery patients' biobank donations include 198 (46%) aorta, 374 (86%) aortic valve, and 314 (73%) plasma samples. The 4D flow CMR was completed for 215 (50%) surgery patients and 243 (49%) medical patients. Patients with BAV aortopathy can be safely followed by a multidisciplinary team to detect indications for surgery. Paired tissue and hemodynamic analysis holds opportunity for biomarker development in BAV aortopathy.

Direct Effects of Empagliflozin on Extracellular Matrix Remodelling in Human Cardiac Myofibroblasts: Novel Translational Clues to Explain EMPA-REG OUTCOME Results.

BACKGROUND: Empagliflozin, an SGLT2 inhibitor, has shown remarkable reductions in cardiovascular mortality and heart failure admissions (EMPA-REG OUTCOME). However, the mechanism underlying the heart failure protective effects of empagliflozin remains largely unknown. Cardiac fibroblasts play an integral role in the progression of structural cardiac remodelling and heart failure, in part, by regulating extracellular matrix (ECM) homeostasis. The objective of this study was to determine if empagliflozin has a direct effect on human cardiac myofibroblast-mediated ECM remodelling. METHODS: Cardiac fibroblasts were isolated via explant culture from human atrial tissue obtained at open heart surgery. Collagen gel contraction assay was used to assess myofibroblast activity. Cell morphology and cell-mediated ECM remodelling was examined with the use of confocal microscopy. Gene expression of profibrotic markers was assessed with the use of reverse-transcription quantitative polymerase chain reaction. RESULTS: Empagliflozin significantly attenuated transforming growth factor ß1-induced fibroblast activation via collagen gel contraction after 72-hour exposure, with escalating concentrations (0.5 µmol/L, 1 µmol/L, and 5 µmol/L) resulting in greater attenuation. Morphologic assessment showed that myofibroblasts exposed to empagliflozin were smaller in size with shorter and fewer number of extensions, indicative of a more quiescent phenotype. Moreover, empagliflozin significantly attenuated cell-mediated ECM remodelling as measured by collagen fibre alignment index. Gene expression profiling revealed significant suppression of critical profibrotic markers by empagliflozin, including COL1A1, ACTA2, CTGF, FN1, and MMP-2. CONCLUSIONS: We provide novel data showing a direct effect of empagliflozin on human cardiac myofibroblast phenotype and function by attenuation of myofibroblast activity and cell-mediated collagen remodelling. These data provide critical insights into the profound effects of empagliflozin as noted in the EMPA-REG OUTCOME study.

Induction of human aortic myofibroblast-mediated extracellular matrix dysregulation: A potential mechanism of fluoroquinolone-associated aortopathy.

OBJECTIVES: Fluoroquinolone (FQ) antibiotics are associated with adverse aortic clinical events. We assessed human aortic myofibroblast-mediated extracellular matrix (ECM) dysregulation as a possible cellular mechanism underlying FQ-associated aortopathy. METHODS: Human aortic myofibroblasts were isolated from patients with aortopathy undergoing elective ascending aortic resection (N = 9). The capacity for extracellular matrix degradation in cells exposed to FQ was assessed by multiplex analysis of secreted matrix metalloproteinases relative to tissue inhibitors of matrix metalloproteinases (TIMPs). Direct evaluation of extracellular matrix degradation was investigated in human aortic cells using a 3-dimensional gelatin-fluorescein isothiocyanate fluorescence microgel assay. Aortic cellular collagen-1 expression following FQ exposure was determined by immunoblotting and immunofluorescent staining. Cell apoptosis, necrosis, and metabolic viability was determined by annexin-V, propidium iodide staining, and water-soluble tetrazolium salt (WST1) assay. RESULTS: FQ exposure significantly decreased aortic cell TIMP-1 (P = .004) and TIMP-2 (P = .0004) protein expression compared with vehicle control. The ratio of matrix metalloproteinase-9/TIMP-2 was increased suggesting an increased capacity for extracellular matrix degradation (P = .01). In collagen gels, we show a trend toward increased aortic myofibroblast-mediated collagen fiber degradation with FQ exposure (P = .09). Similarly, FQ exposure attenuated collagen-1 expression as assessed by immunoblotting (P = .002) and immunofluorescence (P = .02). Cell apoptosis, necrosis, and metabolic viability was not significantly influenced by FQ exposure. CONCLUSIONS: For the first time, we document a putative mechanism underlying FQ-associated aortopathy whereby decreased TIMP expression with impaired compensatory collagen-1 expression results in human aortic myofibroblast-mediated extracellular matrix dysregulation. These novel data may provide a cellular and molecular mechanism to explain the established clinical association between FQ exposure and acute aortic events.

Aortic valve-mediated wall shear stress is heterogeneous and predicts regional aortic elastic fiber thinning in bicuspid aortic valve-associated aortopathy.

OBJECTIVES: The objectives of this study were to investigate an association between the magnitude of flow-mediated aortic wall shear stress (WSS) and medial wall histopathology in patients with bicuspid aortic valve (BAV) with aortopathy. METHODS: Patients with BAV (n = 27; 52 ± 15 years; 3 women; proximal thoracic aorta diameter = 4.4 ± 0.7 and 4.6 ± 0.5 cm) who underwent prophylactic aortic resection received preoperative 3-dimensional time-resolved phase-contrast magnetic resonance imaging with 3-dimensional velocity encoding to quantify WSS relative to a population of healthy age- and sex-matched tricuspid aortic valve control participants (n = 20). Quantitative histopathology was conducted on BAV aorta tissue samples resected at surgery (n = 93), and correlation was performed between elastic fiber thickness and in vivo aortic WSS as continuous variables. Validation of elastic fiber thickness was achieved by correlation relative to tissue stiffness determined using biaxial biomechanical testing (n = 22 samples). RESULTS: Elastic fibers were thinner and WSS was higher along the greater curvature compared with other circumferential regions (vs anterior wall: P = .003 and P = .0001, respectively; lesser curvature: both P = .001). Increased regional WSS was associated with decreased elastic fiber thickness (r = -0.25; P = .02). Patient stratification with subanalysis showed an increase in the correlation between WSS and histopathology with aortic valve stenosis (r = -0.36; P = .002) and smaller aortic diameters (<4.5 cm: r = -0.39; P = .03). Elastic fiber thinning was associated with circumferential stiffness (r = -0.41; P = .06). CONCLUSIONS: For patients with BAV, increased aortic valve-mediated WSS is significantly associated with elastic fiber thinning, particularly with aortic valve stenosis and in earlier stages of aortopathy. Elastic fiber thinning correlates with impaired tissue biomechanics. These novel findings further implicate valve-mediated hemodynamics in the progression of BAV aortopathy.

Human pericardial proteoglycan 4 (lubricin): Implications for postcardiotomy intrathoracic adhesion formation.

OBJECTIVE: Intrapericardial fibrous adhesions increase the risk of sternal reentry. Proteoglycan 4/lubricin (PRG4) is a mucin-like glycoprotein that lubricates tissue compartments and prevents inflammation. We characterized PRG4 expression in human pericardium and examined its effects in vitro on human cardiac myofibroblast fibrotic activity and in vivo as a measure of its therapeutic potential to prevent adhesions. METHODS: Full-length PRG4 expression was determined using Western blot analysis and amplified luminescent proximity homogeneous assay in human pericardial tissues obtained at cardiotomy. The in vitro effects of PRG4 were investigated on human cardiac myofibroblasts for cell adhesion, collagen gel contraction, and cell-mediated extracellular matrix remodeling. The influence of PRG4 on pericardial homeostasis was determined in a chronic porcine animal model. RESULTS: PRG4 is expressed in human pericardial fluid and colocalized with pericardial mesothelial cells. Recombinant human PRG4 prevented human cardiac myofibroblast attachment and reduced myofibroblast activity assessed using collagen gel contraction assay (64.6% ± 8.1% vs 47.1% ± 6.8%; P = .02). Using a microgel assay, human cardiac myofibroblast mediated collagen fiber remodeling was attenuated by PRG4 (1.17 ± 0.03 vs 0.90 ± 0.05; P = .002). In vivo, removal of pericardial fluid alone induced severe intrapericardial adhesion formation, tissue thickening, and inflammatory fluid collections. Restoration of intrapericardial PRG4 was protective against fibrous adhesions and preserved the pericardial space. CONCLUSIONS: For the first time, we show that PRG4 is expressed in human pericardial fluid and regulates local fibrotic myofibroblast activity. Loss of PRG4-enriched pericardial fluid after cardiotomy might induce adhesion formation. Therapeutic restoration of intrapericardial PRG4 might prevent fibrous/inflammatory adhesions and reduce the risk of sternal reentry.

Bicuspid aortic valve aortopathy: mechanistic and clinical insights from recent studies.

PURPOSE OF REVIEW: This focused review summarizes key insights from the past 12 months of basic science and clinical research on bicuspid aortic valve (BAV)-associated aortopathy. RECENT FINDINGS: Recent studies in BAV-associated aortopathy support a heterogeneous spectrum of disease with distinct phenotypes. Basic science studies provide further support for the concept of regional differences in the severity of aortopathy within the aorta of BAV patients. Clinical studies compared outcomes of BAV patients after isolated aortic valve replacement and showed that those with primarily valvular insufficiency as compared with stenosis may be at greater risk for important aortic events over time. These novel insights will be important to optimize future aortic resection strategies and clinical practice guidelines. SUMMARY: As the most common congenital heart defect, BAV disease is a considerable health burden. Recent studies show differences in the clinical manifestation of disease patterns that may have important implications for future research and the evolution toward more patient-specific surgical practice guidelines.

Bioactive Extracellular Matrix Scaffold Promotes Adaptive Cardiac Remodeling and Repair.

Structural cardiac remodeling after ischemic injury can induce a transition to heart failure from progressive loss of cardiac function. Cellular regenerative therapies are promising but face significant translational hurdles. Tissue extracellular matrix (ECM) holds the necessary environmental cues to stimulate cell-based endogenous myocardial repair pathways and promote adaptive remodeling toward functional recovery. Heart epicardium has emerged as an important anatomic niche for endogenous repair pathways including vasculogenesis and cardiogenesis. We show that acellular ECM scaffolds surgically implanted on the epicardium following myocardial infarction (MI) can attenuate structural cardiac remodeling and improve functional recovery. We assessed the efficacy of this strategy on post-MI functional recovery by comparing intact bioactive scaffolds with biologically inactivated ECM scaffolds. We confirm that bioactive properties within the acellular ECM biomaterial are essential for the observed functional benefits. We show that interaction of human cardiac fibroblasts with bioactive ECM can induce a robust cell-mediated vasculogenic paracrine response capable of functional blood vessel assembly. Fibroblast growth factor-2 is uncovered as a critical regulator of this novel bioinductive effect. Acellular bioactive ECM scaffolds surgically implanted on the epicardium post-MI can reprogram resident fibroblasts and stimulate adaptive pro-reparative pathways enhancing functional recovery. We introduce a novel surgical strategy for tissue repair that can be performed as an adjunct to conventional surgical revascularization with minimal translational challenges.

Epicardial infarct repair with bioinductive extracellular matrix promotes vasculogenesis and myocardial recovery.

BACKGROUND: Infarcted myocardium can remodel after successful reperfusion, resulting in left ventricular dilation and heart failure. Epicardial infarct repair (EIR) using a bioinductive extracellular matrix (ECM) biomaterial is a novel surgical approach to promote endogenous myocardial repair and functional recovery after myocardial infarction. Using a pre-clinical porcine model of coronary ischemia-reperfusion, we assessed the effects of EIR on regional functional recovery, safety, and possible mechanisms of benefit. METHODS: An ECM biomaterial (CorMatrix ECM) was applied to the epicardium after 75 minutes of coronary ischemia in a porcine model. Following ischemia-reperfusion injury, animals were randomly assigned in 2:1 fashion to EIR (n = 8) or sham treatment (n = 4). Serial cardiac magnetic resonance imaging was performed on normal (n = 4) and study animals at baseline (1 week) and 6 weeks after treatment. Myocardial function and tissue characteristics were assessed. RESULTS: Functional myocardial recovery was significantly increased by EIR compared with sham treatment (change in regional myocardial contraction at 6 weeks, 28.6 ± 14.0% vs 4.2 ± 13.5% wall thickening, p < 0.05). Animals receiving EIR had reduced adhesions compared with animals receiving sham treatment (1.44 ± 0.51 vs 3.08 ± 0.89, p < 0.05). Myocardial fibrosis was not increased, and EIR did not cause myocardial constriction, as left ventricular compliance by passive pressure distention at matched volumes was similar between groups (13.9 ± 4.0 mm Hg in EIR group vs 16.0 ± 5.2 mm Hg in sham group, p = 0.61). Animals receiving EIR showed evidence of vasculogenesis in the region of functional recovery. CONCLUSIONS: In addition to the beneficial effects of successful reperfusion, EIR using a bioinductive ECM enhances myocardial repair and functional recovery. Clinical translation of EIR early after myocardial infarction as an adjunct to surgical revascularization may be warranted in the future.

Monocytes increase human cardiac myofibroblast-mediated extracellular matrix remodeling through TGF-ß1.

Following myocardial infarction (MI), cardiac myofibroblasts remodel the extracellular matrix (ECM), preventing mechanical complications. However, prolonged myofibroblast activity leads to dysregulation of the ECM, maladaptive remodeling, fibrosis, and heart failure (HF). Chronic inflammation is believed to drive persistent myofibroblast activity; however, the mechanisms are unclear. We assessed the influence of peripheral blood monocytes on human cardiac myofibroblast activity in a three-dimensional (3D) ECM microenvironment. Human cardiac myofibroblasts isolated from surgical biopsies of the right atrium and left ventricle were seeded into 3D collagen matrices. Peripheral blood monocytes were isolated from healthy human donors and cocultured with myofibroblasts. Monocytes increased myofibroblast activity measured by collagen gel contraction (baseline: 57.6 ± 5.9% vs. coculture: 65.2 ± 7.1% contraction; P < 0.01) and increased local ECM remodeling quantified by confocal microscopy. Under coculture conditions that allow indirect cellular interaction via paracrine factors but prevent direct cell-cell contact, monocytes had minimal effects on myofibroblast activity (17.9 ± 11.1% vs. 6.4 ± 7.0% increase, respectively; P < 0.01). When cells were cultured under direct contact conditions, multiplex analysis of the coculture media revealed an increase in the paracrine factors TGF-ß1 and matrix metalloproteinase 9 compared with baseline (122.9 ± 10.1 pg/ml and 3,496.0 ± 190.4 pg/ml, respectively, vs. 21.5 ± 16.3 pg/ml and 183.3 ± 43.9 pg/ml; P < 0.001). TGF-ß blockade abolished the monocyte-induced increase in cardiac myofibroblast activity. These data suggest that direct cell-cell interaction between monocytes and cardiac myofibroblasts stimulates TGF-ß-mediated myofibroblast activity and increases remodeling of local matrix. Peripheral blood monocyte interaction with human cardiac myofibroblasts stimulates myofibroblast activity through release of TGF-ß1. These data implicate inflammation as a potential driver of cardiac fibrosis.

Valve-Related Hemodynamics Mediate Human Bicuspid Aortopathy: Insights From Wall Shear Stress Mapping.

BACKGROUND: Suspected genetic causes for extracellular matrix (ECM) dysregulation in the ascending aorta in patients with bicuspid aortic valves (BAV) have influenced strategies and thresholds for surgical resection of BAV aortopathy. Using 4-dimensional (4D) flow cardiac magnetic resonance imaging (CMR), we have documented increased regional wall shear stress (WSS) in the ascending aorta of BAV patients. OBJECTIVES: This study assessed the relationship between WSS and regional aortic tissue remodeling in BAV patients to determine the influence of regional WSS on the expression of ECM dysregulation. METHODS: BAV patients (n = 20) undergoing ascending aortic resection underwent pre-operative 4D flow CMR to regionally map WSS. Paired aortic wall samples (i.e., within-patient samples obtained from regions of elevated and normal WSS) were collected and compared for medial elastin degeneration by histology and ECM regulation by protein expression. RESULTS: Regions of increased WSS showed greater medial elastin degradation compared to adjacent areas with normal WSS: decreased total elastin (p = 0.01) with thinner fibers (p = 0.00007) that were farther apart (p = 0.001). Multiplex protein analyses of ECM regulatory molecules revealed an increase in transforming growth factor ß-1 (p = 0.04), matrix metalloproteinase (MMP)-1 (p = 0.03), MMP-2 (p = 0.06), MMP-3 (p = 0.02), and tissue inhibitor of metalloproteinase-1 (p = 0.04) in elevated WSS regions, indicating ECM dysregulation in regions of high WSS. CONCLUSIONS: Regions of increased WSS correspond with ECM dysregulation and elastic fiber degeneration in the ascending aorta of BAV patients, implicating valve-related hemodynamics as a contributing factor in the development of aortopathy. Further study to validate the use of 4D flow CMR as a noninvasive biomarker of disease progression and its ability to individualize resection strategies is warranted.