Perivascular adipose tissue remodeling impairs vasoreactivity in thermoneutral-housed rats.

Objective: Vascular pathology, characterized by impaired vasoreactivity and mitochondrial respiration, differs between the sexes. Housing rats under thermoneutral (TN) conditions causes vascular dysfunction and perturbed metabolism. We hypothesized that perivascular adipose tissue (PVAT), a vasoregulatory adipose depot with brown adipose tissue (BAT) phenotype, remodels to a white adipose (WAT) phenotype in rats housed at TN, driving diminished vasoreactivity in a sex-dependent manner. Methods: Male and female Wistar rats were housed at either room temperature (RT) or TN. Endpoints included changes in PVAT morphology, vasoreactivity in vessels with intact PVAT or transferred to PVAT of the oppositely-housed animal, vessel stiffness, vessel mitochondrial respiration and cellular signaling. Results: Remodeling of PVAT was observed in rats housed at TN; animals in this environment showed PVAT whitening and displayed diminished aortae vasodilation (p<0.05), different between the sexes. Juxtaposing PVAT from RT rats onto aortae from TN rats in females corrected vasodilation (p<0.05); this did not occur in males. In aortae of all animals housed at TN, mitochondrial respiration was significantly diminished in lipid substrate experiments (p<0.05), and there was significantly less expression of peNOS (p<0.001). Conclusions: These data are consistent with TN-induced remodeling of PVAT, notably associated with sex-specific blunting of vasoreactivity, diminished mitochondrial respiration, and altered cellular signaling.

Right Ventricle-Pulmonary Artery Coupling in Patients Undergoing Cardiac Interventions.

PURPOSE OF REVIEW: This review aims to summarize the fundamentals of RV-PA coupling, its non-invasive means of measurement, and contemporary understanding of RV-PA coupling in cardiac surgery, cardiac interventions, and congenital heart disease. RECENT FINDINGS: The need for more accessible clinical means of evaluation of RV-PA coupling has driven researchers to investigate surrogates using cardiac MRI, echocardiography, and right-sided pressure measurements in patients undergoing cardiac surgery/interventions, as well as patients with congenital heart disease. Recent research has aimed to validate these alternative means against the gold standard, as well as establish cut-off values predictive of morbidity and/or mortality. This emerging evidence lays the groundwork for identifying appropriate RV-PA coupling surrogates and integrating them into perioperative clinical practice.

Right ventricular performance during acute hypoxic exercise.

Acute hypoxia increases pulmonary arterial (PA) pressures, though its effect on right ventricular (RV) function is controversial. The objective of this study was to characterize exertional RV performance during acute hypoxia. Ten healthy participants (34 ± 10 years, 7 males) completed three visits: visits 1 and 2 included non-invasive normoxic (fraction of inspired oxygen ( F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) = 0.21) and isobaric hypoxic ( F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$  = 0.12) cardiopulmonary exercise testing (CPET) to determine normoxic/hypoxic maximal oxygen uptake ( V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ). Visit 3 involved invasive haemodynamic assessments where participants were randomized 1:1 to either Swan-Ganz or conductance catheterization to quantify RV performance via pressure-volume analysis. Arterial oxygen saturation was determined by blood gas analysis from radial arterial catheterization. During visit 3, participants completed invasive submaximal CPET testing at 50% normoxic V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ and again at 50% hypoxic V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ( F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$  = 0.12). Median (interquartile range) values for non-invasive V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ values during normoxic and hypoxic testing were 2.98 (2.43, 3.66) l/min and 1.84 (1.62, 2.25) l/min, respectively (P < 0.0001). Mean PA pressure increased significantly when transitioning from rest to submaximal exercise during normoxic and hypoxic conditions (P = 0.0014). Metrics of RV contractility including preload recruitable stroke work, dP/dtmax , and end-systolic pressure increased significantly during the transition from rest to exercise under normoxic and hypoxic conditions. Ventricular-arterial coupling was maintained during normoxic exercise at 50% V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ . During submaximal exercise at 50% of hypoxic V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ , ventricular-arterial coupling declined but remained within normal limits. In conclusion, resting and exertional RV functions are preserved in response to acute exposure to hypoxia at an F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$  = 0.12 and the associated increase in PA pressures. KEY POINTS: The healthy right ventricle augments contractility, lusitropy and energetics during periods of increased metabolic demand (e.g. exercise) in acute hypoxic conditions. During submaximal exercise, ventricular-arterial coupling decreases but remains within normal limits, ensuring that cardiac output and systemic perfusion are maintained. These data describe right ventricular physiological responses during submaximal exercise under conditions of acute hypoxia, such as occurs during exposure to high altitude and/or acute hypoxic respiratory failure.

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.

Obesity dominates early effects on cardiac structure and arterial stiffness in people with type 2 diabetes.

OBJECTIVE: Type 2 diabetes (T2D) and obesity are global epidemics leading to excess cardiovascular disease (CVD). This study investigates standard and novel cardiac MRI parameters to detect subclinical cardiac and central vascular dysfunction in inactive people with and without T2D. METHODS: Physically inactive age and BMI-similar premenopausal women and men with ( n  = 22) and without [ n  = 34, controls with overweight/obesity (CWO)] uncomplicated T2D were compared to an age-similar and sex-similar reference control cohort ( n  = 20). Left ventricular (LV) structure, function, and aortic stiffness were assessed by MRI. Global arterial pulse wave velocity (PWV) was assessed using carotid-to-femoral applanation tonometry. Regional PWV was measured via 2D phase-contrast MRI and 4D flow MRI. RESULTS: Global arterial PWV did not differ between CWO and T2D. 2D PC-MRI PWV in the ascending aorta was higher in people with T2D compared with CWOs ( P  < 0.01). 4D flow PWV in the thoracic aorta was higher in CWO ( P  < 0.01), and T2D ( P  < 0.001) compared with RC. End-diastolic volume, end-systolic volume, stroke volume, and cardiac output were lower in CWO and T2D groups compared with reference control. CONCLUSION: Subclinical changes in arterial stiffening and cardiac remodeling in inactive CWO and T2D compared with reference control support obesity and/or physical inactivity as determinants of incipient CVD complications in uncomplicated T2D. Future studies should determine the mechanistic causes of the CVD complications in greater detail in order to create therapeutic targets. CLINICAL TRIAL REGISTRATION: Cardiovascular Mechanisms of Exercise Intolerance in Diabetes and the Role of Sex (NCT03419195).

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.

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.

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.

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.

Hemodynamically Unloading the Distal Pulmonary Circulation in Pulmonary Hypertension: A Modeling Study.

Pulmonary hypertension (PH) is a progressive disease that is characterized by a gradual increase in both resistive and reactive pulmonary arterial (PA) impedance. Previous studies in a rodent model of PH have shown that reducing the hemodynamic load in the left lung (by banding the left PA) reverses this remodeling phenomenon. However, banding a single side of the pulmonary circulation is not a viable clinical option, so-using in silico modeling-we evaluated if the banding effect can be recreated by replacing the proximal vasculature with a compliant synthetic PA. We developed a computational model of the pulmonary circulation by combining a one-dimensional model of the proximal vasculature with a zero-dimensional line transmission model to the 12th generation. Using this model, we performed four simulations: (1) Control; (2) PH; (3) PH with a stenosis in the left PA; and (4) PH with proximal vessel compliance returned to Control levels. Simulations revealed that vascular changes associated with PH result in an increase in pulse pressure (PP), maximum pressure (Pmax), maximum wall shear stress (WSS), and maximum circumferential stress (σθθ) relative to controls, in the distal circulation. Banding the left PA reduced these measurements of hemodynamic stress in the left lung, but increases them in the right lung. Furthermore, left PA banding increased reactive PA impedance. However, returning the proximal PA compliance to Control levels simultaneously decreased all measures of hemodynamic stress in both lungs, and returned reactive PA impedance to normal levels. In conclusion, if future in vivo studies support the idea of hemodynamic unloading as an effective therapy for PH, this can be surgically achieved by replacing the proximal PA with a compliant prosthesis, and it will have the added benefit of reducing reactive right ventricular afterload.

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.

Ventricular-vascular coupling is predictive of adverse clinical outcome in paediatric pulmonary arterial hypertension.

AIMS: Ventricular-vascular coupling, the ratio between the right ventricle's contractile state (Ees) and its afterload (Ea), may be a useful metric in the management of paediatric pulmonary arterial hypertension (PAH). In this study we assess the prognostic capacity of the ventricular-vascular coupling ratio (Ees/Ea) derived using right ventricular (RV) pressure alone in children with PAH. METHODS: One hundred and thirty paediatric patients who were diagnosed with PAH via right heart catheterisation were retrospectively reviewed over a 10-year period. Maximum RV isovolumic pressure and end-systolic pressure were estimated using two single-beat methods from Takeuchi et al (Ees/Ea_(Takeuchi)) and from Kind et al (Ees/Ea_(Kind)) and used with an estimate of end-systolic pressure to compute ventricular-vascular coupling from pressure alone. Patients were identified as either idiopathic/hereditary PAH or associated PAH (IPAH/HPAH and APAH, respectively). Haemodynamic data, clinical functional class and clinical worsening outcomes-separated into soft (mild) and hard (severe) event categories-were assessed. Adverse soft events included functional class worsening, syncopal event, hospitalisation due to a proportional hazard-related event and haemoptysis. Hard events included death, transplantation, initiation of prostanoid therapy and hospitalisation for atrial septostomy and Pott's shunt. Cox proportional hazard modelling was used to assess whether Ees/Ea was predictive of time-to-event. RESULTS: In patients with IPAH/HPAH, Ees/Ea_(Kind) and Ees/Ea_(Takeuchi) were both independently associated with time to hard event (p=0.003 and p=0.001, respectively) and when adjusted for indexed pulmonary vascular resistance (p=0.032 and p=0.013, respectively). Neither Ees/Ea_(Kind) nor Ees/Ea_(Takeuchi) were associated with time to soft event. In patients with APAH, neither Ees/Ea_(Kind) nor Ees/Ea_(Takeuchi) were associated with time to hard event or soft event. CONCLUSIONS: Ees/Ea derived from pressure alone is a strong independent predictor of adverse outcome and could be a potential powerful prognostic tool for paediatric PAH.

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.