Central Venous Waveform Patterns in the Fontan Circulation Independently Contribute to the Prediction of Composite Survival.

It is well appreciated that the Fontan circulation perturbs central venous hemodynamics, with elevated pressure being the clearest change associated with Fontan comorbidities, such as Fontan-associated liver disease (FALD) and protein-losing enteropathy (PLE). Our group has better quantity of these venous perturbations through single- and multi-location analyses of flow waveforms obtained from magnetic resonance imaging of Fontan patients. Here, we determine if such analyses, which yield principal components (PC) that describe flow features, are associated with Fontan survival. Patients with a Fontan circulation (N = 140) that underwent free-breathing and mechanically ventilated cardiac MRI were included in this study. Standard volumetric and functional hemodynamics, as well as flow analysis principal components, were subjected to univariate and bivariate Cox regression analyses to determine composite clinical outcome, including plastic bronchitis, PLE, and referral and receipt of transplant. Unsurprisingly, ventricular function measures of ejection fraction (EF; HR = 0.88, p < 0.0001), indexed end-systolic volume (ESVi; HR 1.02, p < 0.0001), and indexed end-diastolic volume (EDVi; HR = 1.02, p = 0.0007) were found as specific predictors of clinical events, with specificities uniformly > 0.75. Additionally a feature of IVC flow (PC2) indicating increased flow in systole was found as a highly sensitive predictor (HR = 0.851, p = 0.027, sensitivity 0.93). In bivariate prediction, combinations of ventricular function (EF, ESVi, EDVi) with this IVC flow feature yielded best overall prediction of composite outcome. This suggests that central venous waveform analysis relays additional information about Fontan patient survival and that coupling sensitive and specific measures in bivariate analysis is a useful approach for obtaining superior prediction of survival.

Three-Dimensional, Right Ventricular Surface Strain Computation From Three-Dimensional Echocardiographic Images From Patients With Pediatric Pulmonary Hypertension.

Right Ventricular (RV) dysfunction is routinely assessed with echocardiographic-derived global longitudinal strain (GLS). GLS is measured from a two-dimensional echo image and is increasingly accepted as a means for assessing RV function. However, any two-dimensional (2D) analysis cannot visualize the asymmetrical deformation of the RV nor visualize strain over the entire RV surface. We believe three-dimensional surface (3DS) strain, obtained from 3D echo will better evaluate myocardial mechanics. Components of 3DS strain (longitudinal, LS; circumferential, CS; longitudinal-circumferential shear, ɣCL; principal strains PSMax and PSMin; max shear, ɣMax; and principal angle θMax) were computed from RV surface meshes obtained with 3D echo from 50 children with associated pulmonary arterial hypertension (PAH), 43 children with idiopathic PAH, and 50 healthy children by computing strains from a discretized displacement field. All 3DS freewall (FW) normal strain (LS, CS, PSMax, and PSMin) showed significant decline at end-systole in PH groups (p < 0.0001 for all), as did FW-ɣMax (p = 0.0012). FW-θMax also changed in disease (p < 0.0001). Limits of agreement analysis suggest that 3DS LS, PSMax, and PSMin are related to GLS. 3DS strains showed significant heterogeneity over the 3D surface of the RV. Components of 3DS strain agree with existing clinical strain measures, well classify normal -versus- PAH subjects, and suggest that strains change direction on the myocardial surface due to disease. This last finding is similar to that of myocardial fiber realignment in disease, but further work is needed to establish true associations.

Aortic shape variation after frozen elephant trunk procedure predicts aortic events: Principal component analysis study.

Objective: The frozen elephant trunk procedure is a well-established technique for the repair of type A ascending aortic dissection and complex aortic arch pathology. The ultimate shape created by the repair may have consequences in long-term complications. The purpose of this study was to apply a machine learning technique to comprehensively describe 3-dimensional aortic shape variations after the frozen elephant trunk procedure and associate these variations with aortic events. Methods: Computed tomography angiography acquired before discharge of patients (n = 93) who underwent the frozen elephant trunk procedure for type A ascending aortic dissection or ascending aortic arch aneurysm was preprocessed to yield patient-specific aortic models and centerlines. Aortic centerlines were subjected to principal component analysis to describe principal components and aortic shape modulators. Patient-specific shape scores were correlated with outcomes defined by composite aortic event, including aortic rupture, aortic root dissection or pseudoaneurysm, new type B dissection, new thoracic or thoracoabdominal pathologies, residual descending aortic dissection with residual false lumen flow, or thoracic endovascular aortic repair complications. Results: The first 3 principal components accounted for 36.4%, 26.4%, and 11.6% of aortic shape variance, respectively, and cumulatively for 74.5% of the total shape variation in all patients. The first principal component described variation in arch height-to-length ratio, the second principal component described angle at the isthmus, and the third principal component described variation in anterior-to-posterior arch tilt. Twenty-one aortic events (22.6%) were encountered. The degree of aortic angle at the isthmus described by the second principal component was associated with aortic events in logistic regression (hazard ratio, 0.98; 95% confidence interval, 0.97-0.99; P = .046). Conclusions: The second principal component, describing angulation at the region of the aortic isthmus, was associated with adverse aortic events. Observed shape variation should be evaluated in the context of aortic biomechanical properties and flow hemodynamics.

Myocardial strain-curve deformation patterns after Fontan operation.

Myocardial deformation analysis by cardiac MRI (CMR) yielding global circumferential and longitudinal strain (GCS and GLS) is an increasingly utilized method to accurately quantify systolic function and predict clinical events in patients with Fontan circulation. The purpose of this study was to use principal component analysis (PCA) to investigate myocardial temporal deformation patterns derived from strain-time curves to learn about latent strain features beyond peak values. We conducted the study with specific attention to dominant single left or right ventricle (SLV and SRV) morphologies. Methods and Results: Patients remote from Fontan operation who underwent follow-up CMR were analyzed for standard volumetric and function hemodynamics including myocardial deformation parameters including GCS and GLS. We applied PCA to investigate in an unbiased fashion the strain-time curve morphology and to calculate patient specific shape scores. All variables were subjected to single variable Cox regression analysis to detect composite clinical outcome including death, heart transplant, protein losing enteropathy and plastic bronchitis. A total of 122 patients, (SLV = 67, SRV = 55) with a mean age of 12.7 years underwent comprehensive CMR analysis. The PCA revealed 3 primary modes of strain-curve variation regardless of single ventricle morphology and type of strain investigated. Principle components (PCs) described changes in (1) strain-time curve amplitude, (2) time-to-peak strain, and (3) post-systolic slope of the strain-time curve. Considering only SLV patients, GCS was only CMR variable predictive of clinical events (HR 1.46, p = 0.020). In the SRV group, significant CMR predictors of clinical events were derived indexed end-diastolic (HR 1.02, p = 0.023) and end-systolic (HR 1.03, p = 0.022) volumes, GCS (HR 1.91, p = 0.003) and its related first component score (HR 1.20, p = 0.005), GLS (HR 1.32, p = 0.029) and its third component score (HR 1.58, p = 0.017). CMR derived global strain measures are sensitive markers of clinical outcomes in patients with Fontan circulation, particularly in patients with the SRV morphology. Myocardial strain-time curve morphology specific to SLV and SRV patients inspired by unbiased PCA technique can further aid with predicting clinical outcomes.

Extraction and Digitization of ECG Signals from Standard Clinical Portable Document Format Files for the Principal Component Analysis of T-wave Morphology.

INTRODUCTION: T-wave analysis from standard electrocardiogram (ECG) remains one of the most available clinical and research methods for evaluating myocardial repolarization. T-wave morphology was recently evaluated to aid with diagnosis and characterization of diastolic dysfunction. Unfortunately, PDF stored ECG datasets limit additional numerical post-processing of ECG waveforms. In this study, we apply a simple custom process pipeline to extract and re-digitize T-wave signals and subject them to principal component analysis (PCA) to define primary T-wave shape variations. METHODS: We propose simple pre-processing and digitization algorithms programmable as a MATLAB tool using standard thresholding functions without the need for advanced signal analysis. To validate digitized datasets, we compared clinically standard measurements in 20 different ECGs with the original ECG machine interpreted values as a gold standard. Afterwards, we analyzed 212 individual ECGs for T-wave shape analysis using PCA. RESULTS: The re-digitized signal was shown to preserve the original information as evidenced by excellent agreement between original - machine interpreted and re-digitized clinical variables including heart rate: bias ~ 1 bpm (95% CI: -1.0 to 3.5), QT interval: bias ~ 0.000 ms (95% CI: -0.012 to 0.012), PR interval: bias = -0.015 ms (95% CI: -0.015 to 0.003), and QRS duration: bias = -0.001 ms (95% CI: -0.007 to 0.006). PCA revealed that the first principal component universally modulates the T-wave height or amount of repolarization voltage regardless of the investigated ECG lead. The second and third principal components described variation in the T-wave peak onset and the T-wave peak morphology, respectively. CONCLUSION: This study presents a straightforward method for re-digitizing ECGs stored in the PDF format utilized in many academic electronic medical record systems. This process can yield re-digitized lead specific signals which can be retrospectively analyzed using advanced custom post-processing numerical analysis independent of commercially available platforms.

Functional and molecular determinants of right ventricular response to severe pulmonary hypertension in a large animal model.

Right ventricular (RV) failure is the major determinant of outcome in pulmonary hypertension (PH). Calves exposed to 2-wk hypoxia develop severe PH and unlike rodents, hypoxia-induced PH in this species can lead to right heart failure. We, therefore, sought to examine the molecular and structural changes in the RV in calves with hypoxia-induced PH, hypothesizing that we could identify mechanisms underlying compensated physiological function in the face of developing severe PH. Calves were exposed to 14 days of environmental hypoxia (equivalent to 4,570 m/15,000 ft elevation, n = 29) or ambient normoxia (1,525 m/5,000 ft, n = 25). Cardiopulmonary function was evaluated by right heart catheterization and pressure volume loops. Molecular and cellular determinants of RV remodeling were analyzed by cDNA microarrays, RealTime PCR, proteomics, and immunochemistry. Hypoxic exposure induced robust PH, with increased RV contractile performance and preserved cardiac output, yet evidence of dysregulated RV-pulmonary artery mechanical coupling as seen in advanced disease. Analysis of gene expression revealed cellular processes associated with structural remodeling, cell signaling, and survival. We further identified specific clusters of gene expression associated with 1) hypertrophic gene expression and prosurvival mechanotransduction through YAP-TAZ signaling, 2) extracellular matrix (ECM) remodeling, 3) inflammatory cell activation, and 4) angiogenesis. A potential transcriptomic signature of cardiac fibroblasts in RV remodeling was detected, enriched in functions related to cell movement, tissue differentiation, and angiogenesis. Proteomic and immunohistochemical analysis confirmed RV myocyte hypertrophy, together with localization of ECM remodeling, inflammatory cell activation, and endothelial cell proliferation within the RV interstitium. In conclusion, hypoxia and hemodynamic load initiate coordinated processes of protective and compensatory RV remodeling to withstand the progression of PH.NEW & NOTEWORTHY Using a large animal model and employing a comprehensive approach integrating hemodynamic, transcriptomic, proteomic, and immunohistochemical analyses, we examined the early (2 wk) effects of severe PH on the RV. We observed that RV remodeling during PH progression represents a continuum of transcriptionally driven processes whereby cardiac myocytes, fibroblasts, endothelial cells, and proremodeling macrophages act to coordinately maintain physiological homeostasis and protect myocyte survival during chronic, severe, and progressive pressure overload.

Bromocriptine Improves Central Aortic Stiffness in Adolescents With Type 1 Diabetes: Arterial Health Results From the BCQR-T1D Study.

BACKGROUND: The presence of vascular dysfunction is a well-recognized feature in youth with type 1 diabetes (T1D), accentuating their lifetime risk of cardiovascular events. Therapeutic strategies to mitigate vascular dysfunction are a high clinical priority. In the bromocriptine quick release T1D study (BCQR-T1D), we tested the hypothesis that BCQR would improve vascular health in youth with T1D. METHODS: BCQR-T1D was a placebo-controlled, random-order, double-blinded, cross-over study investigating the cardiovascular and metabolic impact of BCQR in T1D. Adolescents in the BCQR-T1D study were randomized 1:1 to phase-1: 4 weeks of BCQR or placebo after which blood pressure and central aortic stiffness measurements by pulse wave velocity, relative area change, and distensibility from phase-contrast magnetic resonance imaging were performed. Following a 4-week washout period, phase 2 was performed in identical fashion with the alternate treatment. RESULTS: Thirty-four adolescents (mean age 15.9±2.6 years, hemoglobin A1c 8.6±1.1%, body mass index percentile 71.4±26.1, median T1D duration 5.8 years) with T1D were enrolled and had magnetic resonance imaging data available. Compared with placebo, BCQR therapy decreased systolic (∆=-5 mmHg [95% CI, -3 to -7]; P<0.001) and diastolic blood pressure (∆=-2 mmHg [95% CI, -4 to 0]; P=0.039). BCQR reduced ascending aortic pulse wave velocity (∆=-0.4 m/s; P=0.018) and increased relative area change (∆=-2.6%, P=0.083) and distensibility (∆=0.08%/mmHg; P=0.017). In the thoraco-abdominal aorta, BCQR decreased pulse wave velocity (∆=-0.2 m/s; P=0.007) and increased distensibility (∆=0.05 %/mmHg; P=0.013). CONCLUSIONS: BCQR improved blood pressure and central and peripheral aortic stiffness and pressure hemodynamics in adolescents with T1D over 4 weeks versus placebo. BCQR may improve aortic stiffness in youth with T1D, supporting future longer-term studies.

Right Ventricular Dysfunction During Endurance Exercise as Determined by Pressure-Volume Analysis.

A 37-year-old athlete completed invasive endurance (90 km) bicycle exercise testing for right ventricular pressure-volume analysis. Increased right ventricular afterload caused declines in ventricular-arterial coupling and cardiac output, causing increased arteriovenous oxygen difference to maintain oxygen uptake. These findings demonstrate effects of changes in right ventricular performance on exercise capacity. (Level of Difficulty: Intermediate.).

The Right Ventricular-Pulmonary Arterial Coupling and Diastolic Function Response to Therapy in Pulmonary Arterial Hypertension.

BACKGROUND: Multiparametric risk assessment is used in pulmonary arterial hypertension (PAH) to target therapy. However, this strategy is imperfect because most patients remain at intermediate or high risk after initial treatment, with low risk being the goal. Metrics of right ventricular (RV) adaptation are promising tools that may help refine our therapeutic strategy. RESEARCH QUESTION: Does RV adaptation predict therapeutic response over time? STUDY DESIGN AND METHODS: We evaluated 52 incident treatment-naive patients with advanced PAH by catheterization and cardiac imaging longitudinally at baseline, follow-up 1 (∼3 months), and follow-up 2 (∼18 months). All patients received goal-directed therapy with parenteral treprostinil and/or combination therapy with treatment escalation if functional class I or II was not achieved. On the basis of their therapeutic response, patients were evaluated at follow-up 1 as nonresponders (died) or as responders, and again at follow-up 2 as super-responders (low risk) or partial responders (high/intermediate risk). Multiparametric risk was based on a simplified European Respiratory Society/European Society of Cardiology guideline score. RV adaptation was evaluated with the single-beat coupling ratio (Ees/Ea) and diastolic function with diastolic elastance (Eed). Data are expressed as mean ± SD or as OR (95% CI). RESULTS: Nine patients (17%) were nonresponders. PAH-directed therapy improved the European Respiratory Society low-risk score from 1 (2%) at baseline to 23 (55%) at follow-up 2. Ees/Ea at presentation was nonsignificantly higher in responders (0.9 ± 0.4) vs nonresponders (0.6 ± 0.4; P = .09) but could not be used to predict super-responder status at follow-up 2 (OR, 1.40 [95% CI, 0.28-7.0]; P = .84). Baseline RV ejection fraction and change in Eed were successfully used to predict super-responder status at follow-up 2 (OR, 1.15 [95% CI, 1.0-1.27]; P = .009 and OR, 0.29 [95% CI, 0.86-0.96]; P = .04, respectively). INTERPRETATION: In patients with advanced PAH, RV-pulmonary arterial coupling could not discriminate irreversible RV failure (nonresponders) at presentation but showed a late trend to improvement by follow-up 2. Early change in Eed and baseline RV ejection fraction were the best predictors of therapeutic response.

Matrix-Degrading Enzyme Expression and Aortic Fibrosis During Continuous-Flow Left Ventricular Mechanical Support.

BACKGROUND: The effects of nonphysiological flow generated by continuous-flow (CF) left ventricular assist devices (LVADs) on the aorta remain poorly understood. OBJECTIVES: The authors sought to quantify indexes of fibrosis and determine the molecular signature of post-CF-LVAD vascular remodeling. METHODS: Paired aortic tissue was collected at CF-LVAD implant and subsequently at transplant from 22 patients. Aortic wall morphometry and fibrillar collagen content (a measure of fibrosis) was quantified. In addition, whole-transcriptome profiling by RNA sequencing and follow-up immunohistochemistry were performed to evaluate CF-LVAD-mediated changes in aortic mRNA and protein expression. RESULTS: The mean age was 52 ± 12 years, with a mean duration of CF-LVAD of 224 ± 193 days (range 45-798 days). There was a significant increase in the thickness of the collagen-rich adventitial layer from 218 ± 110 µm pre-LVAD to 410 ± 209 µm post-LVAD (P < 0.01). Furthermore, there was an increase in intimal and medial mean fibrillar collagen intensity from 22 ± 11 a.u. pre-LVAD to 41 ± 24 a.u. post-LVAD (P < 0.0001). The magnitude of this increase in fibrosis was greater among patients with longer durations of CF-LVAD support. CF-LVAD led to profound down-regulation in expression of extracellular matrix-degrading enzymes, such as matrix metalloproteinase-19 and ADAMTS4, whereas no evidence of fibroblast activation was noted. CONCLUSIONS: There is aortic remodeling and fibrosis after CF-LVAD that correlates with the duration of support. This fibrosis is due, at least in part, to suppression of extracellular matrix-degrading enzyme expression. Further research is needed to examine the contribution of nonphysiological flow patterns on vascular function and whether modulation of pulsatility may improve vascular remodeling and long-term outcomes.

Pulmonary arterial banding in mice may be a suitable model for studies on ventricular mechanics in pediatric pulmonary arterial hypertension.

BACKGROUND: The role of interventricular mechanics in pediatric pulmonary arterial hypertension (PAH) and its relation to right ventricular (RV) dysfunction has been largely overlooked. Here, we characterize the impact of maintained pressure overload in the RV-pulmonary artery (PA) axis on myocardial strain and left ventricular (LV) mechanics in pediatric PAH patients in comparison to a preclinical PA-banding (PAB) mouse model. We hypothesize that the PAB mouse model mimics important aspects of interventricular mechanics of pediatric PAH and may be beneficial as a surrogate model for some longitudinal and interventional studies not possible in children. METHODS: Balanced steady-state free precession (bSSFP) cardiovascular magnetic resonance (CMR) images of 18 PAH and 17 healthy (control) pediatric subjects were retrospectively analyzed using CMR feature-tracking (FT) software to compute measurements of myocardial strain. Furthermore, myocardial tagged-CMR images were also analyzed for each subject using harmonic phase flow analysis to derive LV torsion rate. Within 48 h of CMR, PAH patients underwent right heart catheterization (RHC) for measurement of PA/RV pressures, and to compute RV end-systolic elastance (RV_Ees, a measure of load-independent contractility). Surgical PAB was performed on mice to induce RV pressure overload and myocardial remodeling. bSSFP-CMR, tagged CMR, and intra-cardiac catheterization were performed on 12 PAB and 9 control mice (Sham) 7 weeks after surgery with identical post-processing as in the aforementioned patient studies. RV_Ees was assessed via the single beat method. RESULTS: LV torsion rate was significantly reduced under hypertensive conditions in both PAB mice (p = 0.004) and pediatric PAH patients (p < 0.001). This decrease in LV torsion rate correlated significantly with a decrease in RV_Ees in PAB (r = 0.91, p = 0.05) and PAH subjects (r = 0.51, p = 0.04). In order to compare combined metrics of LV torsion rate and strain parameters principal component analysis (PCA) was used. PCA revealed grouping of PAH patients with PAB mice and control subjects with Sham mice. Similar to LV torsion rate, LV global peak circumferential, radial, and longitudinal strain were significantly (p < 0.05) reduced under hypertensive conditions in both PAB mice and children with PAH. CONCLUSIONS: The PAB mouse model resembles PAH-associated myocardial mechanics and may provide a potential model to study mechanisms of RV/LV interdependency.

Abnormal pulmonary flow is associated with impaired right ventricular coupling in patients with COPD.

Cor Pulmonale or right ventricular (RV) dysfunction due to pulmonary disease is an expected complication of COPD resulting primarily from increased afterload mediated by chronic alveolar hypoxemia and resulting hypoxic pulmonary vasoconstriction. Early detection of elevated RV afterload has been previously demonstrated by visualization of abnormal flow patterns in the proximal pulmonary arteries. Prior analysis of helicity in the pulmonary arteries in pulmonary hypertension patients has demonstrated a strong association between helicity and increased RV afterload. However, these flow hemodynamics have yet to be fully explored in patients with COPD. We hypothesized that patients with COPD will have abnormal pulmonary flow as evaluated by 4D-Flow MRI and associated with RV function and pulmonary arterial stiffness. Patients with COPD (n = 15) (65 years ± 6) and controls (n = 10) (58 years ± 9) underwent 4D-Flow MRI to calculate helicity. The helicity was calculated in the main pulmonary artery (MPA) and along the RV outflow tract (RVOT)-MPA axis. Main pulmonary arterial stiffness was measured using the relative area change (RAC). We found COPD patients had decreased helicity relative to healthy controls in the MPA (19.4 ± 7.8vs 32.8 ± 15.9, P = 0.007) and reduced helicity along the RVOT-MPA axis (33.2 ± 9.0 vs 43.5 ± 8.3, P = 0.010). Our investigation indicates a strong association between helicity along the MPA-RV outflow tract axis and RV function and suggests that 4D-Flow MRI might be a sensitive tool in evaluating RV-pulmonary arterial coupling in COPD.

Short-Term Effects of Inhaled Nitric Oxide on Right Ventricular Flow Hemodynamics by 4-Dimensional-Flow Magnetic Resonance Imaging in Children With Pulmonary Arterial Hypertension.

Background Pulmonary arterial hypertension (PAH) manifests with progressive right ventricular (RV) dysfunction, which eventually impairs the left ventricular function. We hypothesized that 4-dimensional-flow magnetic resonance imaging can detect flow hemodynamic changes associated with efficient intracardiac flow during noninvasive inhaled nitric oxide (iNO) challenge in children with PAH. Methods and Results Children with PAH (n=10) underwent 2 same-day separate iNO challenge tests using: (1) 4-dimensional-flow magnetic resonance imaging and (2) standard catheterization hemodynamics. Intracardiac flow was evaluated using the particle tracking 4-flow component analysis technique evaluating the direct flow, retained inflow, delayed ejection flow, and residual volume. Respective flow hemodynamic changes were compared with the corresponding catheterization iNO challenge results. The RV analysis revealed decreased direct flow in patients with PAH when compared with controls (P<0.001) and increase in residual volume (P<0.001). Similarly, the left ventricular analysis revealed decreased direct flow in patients with PAH when compared with controls (P=0.004) and increased proportion of the residual volume (P=0.014). There was an increase in the RV direct flow during iNO delivery (P=0.009), with parallel decrease in the residual volume (P=0.008). Conclusions Children with PAH have abnormal biventricular flow associated with impaired diastolic filling. The flow efficiency is significantly improved in the RV on iNO administration with no change in the left ventricle. The changes in the RV flow have occurred despite the minimal change in catheterization hemodynamics, suggesting that flow hemodynamic evaluation might provide more quantitative insights into vasoreactivity testing in PAH.

Serum copeptin and NT-proBNP is associated with central aortic stiffness and flow hemodynamics in adolescents with type 1 diabetes: A pilot study.

AIMS: Cardiovascular disease (CVD) is the major cause of mortality in type 1 diabetes (T1D). Biomarkers, N-terminal pro-brain natriuretic peptide (NT-proBNP) and copeptin have been linked with measures of CVD, but their relationship in adolescents with T1D remains incompletely understood. Accordingly, we examined the associations between NT-proBNP and copeptin and hemodynamic markers of central aortic stiffness in adolescents with T1D. METHODS: In this pilot study, forty-nine pubertal adolescents with T1D (mean age 17 ±â€¯2 years, median [Q1-Q3] Tanner Stage 5 [5, 5] and HbA1c 8.5 ±â€¯1.5%), from the EMERALD study, were assessed for copeptin and NT-proBNP, and indices of central aortic stiffness non-invasively assessed by MRI. Pearson correlations and generalized linear regression models, adjusting for confounders, were applied to examine the relationships between biomarkers and vascular measures. RESULTS: Copeptin correlated independently with both ascending aortic (AA) (ß ±â€¯SE: -4.28 ±â€¯1.87, p = 0.03) and descending aortic (DA) relative area change (RAC) (-3.41 ±â€¯1.55, p = 0.04). NT-proBNP was independently associated with DA time-averaged wall shear stress (WSSTA) (0.87 ±â€¯0.25, p = 0.001) and DA maximum wall shear stress (WSSmax) (2.45 ±â€¯1.00, p = 0.02). CONCLUSIONS: Serum copeptin and NT-proBNP may be associated with central aortic stiffness and elevated WSS in youth with T1D, potentially offering a non-invasive way to identify and monitor the development of early CVD in an at-risk population.

Patients with Fontan circulation have abnormal aortic wave propagation patterns: A wave intensity analysis study.

BACKGROUND: Elevated systemic afterload in patients with Fontan circulation may lead to impaired single ventricular function. Wave intensity analysis (WIA) enables evaluation of compression and expansion waves traveling through vasculature. We aimed to investigate the unfavorable wave propagation causing excessive afterload may be an important contributor to the overall single ventricle function and to the limited functional capacity in this patient population. METHODS: Patients with hypoplastic left heart syndrome (HLHS) (n = 25), single left ventricle (SLV) (n = 24), and normal controls (n = 10) underwent phase-contrast MRI based WIA analysis evaluated in the ascending aorta. Forward compression wave (FCW) representing dP/dt, backward compression wave (BCW) reflecting vascular stiffness, and forward decompression wave (FDW) representing LV relaxation were recorded and indexed to each other. RESULTS: FCW was lowest in HLHS patients (1098 mm5/s), and higher in the SLV group (1457 mm5/s), and controls (6457 mm5/s) (P < 0.001). BCW/FCW was increased in HLHS (0.22) and SLV (0.14) groups compared to controls (0.08) (P = 0.003). Peak VO2 correlated with FCW (R = 0.50, P = 0.015), stroke volume (R = 0.72, P < 0.001), and cardiac output (R = 0.44, P = 0.034). CONCLUSIONS: Patients with HLHS and SLV have unfavorable aortic WIA patterns with increased BCW/FCW ratio indicating increased systemic afterload due to retrograde compression waves. Reduced FCW and systolic MRI indices correlated with peak VO2 suggesting that abnormal systolic wave propagation may play a role in exercise intolerance for Fontan patients.

Flow profile characteristics in Fontan circulation are associated with the single ventricle dilation and function: principal component analysis study.

The Fontan circulation is characterized as a nonpulsatile flow propagation without a pressure-generating ventricle. However, flow through the Fontan circulation still exhibits oscillatory waves as a result of pressure changes generated by the systemic single ventricle. Identification of discrete flow patterns through the Fontan circuit may be important to understand single ventricle performance. Ninety-seven patients with Fontan circulation underwent phase-contrast MRI of the right pulmonary artery, yielding subject-specific flow waveforms. Principal component (PC) analysis was performed on preprocessed flow waveforms. Principal components were then correlated with standard MRI indices of function, volume, and aortopulmonary collateral flow. The first principal component (PC) described systolic versus diastolic-dominant flow through the Fontan circulation, accounting for 31.3% of the variance in all waveforms. The first PC correlated with end-diastolic volume (R = 0.34, P = 0.001), and end-systolic volume (R = 0.30, P = 0.003), cardiac index (R = 0.51, P < 0.001), and the amount of aortopulmonary collateral flow (R = 0.25, P = 0.027)-lower ventricular volumes and a smaller volume of collateral flow-were associated with diastolic-dominant cavopulmonary flow. The second PC accounted for 19.5% of variance and described late diastolic acceleration versus deceleration and correlated with ejection fraction-diastolic deceleration was associated with higher ejection fraction. Principal components describing the diastolic flow variations in pulmonary arteries are related to the single ventricle function and volumes. Particularly, diastolic-dominant flow without late acceleration appears to be related to preserved ventricular volume and function, respectively.NEW & NOTEWORTHY The exact physiological significance of flow oscillations of phasic and temporal flow variations in Fontan circulation is unknown. With the use of principal component analysis, we discovered that flow variations in the right pulmonary artery of Fontan patients are related to the single ventricle function and volumes. Particularly, diastolic-dominant flow without late acceleration appears to be related to more ideal ventricular volume and systolic function, respectively.

Relation between right ventricular wall stress, fibrosis, and function in right ventricular pressure loading.

Right ventricle (RV) pressure loading can lead to RV fibrosis and dysfunction. We previously found increased RV, septal hinge-point and left ventricle (LV) fibrosis in experimental RV pressure loading. However, the relation of RV wall stress to biventricular fibrosis and dysfunction is incompletely defined. Rabbits underwent progressive pulmonary artery banding (PAB) over 3 wk with hemodynamics, echocardiography, and myocardial samples obtained at a terminal experiment at 6 wk. An additional group received PAB and treatment with an endothelin receptor antagonist. The endocardial and epicardial borders of short-axis echo images were traced and analyzed with invasive pressures to yield regional end-diastolic (ED) and end-systolic (ES) wall stress. To increase clinical translation, computer model-derived wall stress was compared with Laplace wall stress. The relation of wall stress with fibrosis (picrosirius red staining) and ventricular function was analyzed. ED wall stress in all regions and RV and LV free-wall ES wall stress were increased in PAB rabbits versus sham animals. Laplace wall stress correlated well with computational models. In PAB, fibrosis was highest in the RV free wall, then septal hinge regions, and lowest in the septum and LV free wall. Fibrosis was moderately related to ED (r = 0.47, P = 0.0011), but not ES wall stress. RV ED wall stress was strongly related to echo indexes of function (strain rate: r = 0.71, P = 0.048; E', r = -0.75, P = 0.0077; tricuspid annular plane systolic excursion: r = 0.85, P = 0.0038) and RV fractional area change (r = 0.77, P = 0.027). ED, more than ES, wall stress is related moderately to fibrosis and strongly to function in experimental RV pressure loading, especially at the septal hinge-point regions, where fibrosis is prominent. This suggests that wall stress partially links RV pressure loading, fibrosis, and dysfunction and may be useful to follow clinically.NEW & NOTEWORTHY Biventricular fibrosis and dysfunction impact outcomes in RV pressure loading, but their relation to wall stress is poorly defined. Using a pulmonary artery band rabbit model, we entered echocardiography and catheter data into a computer model to yield regional end-diastolic (EDWS) and end-systolic (ESWS) wall stress. EDWS, more than ESWS, correlated with fibrosis and dysfunction, especially at the fibrosis-intense septal hinge-point regions. Thus, wall stress may be clinically useful in linking RV pressure loading to regional fibrosis and dysfunction.

Parameters of Right Ventricular Function Reveal Ventricular-Vascular Mismatch as Determined by Right Ventricular Stroke Work versus Pulmonary Vascular Resistance in Children with Pulmonary Hypertension.

BACKGROUND: Right ventricular (RV) failure, a determinant of outcomes in pulmonary hypertension (PH), occurs when the right ventricle cannot compensate for increased afterload. The authors showed that RV stroke work (RVSW) can be estimated in children with PH as the product of stroke volume and RV pressure and is related to adverse outcomes. The aim of this study was to test the hypothesis that ventricular-vascular (VV) mismatch (high afterload and low RVSW) is associated with echocardiographic measures of RV performance and adverse outcomes. METHODS: Invasive hemodynamic data and concurrent echocardiograms were reviewed. Fifty subjects with PH were included. Four groups were created by dividing the patients using median RVSW and median pulmonary vascular resistance. For each group, tricuspid annular plane systolic excursion, fractional area change, myocardial performance index, and anterior RV wall thickness were determined. Both major (i.e., death) and minor (i.e., worsening World Health Organization class) clinical outcomes were tabulated. Groups were compared using the Kruskal-Wallis or Fisher exact test. RESULTS: Patients in the high pulmonary vascular resistance/low RVSW cohort (VV mismatch) had the worst RV dysfunction: median tricuspid annular plane systolic excursion, 0.8 cm (interquartile range, 0.7-0.8 cm; P = .0002); median fractional area change, 0.29% (interquartile range, 0.27%-0.30%; P = .004); median myocardial performance index, 0.622 (interquartile range, 0.548-0.789; P = .0004). This group had the highest incidence of adverse outcomes: major events in 40%, minor events in 80%, and syncope in 60%. CONCLUSION: VV mismatch in pediatric PH can be assessed using RVSW and pulmonary vascular resistance and is associated with RV performance and adverse events. RVSW increases in compensated high-afterload states and falls as the right ventricle fails to meet increased load; thus, VV matching status may be a sensitive predictor of outcomes in pediatric PH.

Differences in pulmonary arterial flow hemodynamics between children and adults with pulmonary arterial hypertension as assessed by 4D-flow CMR studies.

Despite different developmental and pathological processes affecting lung vascular remodeling in both patient populations, differences in 4D MRI findings between children and adults with PAH have not been studied. The purpose of this study was to compare flow hemodynamic state, including flow-mediated shear forces, between pediatric and adult patients with PAH matched by severity of pulmonary vascular resistance index (PVRi). Adults (n = 10) and children (n = 10) with PAH matched by pulmonary vascular resistance index (PVRi) and healthy adult (n = 10) and pediatric (n = 10) subjects underwent comprehensive 4D-flow MRI to assess peak systolic wall shear stress (WSSmax) measured in the main (MPA), right (RPA), and left pulmonary arteries (LPA), viscous energy loss (EL) along the MPA-RPA and MPA-LPA tract, and qualitative analysis of secondary flow hemodynamics. WSSmax was decreased in all pulmonary vessels in children with PAH when compared with the same age group (all P < 0.05). Similarly, WSSmax was decreased in all pulmonary vessels in adult PAH patients when compared with healthy adult subjects (all P < 0.01). Average EL was increased in adult patients with PAH when compared with the same age group along both MPA-RPA (P = 0.020) and MPA-LPA (P = 0.025) tracts. There were no differences in EL indices between adults and pediatric patients. Children and adult patients with PAH have decreased shear hemodynamic forces. However, pathological flow hemodynamic formations appear to be more consistent in adult patients, whereas flow hemodynamic abnormalities appear to be more variable in children with PAH for comparable severity of PVRi. NEW & NOTEWORTHY Both children and adult patients with PAH have decreased shear hemodynamic forces inside the pulmonary arteries associated with the degree of vessel dilation and stiffness. These differences also exist between healthy normotensive children and adults. However, pathological flow hemodynamic formations appear to more uniform in adult patients, whereas in children with PAH flow, hemodynamic abnormalities appear to be more variable. Pathological flow formations appear not to have a major effect on viscous energy loss associated with the flow conduction through proximal pulmonary arteries.

Proximal pulmonary vascular stiffness as a prognostic factor in children with pulmonary arterial hypertension.

Aims: Main pulmonary artery (MPA) stiffness and abnormal flow haemodynamics in pulmonary arterial hypertension (PAH) are strongly associated with elevated right ventricular (RV) afterload and associated with disease severity and poor clinical outcomes in adults with PAH. However, the long-term effects of MPA stiffness on RV function in children with PAH remain poorly understood. This study is the first comprehensive evaluation of MPA stiffness in children with PAH, delineating the mechanistic relationship between flow haemodynamics and MPA stiffness as well as the prognostic ability of these measures regarding clinical outcomes. Methods and results: Fifty-six children diagnosed with PAH underwent baseline cardiac magnetic resonance (CMR) acquisition and were compared with 23 control subjects. MPA stiffness and wall shear stress (WSS) were evaluated using phase contrast CMR and were evaluated for prognostic potential along with standard RV volumetric and functional indices. Pulse wave velocity (PWV) was significantly increased (2.8 m/s vs. 1.4 m/s, P < 0.0001) and relative area change (RAC) was decreased (25% vs. 37%, P < 0.0001) in the PAH group, correlating with metrics of RV performance. Decreased WSS was associated with a decrease in RAC over time (r = 0.679, P < 0.001). For each unit increase in PWV, there was approximately a 3.2-fold increase in having a moderate clinical event. Conclusion: MPA stiffness assessed by non-invasive CMR was increased in children with PAH and correlated with RV performance, suggesting that MPA stiffness is a major contribution to RV dysfunction. PWV is predictive of moderate clinical outcomes, and may be a useful prognostic marker of disease activity in children with PAH.