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Contrast-induced nephropathy (CIN) is an important complication following diagnostic radiographic imaging and interventional therapy. It results from administration of intravascular iodinated contrast media (CM) and is currently the third most common cause of hospital-acquired acute kidney injury. CIN is associated with increased morbidity, prolonged hospitalization, and higher mortality. Although the importance of CIN is widely appreciated, and its occurrence can be mitigated by the use of pre- and posthydration protocols and low osmolar instead of high osmolar iodine-containing CM, specific prophylactic therapy is lacking. Remote ischemic preconditioning (RIPC), induced through short cycles of ischemia-reperfusion applied to the limb, is an intriguing new strategy that has been shown to reduce myocardial infarction size in patients undergoing emergency percutaneous coronary intervention. Furthermore, multiple proof-of-principle clinical studies have suggested benefit in several other ischemiareperfusion syndromes, including stroke. Perhaps somewhat surprisingly, RIPC also is emerging as a promising strategy for CIN prevention. In this review, we discuss current clinical and experimental developments regarding the biology of CIN, concentrating on the pathophysiology of CIN, and cellular and molecular mechanisms by which limb ischemic preconditioning may confer renal protection in clinical and experimental models of CIN. [ABSTRACT FROM AUTHOR]

An editorial is presented on the article "Preoperative Predictors of Death and Sustained Ventricular Tachycardia After Pulmonary Valve Replacement in Patients with Repaired Tetralogy of Fallot Enrolled in the INDICATOR Cohort." The authors discuss the results of the study which described preoperative risk factors for postoperative occurrence of death. They suggest the need of more information on the preoperative pathogenesis and postoperative modification of risk factors for poor outcomes.

Background Adults with single ventricle physiology palliated with a Fontan circulation experience high mortality due to circulatory failure. Renin-angiotensin-aldosterone system (RAAS) genotype contributes to adverse cardiovascular outcomes in acquired heart failure. This study evaluated associations between RAAS genotype, ventricular mass and function in a contemporary cohort of adults with a Fontan circulation. Methods This single-center prospective study included adults (n = 106) seen after the Fontan operation (mean age 27 ± 9 years). Patients were genotyped for 5 pro-hypertrophic RAAS gene polymorphisms. Serum BNP, ventricular mass and function, and clinical events were compared between those with ≥ 2 homozygous risk genotypes (“high-risk”, n = 31) versus those with ≤ 1 homozygous risk genotypes (“low risk”, n = 75). Results “High-risk” genotype was associated with diastolic dysfunction and higher serum BNP levels. There was no association between RAAS genotype and either ventricular mass or systolic function. During a mean follow-up duration of 9.5 ± 7.6 years, late Fontan failure occurred in 20% (n = 21) of patients, including 7 deaths. Serum BNP emerged as an independent predictor of late Fontan failure (HR 1.11 [CI 1.01–1.23] for each 50 unit increase in BNP, p = 0.04) and death alone (HR 1.25 [CI 1.07–1.47] for each 50 unit increase in BNP, p = 0.006). RAAS genotype was not associated with adverse clinical events. Conclusions Fontan failure is common among adults with single ventricle physiology. RAAS genotype is not associated with increased ventricular mass but does appear to influence diastolic function late after the Fontan operation. Elevated BNP is an independent predictor of Fontan failure and mortality in adulthood. [ABSTRACT FROM AUTHOR]

The article discusses the morphological, functional, and molecular similarities and differences in right ventricular (RV) and light ventricular (LV) responses to adverse loading and failure. Topics discussed include embryological and physiological differences between RV and LV, how the RV adapt to chronically increased afterload, and mechanical and functional interdependence between the RV and LV.

Objectives The objective was to determine the severity of residual cardiovascular abnormalities in youths after coarctation of the aorta (CoA) repair and their relation to regional blood pressure (BP). Design Prospective cross-sectional study in tertiary health care setting Methods Thirty-six CoAs (age 16±1 years; neonatal surgery only: n=16; surgery and/or stent implantation: n=20) and 37 age-matched controls were examined by very-high resolution ultrasound, echocardiography and applanation tonometry. Results CoA was associated with increased right arm systolic BP (p<0.001), intima-media thickness (IMT) in the common carotid (p<0.001), right brachial (p<0.05) and radial (p<0.05) arteries and ascending aortic stiffness (p<0.05). Carotid IMT correlated positively with age at first intervention (r=0.36, p<0.05). With left subclavian flap type repair, left arm systolic BP (p<0.001) and left brachial (p<0.001), radial (p<0.001) and ulnar (p<0.05) arterial IMTs were all reduced. When adjusted for BP, body mass index, age and gender, only carotid IMT (p<0.001) and LV-mass (p=0.013) of stented patients, as well as left arm arterial IMTs (p<0.01) in subclavian flap type repair patients remained different from controls. The significant associations of stented patients disappeared after adjustment for later patient age at intervention (median 8.7 vs 0.03 years, p<0.001). Residual arm-leg BP gradients correlated positively with carotid and brachial IMT. Conclusion CoA repair in early childhood is associated with increased preductal arterial IMT, LV mass and ascending aortic stiffness in adolescents. The more pronounced cardiovascular abnormalities after CoA stent implantation are likely related to the older patient age at the time of intervention [ABSTRACT FROM AUTHOR]

Objectives Coarctation of the aorta (CoA) has been associated with abnormal vascular function, increased blood pressure (BP) and premature cardiovascular disease even after a successful intervention. The objective was to determine the severity of residual cardiovascular abnormalities in youths after CoA repair and their relation to regional BP. Design Cross-sectional study in tertiary healthcare setting. Methods Thirty-six youths with CoA (age 1661 years; neonatal surgery only: n=16; surgery and/or stent implantation: n=20) and 37 age-matched controls were prospectively examined using a very-high-resolution vascular ultrasound imaging, echocardiography and applanation tonometry. Results CoA was associated with increased right arm systolic BP (p<0.001), intimaemedia thickness (IMT) in the common carotid (p<0.001), right brachial (p<0.05) and radial (p<0.05) arteries and ascending aortic stiffness (p<0.05). Carotid IMT correlated positively with age at first intervention (r=0.36, p<0.05). With left subclavian flap-type repair, left-arm systolic BP (p<0.001) and left brachial (p<0.001), radial (p<0.001) and ulnar (p<0.05) arterial IMTs were all reduced. When adjusted for BP, body mass index, age and gender, only carotid IMT (p<0.001) and left ventricular mass (p=0.013) of stented patients, as well as left-arm arterial IMTs (p<0.01) in subclavian flap-type repair patients, remained different from the controls. The significant associations of the stented patients disappeared after the adjustment for later patient age at intervention (median 8.7 vs 0.03 years, p<0.001). Residual armeleg BP gradients correlated positively with carotid and brachial IMT. No differences between the CoA patients and the controls were found for arterial adventitial thicknesses, lumen dimensions, thigh systolic BP, abdominal aorta and carotid stiffness and right carotid to radial pulse wave velocity. Conclusion CoA repair in early childhood is associated with increased preductal arterial IMT, left ventricular mass and ascending aortic stiffness in adolescents. The more pronounced cardiovascular abnormalities after CoA stent implantation are liACAkely related to older patient age at the time of intervention. [ABSTRACT FROM AUTHOR]

The article discusses the various situations in which pulmonary regurgitation occurs, including repaired Tetralogy of Fallot. It has been found that many patients with right ventricle to pulmonary artery conduit will develop a combination of obstruction and regurgitation across the conduit. Valvar pulmonary stenosis treated with balloon dilatation or surgery can lead to significant pulmonary regurgitation that requires valve replacement.

An introduction is presented in which the editor discusses various reports within the issue on topics including the role of valsartan in systemic right ventricle (RV) patients, congential heart disease and heart failure management.

Open in new tab Download slide Open in new tab Download slide OBJECTIVES Small ventricular septal defects are often considered to be without long-term haemodynamic consequences and so the majority remains unrepaired. However, we recently showed reduced functional capacity and altered right ventricular morphology in adults with small, unrepaired ventricular septal defects. The underlying mechanisms behind these findings remain unclear, and so, biventricular contractility during exercise was evaluated. METHODS Adults with small, unrepaired ventricular septal defects and healthy controls were examined with echocardiography during supine bicycle exercise with increasing workload. Tissue velocity Doppler was used for evaluating isovolumetric acceleration and systolic velocities during exercise. RESULTS In total, 34 patients with ventricular septal defects, a median shunt- ratio of 1.2 (26 ± 6 years), and 28 healthy peers (27 ± 5 years) were included. Right ventricular isovolumetric acceleration was lower in patients as compared with controls at rest (97 ± 40 vs 158 ± 43 cm/s2, P  =   0.01) and at peak heart rate (222 ± 115 vs 410 ± 120 cm/s2, P  <   0.01). Peak systolic velocities were similar at rest, but differed with exercise (13 ± 3 vs 16 ± 3 cm/s, P  =   0.02). Left ventricular isovolumetric acceleration was lower in patients as compared with controls throughout the test (P < 0.01). Septal isovolumetric acceleration was similar at rest, but reduced during increasing exercise as compared with controls (220 ± 108 vs 303 ± 119 cm/s2, P  =   0.03). Left ventricular isovolumetric acceleration was negatively correlated with the shunt- ratio, and right ventricular and septal peak systolic velocities were positively correlated with lower functional capacity. CONCLUSIONS Altered biventricular contractility is present during exercise in adults with small, unrepaired ventricular septal defects. These results add to the growing number of studies showing that long-term outcome in unrepaired ventricular septal defects may not be benign. [ABSTRACT FROM AUTHOR]

The article presents a letter to the editor in response to the article "Direct Comparison of Magnetic Resonance Imaging and Conductance Microcatheter in the Evaluation of Left Ventricular Function in Mice."

Examines cases of several adults with adenocarcinoma of the ileum in cystic fibrosis. Characteristic features of clostridial myonecrosis; Factors predisposing to gastrointestinal cancer; Association of diabetes mellitus and portasystemic shunting with adenocarcinoma.

Abstract: Background: Adverse ventricular-ventricular interactions have been recognized in those with repaired tetralogy of Fallot (TOF) and severe pulmonary regurgitation. Objective: We aimed to examine the impact of pulmonary valve replacement (PVR) on the left heart late after TOF repair. Methods and results: Left ventricular (LV) volumes and ejection fractions (EF) were analyzed in adults with severe pulmonary regurgitation after TOF repair with cardiac magnetic resonance imaging (CMR) before and after PVR. Thirty-nine patients (median age 33[20–65] years) were reviewed. Post-PVR, LVEF improved significantly in the entire cohort (50±9%→54±7%, p<0.001) and in those with moderately impaired (defined as LVEF ≤45%) preoperative LVEF (38±5%→47±6%, p<0.0001), but was not statistically different in those with relatively preserved (defined as LVEF >45%) preoperative LVEF. By multivariate linear regression analysis to evaluate independent CMR predictors of improved LVEF post-PVR for the entire cohort, the only CMR variable to emerge was preoperative LVEF (p=0.012, regression coefficient −0.54, SE 0.13). Whereas PVR resulted in increased LV filling in patients with relatively preserved preoperative LVEF reflected by an increase in LV end-diastolic volumes (77±10→82±16mL/m2, p=0.05), LV end-systolic volumes decreased after PVR in patients with impaired preoperative LVEF (65±12→54±10mL/m2, p=0.001) but LV end-diastolic volumes were not significantly changed. Conclusion: When LVEF is decreased after TOF repair, PVR appears to have a salutary effect on postoperative LVEF, thereby supporting the concept of recovery of adverse right–left heart interactions. Mechanisms of left heart improvement post-PVR differ depending on degree of preoperative LV systolic dysfunction. [Copyright &y& Elsevier]

The article examines the history, development and state of remote preconditioning in cardiovascular disease. A review of related literature on local ischaemic preconditioning in cardiac surgery is offered. It defines remote ischaemic preconditioning as an innate mechanism of multiorgan protection that can be induced by transient occlusion of blood flow to a limb with a blood-pressure cuff. The findings of several studies on remote preconditioning by transient limb ischemia are presented in detail.

Background: Non-invasive imaging markers in patients with repaired tetralogy of Fallot (rTOF) are still being investigated to inform clinical decision making. Atrial function is a prognostic indicator in many acquired and congenital heart diseases. We sought to examine the relationship between cardiac MRI (CMR)-derived indices of left atrial (LA) function, native left ventricular (LV) T1 values, biventricular systolic function, and exercise capacity in rTOF. Methods: Sixty-six patients with rTOF without prior pulmonary valve replacement who underwent CMR (median age 18.5 years) were identified. Twenty-one adult rTOF patients (age range 19–32 years) were compared with 20 age-matched healthy volunteers (age range 19–34 years). LA reservoir, conduit, and pump global longitudinal strain (GLS) and strain rate (SR) were determined by tissue tracking. Native LV T1 values were measured on rTOF patients. Pearson correlations were performed to determine bivariate associations. Results: Adult rTOF patients had higher pump GLS, pump:conduit, and pump:reservoir GLS ratios, and lower conduit:reservoir GLS ratio, LV ejection fraction (EF), and right ventricular EF compared to controls (p < 0.001 for each comparison). LA conduit:reservoir GLS and pump:reservoir GLS had correlations to native LV T1 (ρ = 0.26, p = 0.03 and ρ = − 0.26, p = 0.03, respectively). LA reservoir SR had positive correlation to RV EF (ρ = 0.27, p = 0.03). There were no statistically significant correlations between LA function and exercise capacity. Conclusions: LA function is altered in adolescent and young adult patients with rTOF indicating worse diastolic function and relates to increasing native LV T1 values. Future studies are indicated to investigate the progression of adverse atrial-ventricular interactions and poor outcomes in this population. [ABSTRACT FROM AUTHOR]

Altered autophagy is implicated in several human cardiovascular diseases. Remote ischemic conditioning (RIC) is cardioprotective in multiple cardiovascular injury models and modifies autophagy signaling, but its effect in cardiomyopathy induced by gene manipulation has not been reported. To investigate the cardiac effects of chronically reduced autophagy as a result of Atg5 knockdown and assess whether RIC can rescue the phenotype. Atg5 knockdown was induced with tamoxifen for 14 days in cardiac-specific conditional Atg5 flox mice. Autophagy proteins and cardiac function were evaluated by Western blot and echocardiography, respectively. RIC was induced by cyclical hindlimb ischemia and reperfusion using a tourniquet. RIC or sham procedure was performed daily during tamoxifen induction and, in separate experiments, chronically 3 times per week for 8 weeks. Cardiac responses were assessed by end of the study. Cardiac-specific knockdown of Atg5 reduced protein levels by 70% and was associated with a significant increase in mTOR, a reduction of LC3-II and increased upstream autophagy proteins including LC3-I, P62, and Beclin. The changes in biochemical markers were associated with development of an age-related cardiomyopathy during the 17-month follow-up indicated by increased heart weight body weight ratio, progressive decline in cardiac function, and premature death. RIC increased cardiac ATG5 and rescued some of the Atg5 knockdown-induced cardiomyopathy phenotype and associated morphological remodeling. We conclude that cardiac-specific Atg5 knockdown leads to the development of age-related cardiomyopathy. RIC reverses the molecular and structural phenotype when administered both acutely and chronically. [ABSTRACT FROM AUTHOR]

It has been suggested that miR-144 is pro-atherosclerotic via effects on reverse cholesterol transportation targeting the ATP binding cassette protein. This study used proteomic analysis to identify additional cardiovascular targets of miR-144, and subsequently examined the role of a newly identified regulator of atherosclerotic burden in miR-144 knockout mice receiving a high fat diet. To identify affected secretory proteins, miR-144 treated endothelial cell culture medium was subjected to proteomic analysis including two-dimensional gel separation, trypsin digestion, and nanospray liquid chromatography coupled to tandem mass spectrometry. We identified 5 gel spots representing 19 proteins that changed consistently across the biological replicates. One of these spots, was identified as vimentin. Atherosclerosis was induced in miR-144 knockout mice by high fat diet and vascular lesions were quantified by Oil Red-O staining of the serial sectioned aortic root and from en-face views of the aortic tree. Unexpectedly, high fat diet induced extensive atherosclerosis in miR-144 knockout mice and was accompanied by severe fatty liver disease compared with wild type littermates. Vimentin levels were reduced by miR-144 and increased by antagomiR-144 in cultured cardiac endothelial cells. Compared with wild type, ablation of the miR-144/451 cluster increased plasma vimentin, while vimentin levels were decreased in control mice injected with synthetic miR-144. Furthermore, increased vimentin expression was prominent in the commissural regions of the aortic root which are highly susceptible to atherosclerotic plaque formation. We conclude that miR-144 maybe a potential regulator of the development of atherosclerosis via changes in vimentin signaling. [ABSTRACT FROM AUTHOR]

• Physiological surface tension had a negligible effect on ADV-mediated PO 2 reduction. • Fluid protein concentration was uncorrelated with PO 2 reduction. • Viscosity had a transient effect on PO 2 reduction. • Fluid mixing accelerated PO 2 reduction at physiologic viscosities. • Reduction in the PO 2 in whole blood was demonstrated. Acoustic droplet vaporization (ADV) has been shown to reduce the partial pressure of oxygen (PO 2) in a fluid. The goals of this study were three-fold: 1) to determine the ADV pressure amplitude threshold in fluids that had physiologically relevant values for surface tension, protein concentration, and viscosity; 2) to assess whether these parameters and fluid mixing affect ADV-mediated PO 2 reduction; and 3) to assess the feasibility of ADV-mediated PO 2 reduction in plasma and whole blood. In vitro ADV experiments were conducted using perfluoropentane droplets (number density: 5 × 106 ± 0.2 × 106/mL) dispersed in fluids (saline, polyvinylpyrrolidone solutions, porcine plasma, or porcine whole blood) that had a physiological range of surface tensions (62–68 mN/m), protein concentrations (0 and 68.7 mg/mL), and viscosities (0.7–4 cP). Droplets were exposed to pulsed ultrasound (5 MHz, 4.25 MPa peak negative pressure) while passing through a 37 °C flow system with inline PO 2 sensors. In select experiments, the fluid also passed through mixing channels after ultrasound exposure. Our results revealed that the ADV pressure thresholds were the same for all fluids. Surface tension and protein concentration had no effect on PO 2 reduction. Increasing viscosity attenuated PO 2 reduction. However, the attenuated effect was absent after fluid mixing. Furthermore, ADV-mediated PO 2 reduction in whole blood (30.8 ± 3.2 mmHg) was less than that in a polyvinylpyrrolidone solution (40.2 ± 2.1 mmHg) with equal viscosity. These findings should be considered when planning clinical studies of ADV-mediated PO 2 reduction and other biomedical applications of ADV. [ABSTRACT FROM AUTHOR]

Objective Although heart failure (HF) is the leading cause of premature death in adult congenital heart disease (ACHD), little population-specific data exist. This study reports early experience from a dedicated, sub-specialty adult congenital heart disease-heart failure (ACHD-HF) clinic, aiming to identify risk factors for adverse outcome. Methods Between 2012 and 2015, 126 patients (57% male) attended the ACHD-HF clinic. Baseline and follow-up data were analysed and compared across 4 anatomical/physiological subgroups: cyanotic ACHD, Fontan circulation (1V), biventricular circulation with a subaortic right ventricle (2V-RV) and biventricular circulation with a subaortic left ventricle (2V-LV). Predictors of the composite primary outcome: death, transplant or ventricular assist device (VAD) were identified using multivariable Cox proportional hazard models. Results Mean age at first visit was 38 ± 13 years. Patients were grouped as follows: cyanotic ACHD 10%, 1 V 24%, 2V-RV 29% and 2V-LV 37%. During a median follow-up of 1.7 (IQR 0.8–2.9) years, 38 patients (30%) reached the primary outcome. Event-free survival was 89%, 78% and 63% at 1, 2 and 3 years. Forty (31.7%) patients experienced 69 HF hospitalisations. Between-group differences were noted for systolic function, valvular regurgitation, pacing prevalence and invasive hemodynamics. Multivariable analysis revealed 2V-RV subgroup ( p = 0.001), NYHA class ( p = 0.002) B-type natriuretic peptide > 164 pg/ml ( p = 0.003) and sodium < 136 mmol/L ( p = 0.036) as independently associated with death, transplant or VAD. Conclusions Our young ACHD-HF patients experienced high adverse event rates during a short period of follow-up. The prognostic markers identified will aid clinicians to stratify short-term risk and thereby guide advanced HF management decisions in ACHD. [ABSTRACT FROM AUTHOR]

Death and morbidity in pulmonary arterial hypertension (PAH) are often due to right ventricular (RV) failure and associated left ventricular (LV) dysfunction. We investigated regional myocardial remodeling and function as the basis for adverse ventricular-ventricular interactions in experimental chronic RV pressure overload. Two distinct animal models were studied: A rabbit model of increased RV pressure-load through progressive pulmonary artery banding A rat model of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Regional myocardial function was assessed by speckletracking strain echocardiography and ventricular pressures measured by catheterization before termination. Regional RV and LV myocardium was analyzed for collagen content, apoptosis and pro-fibrotic signaling gene and protein expression. Although the RV developed more fibrosis than the LV; in both models the LV was substantially affected. In both ventricles, particularly the LV, fibrosis developed predominantly at the septal hinge-point regions in association with decreased regional and global circumferential strain, reduced global RV and LV function and up-regulation of regional transforming growth factor-β1 (TGFβ1) and apoptosis signaling. A group of PAH rats who received the TGFb blocker SB431542 showed improved RV function and reduced regional hinge-point myocardial fibrosis. RV pressure-loading and PAH lead to biventricular TGFβ1 signaling, fibrosis and apoptosis, predominantly at the septal hinge-point regions, in association with regional myocardial dysfunction. This suggests that altered geometry and wall stress lead to adverse RV-LV interactions through the septal hinge-points to induce LV fibrosis and dysfunction. [ABSTRACT FROM AUTHOR]

We sought to determine whether a 9-day remote ischemic preconditioning (IPC) causes improvements in exercise performance, energetics, and blood pressure. Ten participants (mean age 24 ± 4 years) had no changes in aerobic capacity (preintervention: 38 ± 10 mL/(kg·min)-1 vs. postintervention: 38 ± 10 mL/(kg·min)-1), blood pressure (preintervention: 112 ± 7/66 ± 6 mm Hg vs. postintervention: 112 ± 10/62 ± 5 mm Hg), cardiac phosphocreatinine-to-adenosine-triphosphate ratio (preintervention: 2.1 ± 0.5 vs. postintervention: 2.3 ± 0.4), and postexercise skeletal muscle phosphocreatine recovery (preintervention: 34 ± 11 s vs. postintervention: 31 ± 11 s). Short-term remote IPC may be ineffective in improving these outcomes. [ABSTRACT FROM AUTHOR]

Background: The left pulmonary artery (LPA) contributes more than the right (RPA) to total pulmonary regurgitation (PR) in patients after tetralogy of Fallot (TOF) repair, but the mechanism of this difference is not well understood. This study aimed to analyze the interplay between heart and lung size, mediastinal geometry, and differential PR. Methods: Forty-eight Cardiovascular Magnetic Resonance (CMR) studies in patients after TOF repair were analyzed. In addition to the routine blood flow and ventricular volume quantification cardiac angle between the thoracic anterior-posterior line and the interventricular septum, right and left lung areas as well as right and left hemithorax areas were measured on an axial image. Statistical analysis was performed to compare flow parameters between RPA and LPA and to assess correlation among right ventricular volume, pulmonary blood flow parameters and lung area. Results: There was no difference between LPA and RPA diameters. The LPA showed significantly less total forward flow (2.49 ± 0.87 L/min/m² vs 2.86 ± 0.89 L/min/m²; p = 0.02), smaller net forward flow (1.40 ± 0.51 vs 1.89 ± 0. 60 mL/min/m²; p = <0.001), and greater regurgitant fraction (RF) (34 ± 10 % vs 43 ± 12 %; p = 0.001) than the RPA. There was no difference in regurgitant flow volume between RPA and LPA (p = 0.29). Indexed right ventricular end-diastolic volume (RVEDVi) correlated with LPA RF (R = 0.48, p < 0.001), but not with RPA RF (p = 0.09). Larger RVEDVi correlated with a more leftward cardiac axis (R = 0.46, p< 0.001) and with smaller left lung area (R = -0.58, p < 0.001). LPA RF, but not RPA RF, correlated inversely with left lung area (R = -0.34, p = 0.02). The follow-up CMRs in 20 patients showed a correlation of the rate of RV enlargement with the rates of LPA RF worsening (R = 0.50, p = 0.03), and of increasing left lung compression (R = -0.55, p = 0.012). Conclusion: An enlarged and levorotated heart is associated with left lung compression and impaired flow into the left lung. Keywords: Differential pulmonary blood flow, Pulmonary regurgitation, Tetralogy of Fallot, Right ventricular enlargement, Cardiovascular magnetic resonance [ABSTRACT FROM AUTHOR]

Background: Pulmonary arterial hypertension is usually fatal due to right ventricular failure and is frequently associated with co-existing left ventricular dysfunction. Endothelin-1 is a powerful pro-fibrotic mediator and vasoconstrictor that is elevated in pulmonary arterial hypertension. Endothelin receptor blockers are commonly used as pulmonary vasodilators, however their effect on biventricular injury, remodeling and function, despite elevated isolated right ventricular afterload is unknown. Methods: Elevated right ventricular afterload was induced by progressive pulmonary artery banding. Seven rabbits underwent pulmonary artery banding without macitentan; 13 received pulmonary artery banding + macitentan; and 5 did not undergo inflation of the pulmonary artery band (sham-operated controls). Results: Right and left ventricular collagen content was increased with pulmonary artery banding compared to sham-operated controls and ameliorated by macitentan. Right ventricular fibrosis signaling (connective tissue growth factor and endothelin-1 protein levels); extra-cellular matrix remodeling (matrix-metalloproteinases 2 and 9), apoptosis and apoptosis-related peptides (caspases 3 and 8) were increased with pulmonary artery banding compared with sham-operated controls and decreased with macitentan. Conclusion: Isolated right ventricular afterload causes biventricular fibrosis, right ventricular apoptosis and extra cellular matrix remodeling, mediated by up-regulation of endothelin-1 and connective tissue growth factor signaling. These pathological changes are ameliorated by dual endothelin receptor blockade despite persistent elevated right ventricular afterload. [ABSTRACT FROM AUTHOR]

Background: Remote ischemic conditioning (RIC), induced by brief periods of limb ischemia has been shown to decrease acute myocardial injury and chronic responses after acute coronary syndromes. While several signaling pathways have been implicated, our understanding of the cardioprotection and its underlying mediators and mechanisms remains incomplete. In this study we examine the effect of RIC on pro-autophagy signaling as a possible mechanism of benefit. Methods and Results: We examined the role of autophagy in the acute/first window (15 minutes after RIC), delayed/second window (24 hours after RIC) and chronic (24 hours after 9 days of repeated RIC) phases of cardioprotection. C57BL/6 mice (N = 69) were allocated to each treatment phase and further stratified to receive RIC, induced by four cycles of 5 minutes of limb ischemia followed by 5 minutes of reperfusion, or control treatment consisting solely of handling without transient ischemia. The groups included, group 1 (1W control), group 2 (1W RIC), group 3 (2W control), group 4 (2W RIC), group 5 (3W control) and group 6 (3W RIC). Hearts were isolated for assessment of cardiac function and infarct size after global ischemia using a Langendorff preparation. Infarct size was reduced in all three phases of cardioprotection, in association with improvements in post-ischemic left ventricular end diastolic pressure (LVEDP) and developed pressure (LVDP) (P<0.05). The pattern of autophagy signaling varied; 1W RIC increased AMPK levels and decreased the activation of mammalian target of rapamycin (mTOR), whereas chronic RIC was associated with persistent mTOR suppression and increased levels of autophagosome proteins, LC3II/I and Atg5. Conclusions: Cardioprotection following transient ischemia exists in both the acute and delayed/chronic phases of conditioning. RIC induces pro-autophagy signaling but the pattern of responses varies depending on the phase, with the most complete portfolio of responses observed when RIC is administered chronically. [ABSTRACT FROM AUTHOR]

Background: Remote ischemic preconditioning (RIPC) induced by transient limb ischemia confers multi-organ protection and improves exercise performance in the setting of tissue hypoxia. We aimed to evaluate the effect of RIPC on exercise capacity in heart failure patients. Methods: We performed a randomized crossover trial of RIPC (4×5-minutes limb ischemia) compared to sham control in heart failure patients undergoing exercise testing. Patients were randomly allocated to either RIPC or sham prior to exercise, then crossed over and completed the alternate intervention with repeat testing. The primary outcome was peak VO2, RIPC versus sham. A mechanistic substudy was performed using dialysate from study patient blood samples obtained after sham and RIPC. This dialysate was used to test for a protective effect of RIPC in a mouse heart Langendorff model of infarction. Mouse heart infarct size with RIPC or sham dialysate exposure was also compared with historical control data. Results: Twenty patients completed the study. RIPC was not associated with improvements in peak VO2 (15.6+/−4.2 vs 15.3+/−4.6 mL/kg/min; p = 0.53, sham and RIPC, respectively). In our Langendorff sub-study, infarct size was similar between RIPC and sham dialysate groups from our study patients, but was smaller than expected compared to healthy controls (29.0%, 27.9% [sham, RIPC] vs 51.2% [controls]. We observed less preconditioning among the subgroup of patients with increased exercise performance following RIPC (p<0.04). Conclusion: In this pilot study of RIPC in heart failure patients, RIPC was not associated with improvements in exercise capacity overall. However, the degree of effect of RIPC may be inversely related to the degree of baseline preconditioning. These data provide the basis for a larger randomized trial to test the potential benefits of RIPC in patients with heart failure. Trial Registration: ClinicalTrials.gov +++++ [ABSTRACT FROM AUTHOR]

The article discusses a study on heart failures involving children. Topics highlighted include a definition of pediatric heart failure (HF) and several processes involved such as respiratory distress and exercise intolerance, a plan for the development of the research needed to study the medical condition and recommendations by the medical working group in the development.

Patients with pulmonary hypertension associated with congenital heart disease survive longer with preserved right ventricular (RV) function compared with those with primary pulmonary hypertension. The purpose of this study was to test the hypothesis that superior RV performance can be demonstrated, at baseline and when challenged with increased RV afterload, in lambs with chronic left-to-right cardiac shunts compared with control lambs. A shunt was placed between the pulmonary artery and the aorta in fetal lambs (shunt). RV pressure-volume loops were obtained 4 wk after delivery in shunt and control lambs, before and after increased afterload was applied using pulmonary artery banding (PAB). Baseline stroke volume (8.7 ± 1.8 vs. 15.8 ± 2.7 ml, P = 0.04) and cardiac index (73.0 ± 4.0 vs. 159.2 ± 25.1 ml.min-1.kgmin-1, P = 0.02) were greater in shunts. After PAB, there was no difference in the change in cardiac index (relative to baseline) between groups; however, heart rate (HR) was greater in controls (168 ± 7.3 vs. 138 ± 6.6 beats/min, P = 0.01), and end-systolic elastance (Ees) was greater in shunts (2.63 vs. 1.31 × baseline, P = 0.02). Control lambs showed decreased mechanical efficiency (71% baseline) compared with shunts. With acute afterload challenge, both controls and shunts maintained cardiac output; however, this was via maladaptive responses in controls, while shunts maintained mechanical efficiency and increased contractility via a proposed enhanced Anrep effect-the second, slow inotropic response in the biphasic ventricular response to increased afterload, a novel finding in the RV. The mechanisms related to these physiological differences may have important therapeutic implications. [ABSTRACT FROM AUTHOR]

Background: While remote ischemic preconditioning (rIPC) protects the mature heart against ischemia-reperfusion (IR) injury, the effect on the neonatal heart is not known. The neonatal heart relies almost solely on carbohydrate metabolism, which is modified by rIPC in the mature heart. We hypothesized that rIPC combined with metabolic support with glucose-insulin (GI) infusion improves cardiac function and reduces infarct size after IR injury in neonatal piglets in-vivo. Methods and results: 32 newborn piglets were randomized into 4 groups: control, GI, GI+rIPC and rIPC. GI and GI+rIPC groups received GI infusion continuously from 40min prior to ischemia. rIPC and GI+rIPC groups underwent four cycles of 5min limb ischemia. Myocardial IR injury was induced by 40min occlusion of the left anterior descending artery followed by 2h reperfusion. Myocardial lactate concentrations were assessed in microdialysis samples analyzed by mass spectrometry. Infarct size was measured using triphenyltetrazolium chloride staining. Systolic recovery (dP/dtmax as % of baseline) after 2h reperfusion was 68.5±13.8% in control, 53.7±11.2% in rIPC (p <0.05), and improved in GI (83.6±18.8%, p <0.05) and GI+rIPC (87.0±15.7%, p <0.01). Conclusion: rIPC+GI protects the neonatal porcine heart against IR injury in-vivo. rIPC alone has detrimental metabolic and functional effects that are abrogated by simultaneous GI infusion. [ABSTRACT FROM AUTHOR]

OBJECTIVES Transposition of the great arteries (TGA) and left ventricular outflow tract obstruction (LVOTO) with or without ventricular septal defect have multiple surgical treatment options. We sought to identify pre- and intraoperative factors that determine the timing of repair, procedure type and subsequent LVOT outcome. METHODS Twenty-eight (8.2% of all TGA) patients with TGA with LVOTO (double outlet ventricle, n = 5, TGA/intact septum, n = 1) between 2000 and 2012 were reviewed. Anatomical factors were identified by prerepair echocardiography. LVOTO complexity was characterized by the degree of obstruction (0 = none, 0.33 = mild, 0.66 moderate and 1 = severe) at various levels: pulmonary valve (PV) dysplasia/hypoplasia, posterior deviation of the infundibular septum, fibromuscular ridge, tissue tag and abnormal chordal attachment. Summation of the obstruction score, at each level, yielded the LVOT complexity score. The descriptive analysis of intraoperative decision-making at late repair was performed. RESULTS Operations: early arterial switch operation (ASO) + LVOT resection (n = 9, 32%), late ASO + LVOT resection (n = 3, 10%), Nikaidoh (n = 8, 29%), Rastelli (n = 6, 21%), single-ventricle palliation (n = 2, 7%). The primary LVOT obstruction mechanism was posterior deviation of the infundibular septum (n = 16, 57%) and PV dysplasia (n = 6, 21%). The early ASO group had a lower PV complexity score (0.42 ± 0.22 vs 0.96 ± 0.55, P = 0.007), tissue tag score (0.03 ± 0.15 vs 0.26 ± 0.34, P = 0.018) and LVOT complexity score (2.11 ± 0.86 vs 3.2 ± 0.96, P = 0.006). The LVOT complexity score in the Nikaidoh group was higher than in the late ASO group (P = 0.019). Of 16 candidates for the Nikaidoh procedure, 6 patients underwent a Rastelli operation due to coronary artery patterns (single coronary, n = 3, 1RL-2Cx, n = 2 or an abnormal left anterior descending coronary artery course, n = 1). Two patients underwent single-ventricle palliation due to the interference of essential chordae. All patients survived the operation. The 3-year survival was 96%. One patient who underwent late ASO required re-LVOT resection. CONCLUSIONS A newly developed scoring system, the LVOT complexity score, helped to quantify the LVOT complexity and was correlated with our choice of the surgical procedure of TGA with LVOTO. The current strategy achieved reasonable survival and LVOT outcome with three quarters of the patients having an anatomically aligned LVOT. The coronary anatomy pattern was the primary determinant in the decision-making between the Nikaidoh procedure and the Rastelli operation. [ABSTRACT FROM PUBLISHER]

Objective The mechanisms underlying adverse electro-mechanical interaction after tetralogy of Fallot (TOF) repair remain unclear. This study investigated biventricular dyssynchrony in children with TOF and its relationship to exercise, QRS duration (QRSd) and ventricular mechanics. Methods 29 asymptomatic children (5-18⇔…years) with repaired TOF were prospectively evaluated by MRI, cardiopulmonary exercise testing and echocardiography at rest and during bicycle exertion. Their dyssynchrony results were compared with those of 44 resting and 27 exercising, age- and sex-matched controls. An intraventricular dyssynchrony index was calculated from the SD of regional time intervals in 12 left ventricular (LV) 'Ts LV-12SD⇔(tm) and eight right ventricular (RV) 'Ts RV-8SD⇔(tm) segments. Ventricular size, volumes, ejection fractions, pulmonary regurgitant volumes and peak oxygen consumption and N-terminal BNP levels were quantified in the patients. Results Despite moderate RV dilatation (median indexed RV end-diastolic volume 145.2⇔…ml/m2) and right bundle branch block (median QRSd 130⇔…ms) compared with controls, children with TOF demonstrated neither RV nor LV dyssynchrony at rest (Ts RV-8SD, 37.9±10.2 vs 44.3±10.3, 95% CI ⇔'11.8 to ⇔'0.99, p=0.02; Ts LV-12SD, 38.6±16.8 vs 34.0±10.8, 95% CI ⇔'1.8 to 11.0, p=0.16). Exercise stress induced biventricular dyssynchrony in patients with TOF but not in controls (Ts RV-8SD, 59.9±34.4 vs 28.2±10.4, p<0.0001, 95% CI 17.2 to 46.3; Ts LV-12SD, 48.0±18.6 vs 31.9±10.7, 95% CI 7.9 to 24.4, p=0.002). This was unrelated to QRSd, ventricular volumes and function, or peak oxygen consumption. Conclusion Exercise induces biventricular mechanical dyssynchrony in children with TOF. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To study the accuracy and feasibility of very-high resolution ultrasound (VHRU, 25–55 MHz) and conventional high resolution ultrasound (HRU, 12 MHz) in the assessment of common carotid intima-media thickness (IMT) in healthy children between 0 and 18 years of life. Methods: IMT was measured with VHRU and HRU in 135 children. Seventeen similar sized porcine arterial specimens were imaged with VHRU and HRU, and the IMT measurements compared to histology. Results: Adequate imaging was obtained and IMT quantified in all children with 25 and 35 MHz, but the far wall was rarely reached with 55 MHz, even in small children. HRU-IMT was significantly thicker compared with VHRU-IMT in young children (<12 years; HRU: 0.434 ± 0.040 vs. VHRU: 0.341 ± 0.054 mm, N = 66; p < 0.001). No differences between HRU-IMT and VHRU-IMT were found among older children. No differences were found between far and near wall VHRU-IMT. An increase in porcine arterial IMT with decreasing transducer frequency was observed in comparison to histology. HRU-IMT was significantly overestimated compared with VHRU-IMT and histology-IMT in porcine vessels with an IMT within the pediatric range (0.20–0.50 mm). Conclusion: VHRU is feasible and more accurate than HRU in quantifying CIMT in young children (<12 years). We recommend using the highest ultrasound transducer frequency applicable to quantify CIMT in the pediatric population. [Copyright &y& Elsevier]

Background An acute increase in right ventricular (RV) afterload leads to RV dilation, reduced systolic function, and low cardiac output. It has previously been shown, experimentally, that an additional increase of left ventricular afterload by aortic constriction can reverse some of these changes.We studied the clinically more relevant effects of intravenous vasopressors on this phenomenon in an animal model. Methods Acute RV failure was induced by pulmonary artery constriction in adult New Zealand white rabbits. We then assessed the effect of aortic constriction on the functional performance of the failing RV using conductance catheters. We compared the impact of aortic constriction on RV contractility with the effects of 0.05, 0.1, 0.5, and 1 mcg/kg X min-1 norepinephrine and epinephrine. Results Aortic constriction lead to increased RV end-systolic pressure-volume relation (RVESPVR 3.2 (±0.6) versus 5.2 (±0.7) mm Hg/mL (p = 0.0002). Cardiac output (131 (±23.7) versus 134.8 (±32.5) mL/min), and heart rate remained unchanged. Administration of norepinephrine and epinephrine lead to similar effects on RV contractility with the maximum increase in RVESPVR observed with 0.5 mcg/kg X min-11 norepinephrine (RVESPVR 4.8 (±0.4) mm Hg/mL, p = 0.007). However, in contrast to aortic constriction, cardiac output also markedly increased during vasopressor therapy, the most significant effect seen with 1mcg/kg X min-1 epinephrine (214.8 (±46.8)mL/min, p = 0.04). Conclusions Aortic constriction improves RV contractility but not cardiac output in acute right heart failure. A comparable effect on RV functional performance with increased cardiac output was achieved by administration of systemic vasopressors. These data may have implications for management of clinical right heart failure. [ABSTRACT FROM AUTHOR]

The article discusses the results of a study on the effectiveness of lung airway pressure release ventilation in enhancing pulmonary blood flow in children after the tetralogy of Fallot surgery and a cavopulmonary shunt. The study shows that the mean pulmonary blood flow and oxygen delivery increased in pediatric patients in the presence of spontaneous ventilation. Lung perfusion also improved in patients under airway pressure release ventilation.

Objectives: Coarctation of the aorta (CoA) has been associated with abnormal vascular function, increased blood pressure (BP) and premature cardiovascular disease even after a successful intervention. The objective was to determine the severity of residual cardiovascular abnormalities in youths after CoA repair and their relation to regional BP. Design: Cross-sectional study in tertiary healthcare setting. Methods: Thirty-six youths with CoA (age 16±1 years; neonatal surgery only: n=16; surgery and/or stent implantation: n=20) and 37 age-matched controls were prospectively examined using a very-high-resolution vascular ultrasound imaging, echocardiography and applanation tonometry. Results: CoA was associated with increased right arm systolic BP (p<0.001), intima-media thickness (IMT) in the common carotid (p<0.001), right brachial (p<0.05) and radial (p<0.05) arteries and ascending aortic stiffness (p<0.05). Carotid IMT correlated positively with age at first intervention (r=0.36, p<0.05). With left subclavian flap-type repair, left-arm systolic BP (p<0.001) and left brachial (p<0.001), radial (p<0.001) and ulnar (p<0.05) arterial IMTs were all reduced. When adjusted for BP, body mass index, age and gender, only carotid IMT (p<0.001) and left ventricular mass (p=0.013) of stented patients, as well as left-arm arterial IMTs (p<0.01) in subclavian flap-type repair patients, remained different from the controls. The significant associations of the stented patients disappeared after the adjustment for later patient age at intervention (median 8.7 vs 0.03 years, p<0.001). Residual arm-leg BP gradients correlated positively with carotid and brachial IMT. No differences between the CoA patients and the controls were found for arterial adventitial thicknesses, lumen dimensions, thigh systolic BP, abdominal aorta and carotid stiffness and right carotid to radial pulse wave velocity. Conclusion: CoA repair in early childhood is associated with increased preductal arterial IMT, left ventricular mass and ascending aortic stiffness in adolescents. The more pronounced cardiovascular abnormalities after CoA stent implantation are likely related to older patient age at the time of intervention. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress is activated during and contributes to ischemia-reperfusion (I/R) injury. Attenuation of ER stress-induced apoptosis protects the heart against I/R injury. Using apelin, a ligand used to activate the apelin APJ receptor, which is known to be cardioprotective, this study was designed to investigate 1) the time course of changes in I/R injury after ER stress; 2) whether apelin infusion protects the heart against I/R injury via modulation of ER stress-dependent apoptosis signaling pathways; and 3) how phosphatidylinositol 3-kinase (PI3K)/Akt, endothelial nitric oxide synthase (eNOS), AMP-activated protein kinase (AMPK), and ERK activation are involved in the protection offered by apelin treatment. The results showed that, using an in vivo rat I/R model induced by 30 min of ischemia followed by reperfusion, infarct size (IS) increased from 2 h of reperfusion (34.85 ± 2.14%) to 12 h of reperfusion (48.98 ± 3.35, P < 0.05), which was associated with an abrupt increase in ER stress-dependent apoptosis activation, as evidenced by increased CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, and JNK activation (CHOP: 2.49-fold increase, caspase-12: 2.09-fold increase, and JNK: 3.38-fold increase, P < 0.05, respectively). Administration of apelin at 1 μg/kg not only completely abolished the activation of ER stress-induced apoptosis signaling pathways at 2 h of reperfusion but also significantly attenuated time-related changes at 24 h of reperfusion. Using pharmacological inhibition, we also demonstrated that PI3K/Akt, AMPK, and ERK activation were involved in the protection against I/R injury via inhibition of ER stress-dependent apoptosis activation. In contrast, although eNOS activation played a role in decreasing IS at 2 h of reperfusion, it failed to modify either IS or ER stress-induced apoptosis signaling pathways at 24 h after reperfusion. [ABSTRACT FROM AUTHOR]

The article presents a study on the benefits of remote ischemic preconditioning (RIPC) in improving the performance of highly trained athletes. It describes the methodology of the randomized study that was conducted on national-level swimmers between the age of 13-27 years who were put on RIPC. It reveals that RIPC led to improvement in the maximal swim time and concludes that RIPC is beneficial in improving the performance of highly trained swimmers and can also be applicable for performance enhancement in other sports.

Objectives: This study aimed to determine the normal variation of left ventricular (LV) isovolumic acceleration (IVA) in healthy children and to assess the feasibility of an entirely noninvasive method for demonstration of the LV force-frequency relationship (FFR). Background: Pediatric cardiologists continue to seek noninvasive, load-independent indexes for the assessment of LV contractility and myocardial reserve. Methods: Resting LV IVA was measured by echocardiogram in 236 healthy children and compared with their clinical characteristics. Further measurements were made in 51 children at incremental heart rates during semi-recumbent exercise. For these, FFRs were constructed by plotting LV IVA against heart rate. To assess potential clinical applications, pilot FFR data were collected from 16 children previously treated with anthracyclines. Results: In healthy children, median resting LV IVA was 1.2 m/s2, interquartile range 0.9 to 1.6 m/s2. Resting LV IVA was unaffected by age, sex, weight, height, and body surface area but associated with baseline heart rate (r = 0.18, p = 0.0006). Noninvasive evaluation of the LV FFR was possible in 98% of subjects. Positive FFRs were confirmed in all the healthy children. By comparison, several of the children with anthracycline exposure demonstrated flattened force-frequency curves that were largely independent of resting LV ejection fraction and suggest reduced contractile reserve. Conclusions: In children over 7 years, it is possible to demonstrate the LV FFR by interval measurement of IVA during exercise. The availability of pediatric normal values for both this relation and resting LV IVA might facilitate future investigation of LV contractility and myocardial contractile reserve during childhood. [Copyright &y& Elsevier]

Ischemic postconditioning (PostC) and perconditioning (PerC) provide practical methods for protecting the heart against ischemia-reperfusion (l/R) injury, but their combined effects have not been studied in detail. Using an in vivo rat hR model, we tested 1) whether additive effects were produced when local PostC was preceded by varying doses of remote PerC, and whether the optimal PostC+PerC regime is additive to local ischemic preconditioning (IPC), and 2) how combined PostC+PerC alters the activity of the reperfusion injury salvage kinase pathway. The optimal combination of PerC and PostC therapy was produced by PerC delivered with four cycles of 5 mm of limb ischemia followed by 5-mm reperfusion. This resulted in lower infarct size (22.56 ± 4.45%) compared with rats with PostC alone (29.39 ± 3.66%) and PerC alone (33.49 ± 5.81%) and complementary differences in the generation of reactive oxygen species and apoptotic signaling. However, this optimal combination of PostC+PerC resulted in protection similar to local 1PC alone (18.8 ± 2.54%, P = 0. 13), and when added to IPC there was no additional protection (19.62 ± 2.89%, P = 0.675). Akt and ERKI/2 phosphorylation was induced by PostC and PerC and maximally by combined PostC+PerC treatment, and protection was abolished by phosphatidylinositol 3-kinase or ERKI/2 inhibitors. This study shows that neither PostC nor a maximized "dose" of PerC leads to optimal kinase signaling or cardioprotection compared with IPC alone. However, combined PostC+PerC may result in complementary effects on kinase signaling to recapitulate the effects of local IPC. Finally, combined PostC+PerC is not additive to IPC, suggesting that each works via a common pathway. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of our study was to characterize the hemodynamic and corresponding pharmacokinetic responses to a single dose of oral sildenafil by children with pulmonary arterial hypertension (PAH) undergoing invasive testing. Background: Although used frequently for the treatment of children with PAH, data regarding the acute responses to sildenafil are limited. Methods: Thirty-six patients (mean age 7.5 ± 5.9 years; 24 females) were studied during cardiac catheterization with general anesthesia. Eight of 36 (22%) had idiopathic PAH; the remainder had associated congenital heart disease. Hemodynamics and serum cyclic-guanosine monophosphate levels (cGMP) were evaluated at baseline and after inhaled nitric oxide (NO) (40 ppm). In addition, cGMP and sildenafil levels were measured 30 min after administration of sildenafil (0.5 mg/kg, suspended in 5 ml sterile water) through a nasogastric tube. Results: For the 36 patients, the pulmonary vasodilating capability of oral sildenafil was lower than that of inhaled NO (2.8% vs. 11.6% reduction in pulmonary vascular resistance indexed to body surface area [PVRI], respectively; p = 0.01). However, only 21 of 36 (58%) patients had a detectable sildenafil level. In those with detectable sildenafil levels, the fall in PVRI was greater (−11.6% vs. −19.1%, p = NS). Mean cGMP levels at baseline and after NO were 41.8 ± 20.0 pmol/ml and 83.8 ± 35.5 pmol/ml, respectively (p < 0.0001). Surprisingly, there was no significant increase in cGMP in patients with either undetectable (37.5 ± 29.8 pmol/ml) or detectable (44.4 ± 31.7 pmol/ml) sildenafil levels (p = NS compared with baseline) with sildenafil. Conclusions: Our study demonstrates suboptimal absorption of sildenafil in almost half the children undergoing acute hemodynamic testing. When detectable, there was no statistically significant difference between the fall in PVRI associated with sildenafil and NO despite lower circulating cGMP levels in the sildenafil group. These data should be taken into account when designing acute testing protocols, and assessing the acute response to sildenafil in patients with PAH. [Copyright &y& Elsevier]

Objectives: We sought to determine whether the introduction of these agents had altered the outcome of dilated cardiomyopathy (DC) in childhood. Background: Pediatric DC has a poor prognosis. Angiotensin-converting enzyme inhibitors (ACEIs) and beta-adrenergic receptor blockers (BBs) improve survival in adults with DC, but their effectiveness in children has not been confirmed. Methods: We performed a single-institution retrospective review of all diagnosed cases of DC and related phenotypic variants between 1976 and 2005, with multivariate analysis of risk factors for the end point of death or cardiac transplantation. Results: A total of 189 patients presented between January 1, 1976, and March 31, 2005. Forty-four patients died, 34 underwent cardiac transplantation, and 10 were lost to follow-up during this period. The 2- and 5-year transplantation-free survival rates for all patients were 63.6% (95% confidence interval [CI]: 56.4% to 70.8%) and 56.3% (95% CI: 48.5% to 64.1%), respectively. For patients treated with digoxin but neither an ACEI nor a BB (n = 51), the 5-year transplantation free survival rate was 67.5% (95% CI: 53.5% to 82.0%) and for those treated with the addition of an ACEI but no BB (n = 65), the rate was 57.2% (95% CI: 43.6% to 69.4%) (p = NS). Combination therapy with an ACEI and a BB (n = 57) was not associated with an improvement in 5-year transplantation-free survival (58.5%; 95% CI: 42.5% to 72.0%, p = NS). In multivariable analysis, presentation with a low left ventricular ejection fraction increased the risk of death or transplantation, but the end point was not influenced by time era or treatment strategy. Conclusions: DC in childhood has a high risk of death or the need for transplantation. Medical treatment has shifted toward combination ACEI and BB therapy in the current era. Our retrospective data, however, suggest only a transient survival advantage associated with the combined use of ACEI and BB over ACEI alone and no obvious or sustained improvement in transplantation-free survival accompanying the change from digoxin-based medical therapy. [Copyright &y& Elsevier]

The article discusses a randomised trial which tested the hypothesis on the link between myocardial salvage and remote ischaemic conditioning during evolving ST-elevation myocardial infarction before primary percutaneous coronary intervention. The study involved 333 consecutive adult patients with suspected first acute myocardial infarction, who received remote conditioning before hospital admission. The researchers concluded that myocardial salvage could be increased by remote ischaemic conditioning before hospital admission and could serve as a complement to angioplasty.

Remote ischemic conditioning is a novel concept of protection against ischemia-reperfusion injury. Brief controlled episodes of intermittent ischemia of the arm or leg may confer a powerful systemic protection against prolonged ischemia in a distant organ. This conditioning phenomenon is clinically applicable and can be performed before—preconditioning, during—perconditioning, or after—postconditioning prolonged distant organ ischemia. The remote ischemic conditioning may have an immense impact on clinical practice in the near future. (J Card Surg 2010;25:127-134) [ABSTRACT FROM AUTHOR]

Objectives: Preconditioning of cells or organs by transient sublethal ischemia-reperfusion (IR), termed ischemic preconditioning (IPC), protects the cell or organ from a subsequent prolonged ischemic insult. The mechanisms of this effect remain to be fully elucidated. We have recently reported that IPC of a forearm results in alterations in gene expression profiles of circulating polymorphonuclear leukocytes. The goal of the current study was to determine if the observed changes in gene expression lead to functional changes in neutrophils. Methods: We examined the effect of repetitive transient human forearm ischemia (three cycles of 5 min ischemia, followed by 5 min of reperfusion) on the function of circulating neutrophils. Neutrophil functions were examined before, after 1 d, and after 10 d of daily transient forearm ischemia. To modulate IR-induced inflammation the neutrophils were stimulated with N-formyl-methionyl-leucyl phenylalanine (FMLP) and lipopolysaccharide (LPS). Results: Neutrophil adhesion was significantly decreased on day 1 and remained low on day 10 (P = 0.0149) without significant change in CD11b expression. Phagocytosis was significantly suppressed on day 10 compared with day 0 (P < 0.0001). Extracellular cytokine levels were low in the absence of an exogenous stimulus but stimulation with LPS induced significant changes on day 10. We observed a trend in reduction of apoptosis on day 1 and day 10 that did not reach statistical significance (P < 0.08). Conclusion: This study indicates that repetitive IPC of the forearm results in substantial alterations in neutrophil function, including reduced adhesion, exocytosis, phagocytosis, and modified cytokine secretion. [Copyright &y& Elsevier]

Left ventricular (LV) dysfunction is a predictor of adverse outcomes in patients with repaired tetralogy of Fallot (TOF). However, the mechanisms for LV dysfunction are not well understood. The aim of the study was to determine whether the prolonged QRS duration of right branch bundle block was associated with adverse LV mechanics. Seventy-five patients (mean age 31 ± 2 years) with repaired TOF were studied. LV and right ventricular (RV) volumes and ejection fractions (EFs) were assessed using cardiac magnetic resonance imaging. Vector velocity imaging was used to assess longitudinal strain and intraventricular dyssynchrony. Prolonged QRS duration was associated with increased RV and LV dimensions (p = 0.01) and decreased function (RVEF r = −0.60, p <0.001 and LVEF r = −0.77, p <0.001). In addition, prolonged QRS duration was associated with heterogeneous ventricular mechanical activation and reduced strain in the lateral and septal left ventricle walls. Degree of intraventricular dyssynchrony correlated with LVEF (r = −0.59, p <0.001), QRS duration (r = 0.74, p <0.001), and septal strain (r = 0.70, p <0.001). In conclusion, LV dysfunction and dyssynchrony were observed in patients with TOF and were associated with QRS duration. It was possible that abnormal LV mechanics in combination with RV dysfunction may explain the relation between QRS duration and adverse cardiac outcomes. [Copyright &y& Elsevier]

At the end of every heartbeat, cardiac myocytes must relax to allow filling of the heart. Impaired relaxation is a significant factor in heart failure, but all pathways regulating the cardiac relaxation apparatus are not known. Haploinsufficiency of the T-box transcription factor Tbx5 in mouse and man causes congenital heart defects (CHDs) as part of Holt-Oram syndrome (HOS). Here, we show that haploinsufficiency of Tbx5 in mouse results in cell-autonomous defects in ventricular relaxation. Tbx5 dosage modulates expression of the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2a encoded by Atp2a2 and Tbx5 haploinsufficiency in ventricular myocytes results in impaired Ca2+ uptake dynamics and Ca2+ transient prolongation. We also demonstrate that Tbx5 can activate the Atp2a2 promoter. Furthermore, we find that patients with HOS have significant diastolic filling abnormalities. These results reveal a direct genetic pathway that regulates cardiac diastolic function, implying that patients with structural CHDs may have clinically important underlying anomalies in heart function that merit treatment. [ABSTRACT FROM AUTHOR]

The conductance catheter (CC) allows thorough evaluation of cardiac function because it simultaneously provides measurements of pressure and volume. Calibration of the volume signal remains challenging. With different calibration techniques, in vivo left ventricular volumes (VCC) were measured in mice (n = 52) with a Millar CC (SPR-839) and compared with MRI-derived volumes (VMRI). Significant correlations between VCC and VMRI [end-diastolic volume (EDV): R² = 0.85, P < 0.01; end-systolic volume (ESV): R² = 0.88, P < 0.01] were found when injection of hypertonic saline in the pulmonary artery was used to calibrate for parallel conductance and volume conversion was done by individual cylinder calibration. However, a significant underestimation was observed [EDV = -17.3 µl (-22.7 to -11.9 µl); ESV = -8.8 µl (-12.5 to -5.1 µl)]. Intravenous injection of the hypertonic saline bolus was inferior to injection into the pulmonary artery as a calibration method. Calibration with an independent measurement of stroke volume decreased the agreement with VMRI. Correction for an increase in blood conductivity during the in vivo experiments improved estimation of EDV. The dual-frequency method for estimation of parallel conductance failed to produce VCC that correlated with VMRI. We conclude that selection of the calibration procedure for the CC has significant implications for the accuracy and precision of volume estimation and pressure-volume loop-derived variables like myocardial contractility. Although VCC may be underestimated com- pared with MRI, optimized calibration techniques enable reliable volume estimation with the CC in mice. [ABSTRACT FROM AUTHOR]

Pulmonary vein pathologies often present a diagnostic challenge. Among the different imaging modalities used for the evaluation of pulmonary veins, magnetic resonance is the most comprehensive in assessing anatomy and pathophysiology at the same time. Bright blood cine sequences and contrast-enhanced magnetic resonance angiography outline the course and connections of the pulmonary veins. Phase-contrast velocity mapping measures flow patterns, velocities, and volumes throughout the pulmonary circulation. This paper reviews contemporary utilization of magnetic resonance in the evaluation of pulmonary venous abnormalities in children, based on our experience over the last 5 years and on that of other investigators. We summarize how magnetic resonance imaging enhances our understanding of pulmonary vein physiology and how it can influence the diagnostic approach to children and adults with a pulmonary venous pathology, and we discuss its limitations. [ABSTRACT FROM AUTHOR]