Inhibition of MRTF-A Ameliorates Pathological Remodeling of the Pressure-loaded Right Ventricle.

Right ventricular (RV) fibrosis is associated with RV dysfunction in a variety of RV pressure-loading conditions where RV mechanical stress is increased, but the underlying mechanisms driving RV fibrosis are incompletely understood. In pulmonary and cardiovascular diseases characterized by elevated mechanical stress and transforming growth factor - beta-1 (TGF-ß1) signaling, myocardin-related transcription factor A (MRTF-A) is a mechanosensitive protein critical to driving myofibroblast transition and fibrosis. Here we investigated whether MRTF-A inhibition improves RV pro-fibrotic remodeling and function in response to a pulmonary artery banding (PAB) model of RV pressure-loading. Rats were assigned into either 1) sham or 2) PAB groups. MRTF-A inhibitor CCG-1423 was administered daily at 0.75mg/kg in a subset of PAB animals. Echocardiography and pressure-volume hemodynamics were obtained at a terminal experiment 6-weeks later. RV myocardial samples were analyzed for fibrosis, cardiomyocyte hypertrophy, and pro-fibrotic signaling. MRTF-A inhibition slightly reduced systolic dysfunction in PAB rats reflected by increased lateral tricuspid annulus peak systolic velocity, while diastolic function parameters were not significantly improved. RV remodeling was attenuated in PAB rats with MRTF-A inhibition, displaying reduced fibrosis. This was accompanied with a reduction in PAB-induced upregulation of yes-associated protein (YAP) and its paralog transcriptional co-activator with PDZ-binding motif (TAZ). We also confirmed using a second-generation MRTF-A inhibitor CCG-203971 that MRTF-A is critical in driving RV fibroblast expression of TAZ and markers of myofibroblast transition in response to TGF-ß1 stress and RhoA activation. These studies identify RhoA, MRTF-A, and YAP/TAZ as interconnected regulators of pro-fibrotic signaling in RV pressure-loading, and as potential targets to improve RV pro-fibrotic remodeling.

Regulation of the RhoA exchange factor GEF-H1 by profibrotic stimuli through a positive feedback loop involving RhoA, MRTF, and Sp1.

RhoA and its effectors, the transcriptional coactivators myocardin-related transcription factor (MRTF) and serum response factor (SRF), control epithelial phenotype and are indispensable for profibrotic epithelial reprogramming during fibrogenesis. Context-dependent control of RhoA and fibrosis-associated changes in its regulators, however, remain incompletely characterized. We previously identified the guanine nucleotide exchange factor GEF-H1 as a central mediator of RhoA activation in renal tubular cells exposed to inflammatory or fibrotic stimuli. Here we found that GEF-H1 expression and phosphorylation were strongly elevated in two animal models of fibrosis. In the Unilateral Ureteral Obstruction mouse kidney fibrosis model, GEF-H1 was upregulated predominantly in the tubular compartment. GEF-H1 was also elevated and phosphorylated in a rat pulmonary artery banding (PAB) model of right ventricular fibrosis. Prolonged stimulation of LLC-PK1 tubular cells with tumor necrosis factor (TNF)-α or transforming growth factor (TGF)-ß1 increased GEF-H1 expression and activated a luciferase-coupled GEF-H1 promoter. Knockdown and overexpression studies revealed that these effects were mediated by RhoA, cytoskeleton remodeling, and MRTF, indicative of a positive feedback cycle. Indeed, silencing endogenous GEF-H1 attenuated activation of the GEF-H1 promoter. Of importance, inhibition of MRTF using CCG-1423 prevented GEF-H1 upregulation in both animal models. MRTF-dependent increase in GEF-H1 was prevented by inhibition of the transcription factor Sp1, and mutating putative Sp1 binding sites in the GEF-H1 promoter eliminated its MRTF-dependent activation. As the GEF-H1/RhoA axis is key for fibrogenesis, this novel MRTF/Sp1-dependent regulation of GEF-H1 abundance represents a potential target for reducing renal and cardiac fibrosis.NEW & NOTEWORTHY We show that expression of the RhoA regulator GEF-H1 is upregulated in tubular cells exposed to fibrogenic cytokines and in animal models of kidney and heart fibrosis. We identify a pathway wherein GEF-H1/RhoA-dependent MRTF activation through its noncanonical partner Sp1 upregulates GEF-H1. Our data reveal the existence of a positive feedback cycle that enhances Rho signaling through control of both GEF-H1 activation and expression. This feedback loop may play an important role in organ fibrosis.

Biventricular responses to exercise and their relation to cardiorespiratory fitness in pediatric pulmonary hypertension.

Despite exercise intolerance being predictive of outcomes in pulmonary arterial hypertension (PAH), its underlying cardiac mechanisms are not well described. The aim of the study was to explore the biventricular response to exercise and its associations with cardiorespiratory fitness in children with PAH. Participants underwent incremental cardio-pulmonary exercise testing and simultaneous exercise echocardiography on a recumbent cycle ergometer. Linear mixed models were used to assess cardiac function variance and associations between cardiac and metabolic parameters during exercise. Eleven participants were included with a mean age 13.4 ±2.9 years. Right ventricle (RV) systolic pressure (RVsp) increased from a mean of 59 ±25 mmHg at rest to 130 ±40 mmHg at peak exercise (p<0.001), while RV fractional area change (RV-FAC) and RV free wall longitudinal strain (RVFW-Sl) worsened (35.2% vs 27%, p=0.09 and -16.6% vs -14.6%, p=0.1, respectively). At low and moderate intensity exercise, RVsp was positively associated with stroke volume and O2 pulse (p<0.1). At high intensity exercise RV-FAC, RVFW-Sl and left ventricular longitudinal strain were positively associated with oxygen uptake and O2 pulse (p<0.1), while stroke volume decreased towards peak (p=0.04). In children with PAH, the increase of pulmonary pressure alone does not limit peak exercise, but rather the concomitant reduced RV functional reserve, resulting in RV-PA uncoupling, worsening of inter-ventricular interaction and LV dysfunction. A better mechanistic understanding of PAH exercise physiopathology can inform stress testing and cardiac rehabilitation in this population.

Left ventricular remodelling in rheumatic heart disease - trends over time and implications for follow-up in childhood.

BACKGROUND: Rheumatic heart disease (RHD) is the most common form of acquired heart disease worldwide. In RHD, volume loading from mitral regurgitation leads to left ventricular (LV) dilatation, increased wall stress, and ultimately LV dysfunction. Improved understanding of LV dynamics may contribute to refined timing of intervention. We aimed to characterize and compare left ventricular remodelling between rheumatic heart disease (RHD) severity groups by way of serial echocardiographic assessment of volumes and function in children. METHODS: Children with RHD referred to Perth Children's Hospital (formally Princess Margaret Hospital) (1987-2020) were reviewed. Patients with longitudinal pre-operative echocardiograms at diagnosis, approximately 12 months and at most recent follow-up, were included and stratified into RHD severity groups. Left ventricular (LV) echocardiographic parameters were assessed. Adjusted linear mixed effect models were used to compare interval changes. RESULTS: 146 patients (median age 10 years, IQR 6-14 years) with available longitudinal echocardiograms were analysed. Eighty-five (58.2%) patients had mild, 33 (22.6%) moderate and 28 (19.2%) severe RHD at diagnosis. Mean duration of follow-up was 4.6 years from the initial diagnosis. Severe RHD patients had significantly increased end-systolic volumes (ESV) and end-diastolic volumes (EDV) compared to mild/moderate groups at diagnosis (severe versus mild EDV mean difference 27.05 ml/m2, p < 0.001, severe versus moderate EDV mean difference 14.95 ml/m2, p = 0.006). Mild and moderate groups experienced no significant progression of changes in volume measures. In severe RHD, LV dilatation worsened over time. All groups had preserved cardiac function. CONCLUSIONS: In mild and moderate RHD, the lack of progression of valvular regurgitation and ventricular dimensions suggest a stable longer-term course. Significant LV remodelling occurred at baseline in severe RHD with progression of LV dilatation over time. LV function was preserved across all groups. Our findings may guide clinicians in deciding the frequency and timing of follow-up and may be of clinical utility during further reiterations of the Australia and New Zealand RHD Guidelines.

Reversal of right ventricular pressure loading improves biventricular function independent of fibrosis in a rabbit model of pulmonary artery banding.

Right ventricular (RV) pressure loading leads to RV and left ventricular (LV) dysfunction through RV hypertrophy, dilatation and fibrosis. Relief of RV pressure load improves RV function. However, the impact and mechanisms on biventricular reverse-remodelling and function are only partially characterized. We evaluated the impact of RV pressure overload relief on biventricular remodelling and function in a rabbit model of reversible pulmonary artery banding (PAB). Rabbits were randomized to three groups: (1) Sham-operated controls (n = 7); (2) PAB (NDef, n = 7); (3) PAB followed by band deflation (Def, n = 5). Sham and NDef animals were sacrificed at 6 weeks after PAB surgery. Def animals underwent PAB deflation at 6 weeks and sacrifice at 9 weeks. Biventricular geometry, function, haemodynamics, hypertrophy and fibrosis were compared between groups using echocardiography, magnetic resonance imaging, high-fidelity pressure-tipped catheters and histology. RV pressure loading caused RV dilatation, systolic dysfunction, myocyte hypertrophy and LV compression which improved after PAB deflation. RV end-diastolic pressure (RVEDP) decreased after PAB deflation, although remaining elevated vs. Sham. LV end-diastolic pressure (LVEDP) was unchanged following PAB deflation. RV and LV collagen volumes in the NDef and Def group were increased vs. Sham, whereas RV and LV collagen volumes were similar between NDef and Def groups. RV myocyte hypertrophy (r = 0.75, P < 0.001) but not collagen volume was related to RVEDP. LV myocyte hypertrophy (r = 0.58, P = 0.016) and collagen volume (r = 0.56, P = 0.031) correlated with LVEDP. In conclusion, relief of RV pressure overload improves RV and LV geometry, hypertrophy and function independent of fibrosis. The long-term implications of persistent fibrosis and increased biventricular filling pressures, even after pressure load relief, need further study. KEY POINTS: Right ventricular (RV) pressure loading in a pulmonary artery banding rabbit model is associated with RV dilatation, left ventricular (LV) compression; biventricular myocyte hypertrophy, fibrosis and dysfunction. The mechanisms and impact of RV pressure load relief on biventricular remodelling and function has not been extensively studied. Relief of RV pressure overload improves biventricular geometry in conjunction with improved RV myocyte hypertrophy and function independent of reduced fibrosis. These findings raise questions as to the importance of fibrosis as a therapeutic target.

The SGLT2i Dapagliflozin Reduces RV Mass Independent of Changes in RV Pressure Induced by Pulmonary Artery Banding.

BACKGROUND: Sodium glucose linked transporter 2 (SGLT2) inhibition not only reduces morbidity and mortality in patients with diagnosed heart failure but also prevents the development of heart failure hospitalization in those at risk. While studies to date have focused on the role of SGLT2 inhibition in left ventricular failure, whether this drug class is efficacious in the treatment and prevention of right heart failure has not been explored. HYPOTHESIS: We hypothesized that SGLT2 inhibition would reduce the structural, functional, and molecular responses to pressure overload of the right ventricle. METHODS: Thirteen-week-old Fischer F344 rats underwent pulmonary artery banding (PAB) or sham surgery prior to being randomized to receive either the SGLT2 inhibitor: dapagliflozin (0.5 mg/kg/day) or vehicle by oral gavage. After 6 weeks of treatment, animals underwent transthoracic echocardiography and invasive hemodynamic studies. Animals were then terminated, and their hearts harvested for structural and molecular analyses. RESULTS: PAB induced features consistent with a compensatory response to increased right ventricular (RV) afterload with elevated mass, end systolic pressure, collagen content, and alteration in calcium handling protein expression (all p < 0.05 when compared to sham + vehicle). Dapagliflozin reduced RV mass, including both wet and dry weight as well as normalizing the protein expression of SERCA 2A, phospho-AMPK and LC3I/II ratio expression (all p < 0.05). SIGNIFICANCE: Dapagliflozin reduces the structural, functional, and molecular manifestations of right ventricular pressure overload. Whether amelioration of these early changes in the RV may ultimately lead to a reduction in RV failure remains to be determined.

Impaired right and left ventricular function and relaxation induced by pulmonary regurgitation are not reversed by tardive antifibrosis treatment.

Pulmonary regurgitation (PR) after repair of tetralogy of Fallot (rTOF) is associated with progressive right (RV) and left (LV) ventricular dysfunction and fibrosis. However, angiotensin II receptor blockade therapy has shown mixed and often disappointing results. The aim of this study was to serially assess changes in biventricular remodeling, dysfunction, and interactions in a rat model of isolated severe PR and to study the effects of angiotensin II receptor blockade. PR was induced in Sprague-Dawley rats by leaflet laceration. Shams (n = 6) were compared with PR (n = 5) and PR + losartan treatment (n = 6). In the treatment group, oral losartan (50 mg·kg-1·day-1) was started 6 wk after PR induction and continued for 6 wk until the terminal experiment. In all groups, serial echocardiography was performed every 2 wk until the terminal experiment where biventricular myocardium was harvested and analyzed for fibrosis. PR and PR + losartan rats experienced early progressive RV dilatation by 2 wk which then stabilized. RV systolic dysfunction occurred from 4 wk after insult and gradually progressed. In PR rats, RV dilatation caused diastolic LV compression and impaired relaxation. PR rats developed increased RV fibrosis compared with shams. Although losartan decreased RV fibrosis, RV dilatation and dysfunction were not improved. This suggests that RV dilatation is an early consequence of PR and affects LV relaxation. RV dysfunction may progress independent of further remodeling. Reduced RV fibrosis was not associated with improved RV function and may not be a viable therapeutic target in rTOF with predominant RV volume loading.NEW & NOTEWORTHY The time-course of RV dilatation and the mechanisms of biventricular dysfunction caused by PR have not been well characterized and the effect of losartan in volume-overloaded RV remains controversial. Our findings suggest that severe PR induces early onset of RV dilatation and dysfunction with little progression after the first 4 wk. The RV dilatation distorts LV geometry with associated impaired LV relaxation. Losartan reduced RV fibrosis but did not reverse RV dilatation and dysfunction.

Association between genetic variants in the HIF1A-VEGF pathway and left ventricular regional myocardial deformation in patients with hypertrophic cardiomyopathy.

BACKGROUND: Information on genetic etiology of pediatric hypertrophic cardiomyopathy (HCM) rarely aids in risk stratification and prediction of disease onset. Little data exist on the association between genetic modifiers and phenotypic expression of myocardial performance, hampering an individual precision medicine approach. METHODS: Single-nucleotide polymorphism genotyping for six previously established disease risk alleles in the hypoxia-inducible factor-1α-vascular endothelial growth factor pathway was performed in a pediatric cohort with HCM. Findings were correlated with echocardiographic parameters of systolic and diastolic myocardial deformation measured by two-dimensional (2-D) speckle-tracking strain. RESULTS: Twenty-five children (6.1 ± 4.5 years; 69% male) with phenotypic and genotypic (60%) HCM were included. Out of six risk alleles tested, one, VEGF1 963GG, showed an association with reduced regional systolic and diastolic left ventricular (LV) myocardial deformation. Moreover, LV average and segmental systolic and diastolic strain and strain rate were significantly reduced, as assessed by the standardized difference, in patients harboring the risk allele. CONCLUSIONS: This is the first study to identify an association between a risk allele in the VEGF pathway and regional LV myocardial function, with the VEGF1 963GG allele associated with reduced LV systolic and diastolic myocardial performance. While studies are needed to link this information to adverse clinical outcomes, this knowledge may help in risk stratification and patient management in HCM. IMPACT: Risk allele in the VEGF gene impacts on LV myocardial deformation phenotype in children with HCM. LV 2-D strain is significantly reduced in patients with risk allele compared to non-risk allele patients within HCM patient groups. Describes that deficiencies in LV myocardial performance in children with HCM are associated with a previously identified risk allele in the angiogenic transcription factor VEGF. First study to identify an association between a risk allele in the VEGF pathway and regional LV myocardial deformation measured by 2-D strain in children with HCM.

Heart Rate Reduction Improves Right Ventricular Function and Fibrosis in Pulmonary Hypertension.

The potential benefit of heart rate reduction (HRR), independent of ß-blockade, on right ventricular (RV) function in pulmonary hypertension (PH) remains undecided. We studied HRR effects on RV fibrosis and function in PH and RV pressure-loading models. Adult rats were randomized to 1) sham controls, 2) monocrotaline (MCT)-induced PH, 3) SU5416 + hypoxia (SUHX)-induced PH, or 4) pulmonary artery banding (PAB). Ivabradine (IVA) (10 mg/kg/d) was administered from 2 weeks after PH induction or PAB. Exercise tolerance, echocardiography, and pressure-volume hemodynamics were obtained at a terminal experiment 3 weeks later. RV myocardial samples were analyzed for putative mechanisms of HRR effects through fibrosis, profibrotic molecular signaling, and Ca++ handling. The effects of IVA versus carvedilol on human induced pluripotent stem cell-derived cardiomyocytes beat rate and relaxation properties were evaluated in vitro. Despite unabated severely elevated RV systolic pressures, IVA improved RV systolic and diastolic function, profibrotic signaling, and RV fibrosis in PH/PAB rats. RV systolic-elastance (control, 121 ± 116; MCT, 49 ± 36 vs. MCT+IVA, 120 ± 54; PAB, 70 ± 20 vs. PAB+IVA, 168 ± 76; SUHX, 86 ± 56 vs. SUHX +IVA, 218 ± 111; all P < 0.05), the time constant of RV relaxation, echo indices of RV function, and fibrosis (fibrosis: control, 4.6 ± 1%; MCT, 13.4 ± 6.5 vs. MCT+IVA, 6.7 ± 2.6%; PAB, 11.4 ± 4.5 vs. PAB+IVA, 6.4 ± 5.1%; SUHX, 10 ± 4.6 vs. SUHX+IVA, 3.9 ± 2.2%; all P < 0.001) were improved by IVA versus controls. IVA had a dose-response effect on induced pluripotent stem cell-derived cardiomyocytes beat rate by delaying Ca++ loss from the cytoplasm. In experimental PH or RV pressure loading, HRR improves RV fibrosis, function, and exercise endurance independent of ß-blockade. The balance between adverse tachycardia and bradycardia requires further study, but judicious HRR may provide a promising strategy to improve RV function in clinical PH.

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.

Nomograms of Fetal Right Ventricular Fractional Area Change by 2D Echocardiography.

OBJECTIVES: Fetal right ventricular (RV) function assessment is challenging due to the RV geometry and limitations of in utero assessment. Postnatally, 2D echocardiographic RV fractional area change (FAC) is used to assess RV global systolic function by calculating the percentage of change in RV area from systole to diastole. Reports on FAC are scarce in prenatal life, and nomograms throughout pregnancy are not available. Our aims were (1) to study prenatal RV FAC feasibility and reproducibility and (2) to construct nomograms for RV FAC and end-diastolic (ED) and end-systolic (ES) RV areas from 18 to 41 weeks of gestation. METHODS: Prospective cohort study including 602 low-risk singleton pregnancies undergoing a fetal echocardiography from 18 to 41 weeks of gestation. RV ED and ES areas were measured following standard recommendations for ventricular dimensions and establishing strict landmarks to identify the different phases of the cardiac cycle. RV FAC was calculated as: ([ED area - ES area]/ED area) × 100. RV FAC intra- and inter-observer reproducibility was evaluated in 45 fetuses by calculating the intraclass correlation coefficient (ICC). Parametric regressions were tested to model each parameter against gestational age (GA) and estimated fetal weight (EFW). RESULTS: RV areas and FAC were successfully obtained in ∼99% of fetuses with acceptable reproducibility throughout gestation (RV ED area inter-observer ICC [95% CI] 0.96 [0.93-0.98], RV ES area 0.97 [0.94-0.98], and FAC 0.69 [0.44-0.83]). Nomograms were constructed for RV ED and ES areas and FAC. RV areas showed a quadratic and logarithmic increase with GA and EFW, respectively. In contrast, RV FAC showed a slight quadratic decrease throughout gestation (mean RV FAC ranged from 36% at 18 weeks of gestation [10-90th centiles: 25-47%, respectively] to 29% at 41 weeks [10-90th centiles: 18-40%, respectively]). The best models for RV areas and FAC were a second-degree polynomial. CONCLUSIONS: RV FAC is a feasible and reproducible parameter to assess RV global systolic function in fetal life. We provide reference ranges adjusted by GA and EFW that can be used as normal references for the assessment of RV function in prenatal conditions.

Right ventricular function in patients with pulmonary regurgitation with versus without tetralogy of Fallot.

BACKGROUND: Right ventricular (RV) dilation from pulmonary valve regurgitation (PR) is common after intervention(s) for pulmonary stenosis (PS) or atresia and intact ventricular septum (PA/IVS). It is not well established whether PR and RV dilation have similar effects on RV function and exercise capacity in these patients compared to patients after repair of tetralogy of Fallot (rToF). The aims of this study were to compare exercise tolerance, RV function and myocardial mechanics in non-ToF versus rToF children with significantly increased and comparable RV volumes. METHODS: Thirty PS or PA/IVS children after intervention(s) with significant PR and RV dilation (non-ToF group) were retrospectively matched for RV end-diastolic volume index (RVEDVi) and age with 30 rToF patients. Clinical characteristics, RV function by echocardiography and CMR, ECG and exercise capacity were compared between groups. RESULTS: The groups were well matched for RVEDVi and age. Global RV function (RVEF: 48.7 ±â€¯6.4% vs. 48.5 ±â€¯7.2%, P = .81) and exercise capacity (% predicted peak VO2:82.5 ±â€¯17.7% vs. 75.6 ±â€¯20.4%, P = .27) were similarly reduced between groups. RVEDVi correlated inversely with RVEF in both groups (non-ToF:r = -0.39, P = .04, rToF:r = -0.40, P = .03). QRS duration was wider in rToF patients, and in both groups inversely correlated with RVEF (non-ToF:r = -0.77, P < .001, rToF:r = -0.69, P < .001). In contrast to global function, longitudinal RV strain was lower in rTOF vs non-TOF (-20.1 ±â€¯3.9 vs.-25.7 ±â€¯4.4, P < .001). CONCLUSIONS: Global RV function and exercise capacity are similarly reduced in non-ToF and rToF patients with severely dilated RV, after matching by RVEDVi, suggesting a comparable impact of RV dilation on RV global function. The significance of reduced RV longitudinal function and worse dyssynchrony in rToF patients require further exploration.

Right ventricular failure in congenital heart disease.

PURPOSE OF REVIEW: We aim to review select literature pertaining to congenital heart disease (CHD)-induced right ventricular (RV) function and failure. RECENT FINDINGS: We review recent findings pertaining to children and adults with repaired tetralogy of Fallot (rTOF), systemic RV and hypoplastic left heart syndrome (HLHS). We emphasize pathophysiological mechanisms contributing to RV dysfunction in these conditions, the risk factors for adverse outcomes and the continuing challenges in treating these patients. We discuss how recent pathology findings, as well as developments in imaging and computer modeling have broadened our understanding of the pathophysiology of these conditions. We further review developments in the molecular and cellular basis of RV failure; and in particular, the RV molecular response to stress in repaired tetralogy of Fallot (rTOF). We highlight some of the genetic complexities in HLHS and how these may influence the long-term outcomes in these patients. SUMMARY: Recent literature has led to new understandings in the pathology, pathophysiology, risk factors for adverse outcomes, molecular and genetic basis for RV dysfunction and failure in CHD. Although these findings provide new therapeutic targets, the treatment of RV failure at this time remains limited.

Comparison of echocardiographic measurements to invasive measurements of diastolic function in infants with single ventricle physiology: a report from the Pediatric Heart Network Infant Single Ventricle Trial.

BACKGROUND: While echocardiographic parameters are used to quantify ventricular function in infants with single ventricle physiology, there are few data comparing these to invasive measurements. This study correlates echocardiographic measures of diastolic function with ventricular end-diastolic pressure in infants with single ventricle physiology prior to superior cavopulmonary anastomosis. METHODS: Data from 173 patients enrolled in the Pediatric Heart Network Infant Single Ventricle enalapril trial were analysed. Those with mixed ventricular types (n = 17) and one outlier (end-diastolic pressure = 32 mmHg) were excluded from the analysis, leaving a total sample size of 155 patients. Echocardiographic measurements were correlated to end-diastolic pressure using Spearman's test. RESULTS: Median age at echocardiogram was 4.6 (range 2.5-7.4) months. Median ventricular end-diastolic pressure was 7 (range 3-19) mmHg. Median time difference between the echocardiogram and catheterisation was 0 days (range -35 to 59 days). Examining the entire cohort of 155 patients, no echocardiographic diastolic function variable correlated with ventricular end-diastolic pressure. When the analysis was limited to the 86 patients who had similar sedation for both studies, the systolic:diastolic duration ratio had a significant but weak negative correlation with end-diastolic pressure (r = -0.3, p = 0.004). The remaining echocardiographic variables did not correlate with ventricular end-diastolic pressure. CONCLUSION: In this cohort of infants with single ventricle physiology prior to superior cavopulmonary anastomosis, most conventional echocardiographic measures of diastolic function did not correlate with ventricular end-diastolic pressure at cardiac catheterisation. These limitations should be factored into the interpretation of quantitative echo data in this patient population.

Heart rate reduction improves biventricular function and interactions in experimental pulmonary hypertension.

The objective of the present study was to investigate mechanisms of heart rate (HR) reduction on biventricular function and interactions in experimental pulmonary arterial hypertension (PAH). We compared cardiac cycle mechanics and interventricular interactions in 15 sham, 8 monocrotaline-PAH, 9 PAH + carvedilol, and 8 PAH + ivabradine rats. We used echocardiography to assess biventricular function, timing of cardiac cycle events, and septal position in PAH rats and related HR reduction effects on biventricular function measured by echocardiography and conductance catheter. HR was 302 beats/min in PAH + carvedilol rats and 303 beats/min in PAH + ivabradine rats versus 359 beats/min in PAH rats ( P < 0.01). Sham rats showed temporal alignment between right ventricular (RV) and left ventricular (LV) events, whereas PAH rats showed increased biventricular isovolumic contraction times (ICTs), delayed RV peak radial motion, and impaired early relaxation. Temporal malalignment was associated with decreased tricuspid and mitral diastolic annular peak velocities (3.7 vs. 6.4 and 3.4 vs. 5.3 cm/s, respectively, P < 0.001), delayed and shortened biventricular filling, and reduced early diastolic LV filling velocity (0.56 vs. 0.81 cm/s, P < 0.01). LV eccentricity index was increased at systole (2.0 vs. 1.2, P < 0.001), early diastole (2.1 vs. 1.1, P < 0.001), and end diastole (1.6 vs. 1.1, P < 0.001) in PAH versus sham rats. HR reduction with carvedilol and ivabradine shortened biventricular ICTs and the time to biventricular peak radial motion, improved RV relaxation, and increased early diastolic LV filling through reduced interventricular interaction and improved timing. These improvements corresponded with enhanced hemodynamics (increased cardiac output, RV contractility, and diastolic relaxation). In conclusion, HR reduction by carvedilol and ivabradine improves biventricular filling and hemodynamics in experimental PAH through realignment of RV-LV cardiac cycle events and improved interventricular interactions. NEW & NOTEWORTHY Carvedilol improves biventricular function in experimental pulmonary arterial hypertension, but the mechanisms of heart rate reduction versus ß-blocker effect are inadequately defined. Here, we demonstrate that reducing heart rate using either carvedilol or ivabradine (hyperpolarization-activated current inhibitor without ß-blocker effect) improves right ventricular filling and biventricular hemodynamics through the realignment of right ventricular-left ventricular cardiac cycle events and improved interventricular interactions.

Ventricular mechanics in adolescent and adult patients with a Fontan circulation: Relation to geometry and wall stress.

BACKGROUND: Patients with single ventricle physiology and Fontan circulation are at increased risk for late complications and reduced survival. The aim of the study was to investigate the correlation between ventricular geometry and systolic regional function in different underlying anatomic conditions in adolescent and adult Fontan-palliated patients. METHOD: In a retrospective cross-sectional study, we measured 2D strain, ventricular diameters, ventricular volumes, ejection fraction (EF), global and segmental wall stress, and sphericity index. The same analyses were performed in 99 age- and gender-matched healthy individuals. RESULTS: One hundred and one patients were included at a mean age of 21 (range 14-59) years. In comparison with healthy subjects, patients with Fontan circulation displayed larger ventricular volumes (153 ± 78 mL vs 116 ± 38 mL P < 0.05), reduced EF (43% ± 15% vs 55% ± 8% P < 0.05), reduced longitudinal (-13% ± 6% vs -21% ± 4% P < 0.05) and circumferential strain values (-15% ± 7% vs -22% ± 4% P < 0.05). Functionally single ventricles were more spherical (ratio of longitudinal to short-axis diameters 1.3 ± 0.3 vs 1.7 ± 0.2 P < 0.05). Circumferential strain correlated well with global wall stress and the degree of sphericity (R2  = 0.320), while segmental strain did not correlate with segmental wall stress. The percentage of segments with akinesia was relatively high (16 ± 16% vs 0 ± 0% P < 0.05) indicating reduced segmental contractile function. CONCLUSION: Functionally single ventricles after Fontan palliation have significantly reduced systolic regional and global function with a high intersegmental inhomogeneity. The underlying pathological mechanisms might be multifactorial, including ventricular geometry, sphericity, and regional contractile properties. Future studies are needed to investigate the role of ventricular geometry for clinical performance and outcome.

The continuing challenge of evaluating diastolic function by echocardiography in children: developing concepts and newer modalities.

PURPOSE OF REVIEW: Assessment of diastolic function by echocardiography is challenging but important. Left ventricular filling has been more extensively studied than the right ventricle, and predominantly in adult populations. Although multiple parameters exist to assess diastolic function, they all have limitations, including load and heart rate dependency, which make assessment of diastolic function particularly challenging. The purpose of this article is to review evolving concepts and modalities for echo assessment of diastolic function in children. RECENT FINDINGS: The paradigm whereby diastolic dysfunction severity progresses in a staged fashion from impaired relaxation to increasing ventricular stiffness, may not apply in children. In addition, previous adult guidelines are not readily applicable to children with cardiomyopathy and the applicability of the newly revised adult guidelines needs to be evaluated in children. It is unlikely that any one single echocardiographic diastolic parameter will adequately reflect diastolic function. Hence, parameters derived from atrioventricular valve inflow, pulmonary venous, and tissue Doppler need to be integrated. Newer modalities such as diastolic strain rate and rotation mechanics may be useful as more sensitive markers of early ventricular dysfunction but have important limitations and require more evaluation before routine use in practice. Assessment of systolic-diastolic coupling may enhance assessment of diastolic function. SUMMARY: Diastolic function impacts outcomes and should be part of routine echocardiographic assessment of function. An integrative approach combining different parameters, possibly with contribution of newer modalities in the future, is required.

Imaging in repaired tetralogy of Fallot with a focus on recent advances in echocardiography.

PURPOSE OF REVIEW: Imaging is essential for the management of adults with repaired tetralogy of Fallot (rToF). Echocardiography and cardiac magnetic resonance imaging are the central modalities to assess rToF. Here we review recent literature on imaging rToF, focusing on echocardiography and advances in assessment of cardiac mechanics. RECENT FINDINGS: Several two-dimensional, three-dimensional, and Doppler echo parameters have been proposed to assess pulmonary regurgitation, right ventricular volumes and ejection fraction, but most of them still have important limitations in their feasibility and reliability compared to cardiac magnetic resonance (CMR). Myocardial deformation imaging to study ventricular and atrial mechanics, regional function, ventricular-ventricular interactions, and electro-mechanical dyssynchrony has yielded insights into the pathophysiologic mechanisms of right ventricular and left ventricular dysfunction; thereby predicting clinical outcomes and exercise capacity, allowing among others, evaluation of the impact of pulmonary valve replacement (PVR). Emerging technologies are expected to further our understanding of the drivers of dysfunction and guide indications and timing of PVR. SUMMARY: Echocardiography and CMR have complementary and overlapping roles in rToF and contribute to our understanding of its pathophysiology and management.

Regional right ventricular remodeling and function in children with idiopathic pulmonary arterial hypertension vs those with pulmonary valve stenosis: Insights into mechanics of right ventricular dysfunction.

BACKGROUND: Right ventricular (RV) pressure overload in the context of pulmonary stenosis (PS) has a much better prognosis than in the context of idiopathic pulmonary arterial hypertension (iPAH), which may be related to differences in global and regional RV remodeling and systolic function. We compared RV mechanics in children with PS to those with iPAH, aiming to identify mechanisms and markers of RV dysfunction. METHODS: Eighteen controls, 18 iPAH and 16 PS patients were retrospectively studied. Age, BSA, and sex distribution were comparable. Two-dimensional echocardiography, blood flow and tissue Doppler, and longitudinal RV deformation were analyzed. ANCOVA-including RV systolic pressure (RVSP) and length as covariates-was used to compare patient groups. RESULTS: RV systolic pressure was higher in iPAH vs PS (96.8±25.4 vs 75.4±18.9 mm Hg, P=.011). Compared to controls, PS patients showed mild dilation (P<.01) and decreased longitudinal deformation (P<.001) at the RV apex. Compared to both PS and controls, iPAH patients showed marked spherical RV dilation (P<.001), reduced global, RV free wall and septal longitudinal deformation (iPAH -22.07%±4.35% vs controls -28.18%±1.69%; -9.98%±4.30% vs -17.45%±2.52%; P<.001) and RV postsystolic shortening (P<.001). RV transverse shortening (radial performance) was increased in PS (31.75%±10.35%; P<.001) but reduced in iPAH (-1.62%±11.11% vs controls 12.00%±7.74%; P<.001). CONCLUSION: Children with iPAH demonstrate adverse global and regional RV remodeling and mechanics compared to those with PS. Mechanisms of RV systolic dysfunction in iPAH include decreased longitudinal deformation, decreased or absent transverse shortening, and postsystolic shortening. These markers may be useful to identify children at risk of RV failure.

Speckle-Tracking Echocardiographic Measures of Right Ventricular Diastolic Function Correlate with Reference Standard Measures Before and After Preload Alteration in Children.

The accuracy of echocardiographic measures of right ventricular (RV) diastolic function has been sparsely studied. Our objective was to evaluate the correlation between echocardiographic and reference standard measures of RV diastolic function derived from micromanometer pressure analysis before and after preload alteration in children. Echocardiograms and micromanometer pressure analyses were prospectively performed before and after fluid bolus in children undergoing right heart catheterization. The isovolumic relaxation time constant (τ) and end-diastolic pressure (EDP) were measured. Conventional and speckle-tracking echocardiographic (STE) parameters of RV systolic and diastolic function were assessed. Normal saline bolus was given to increase RV EDP by 20 %. Twenty-eight studies were performed in 22 patients with congenital heart disease or postheart transplantation. Mean age was 8.7 ± 6.1 years. RV longitudinal early diastolic strain rate (EDSR) correlated with τ before (r = 0.57, p = 0.001) and after fluid bolus (r = 0.48, p = 0.008). No conventional echocardiographic measures correlated with τ both before and after fluid bolus. Multiple regression analysis revealed RV EDSR and LV circumferential EDSR as independent predictors of RV τ. There were no independent predictors of EDP. RV EDSR appears to correlate with the reference standard measure of early active ventricular relaxation in children at baseline and after changes in preload. Conventional echocardiographic measures of diastolic function were not predictive of diastolic function after preload alteration. Future studies should assess the prognostic significance of STE measures of diastolic function in this population.