Search

Aim: To define the clinical characteristics, hemodynamics, and adverse events for pediatric patients with pulmonary arterial hypertension (PAH) undergoing right heart catheterization (RHC). Methods: The large referral single center data of 591 diagnostic RHC procedures performed between 2005 and 2020 on pediatric PAH patients was retrospectively collected and analyzed. Results: A total of 591 RHC procedures performed on 469 patients with congenital heart disease (CHD)-PAH (median age 8.8 years, 7.9% New York Heart Association (NYHA) class > II, 1.5% with syncope) and 122 patients with idiopathic PAH (median age of 9.0 years, 27.0% NYHA class > II, 27.0% with syncope) were included. Of those, 373 (63.1%) procedures were performed under general anesthesia. Eighteen patients (18/591, 3.0%) suffered adverse events (mainly pulmonary hypertensive crisis, PHC, n = 17) during the RHC procedure, including 14 idiopathic pulmonary arterial hypertension (IPAH) patients and 4 CHD-PAH patients, and one IPAH patient died in hospital 63 hours after RHC. The risk of developing PHC was significantly increased in patients with IPAH (OR = 14.02, 95%CI: 4.49–43.85, p < 0.001), atrial blood gas pH < 7.35 (OR = 12.504, 95%CI: 3.545–44.102, p < 0.001) and RAP > 14 mmHg (OR = 10.636, 95%CI: 3.668–30.847, p < 0.001). Conclusions: RHC is generally a low-risk procedure in pediatric patients with PAH. However, PHC occur in approximately 3% of patients. Therefore, RHC should be performed in a large, experienced referral pediatric cardiology center, especially in pediatric patients with IPAH requiring general anesthesia. [ABSTRACT FROM AUTHOR]

Caffeine consumption during pregnancy is reported to increase the risk of in utero growth restriction and spontaneous abortion. In the present study, we tested the hypothesis that modest maternal caffeine exposure affects in utero developing embryonic cardiovascular (CV) function and growth without altering maternal hemodynamics. Caffeine (10 mg.[kg.sup-1].[day.sup.-1] subcutaneous) was administered daily to pregnant CD-1 mice from embryonic days (EDs) 9.5 to 18.5 of a 21-day gestation. We assessed maternal and embryonic CV function at baseline and at peak maternal serum caffeine concentration using high-resolution echocardiography on EDs 9.5, 11.5, 13.5, and 18.5. Maternal caffeine exposure did not influence maternal body weight gain, maternal CV function, or embryo resorption. However, crown-rump length and body weight were reduced in maternal caffeine treated embryos by ED 18.5 (P < 0.05). At peak maternal serum caffeine concentration, embryonic carotid artery, dorsal aorta, and umbilical artery flows transiently decreased from baseline at ED 11.5 (P < 0.05). By ED 13.5, embryonic aortic and umbilical artery flows were insensitive to the peak maternal caffeine concentration; however, the carotid artery flow remained affected. By ED 18.5, baseline embryonic carotid artery flow increased and descending aortic flow decreased versus non-caffeine-exposed embryos. Maternal treatment with the adenosine [A.sub.2A] receptor inhibitor reproduced the embryonic hemodynamic effects of maternal caffeine exposure. Adenosine [A.sub.2A] receptor gene expression levels of ED 11.5 embryo and ED 18.5 uterus were decreased. Results suggest that modest maternal caffeine exposure has adverse effects on developing embryonic CV function and growth, possibly mediated via adenosine [A.sub.2A] receptor blockade. adenosine [A.sub.2A] receptor; cardiovascular development; carotid artery; pregnancy

As in the adult dorsal aorta, the embryonic dorsal aorta is an important determinant of cardiovascular function, and increased stiffness may have secondary effects on cardiac and microcirculatory development. We previously showed that acutely and chronically increased arterial load via vitelline artery ligation (VAL) increases systemic arterial stiffness. To test the hypothesis that local dorsal aortic stiffness also increases, we measured aortic pulse-wave velocity (PWV) and assessed the active and passive properties (stress and strain) of isolated aortic segments. PWV along the dorsal aorta increased acutely and chronically after VAL. Analysis of isolated aortic active properties suggests that load-exposed aortas experienced higher stress, but not strain, at similar intraluminal pressures. When smooth muscle tone was relaxed, strain decreased in VAL vessels, whereas stress became similar to control vessels. Immunohistochemical analysis revealed that although aortic smooth muscle a-actin content was similar between groups, more cell layers expressed smooth muscle [alpha]-actin, and myocyte cell shape was markedly rounder in VAL embryos. Additionally, aortic and perivascular collagen type I and III content significantly increased in load-exposed VAL vessels. Increased production of these proteins is consistent with the observed increase in aortic PWV and decreased strain in VAL passive aortic segments. Thus the embryonic dorsal aorta is sensitive to increased arterial load and adapts by altering its material properties via changes in collagen content. arterial mechanics; pulse-wave velocity; chick; collagen

Embryonic myocardium has a high rate of cell proliferation and regulates cellular proliferation, contractile function, and myocardial architecture in response to changes in external mechanical loads. However, the small and complex three-dimensional (3D) structure of the embryonic myocardium limits our ability to directly investigate detailed relationships between mechanical load, contractile function, and cardiomyocyte proliferation. We developed a novel 3D engineered early embryonic cardiac tissue (EEECT) from early embryonic ventricular cells to test the hypothesis that EEECT retains the proliferative and contractile properties of embryonic myocardium. We combined freshly isolated White Leghorn chicken embryonic ventricular cells at Hamburger-Hamilton (HH) stage 31 (day 7 of a 46-stage, 21-day incubation period), collagen type I, and matrix factors to construct cylindrical-shaped EEECTs. We studied tissue architecture, cell proliferation patterns, and contractile function. We then generated engineered fetal cardiac tissue (EFCT) from HH stage 40 (day 14) fetal ventricular cells for direct comparison with EEECT. Tissue architecture was similar in EEECT and EFCT. EEECT maintained high cell proliferation patterns by culture day 12, whereas EFCT decreased cell proliferation rate by culture day 9 (P < 0.05). EEECT increased active contractile force from culture day 7 to day 12. The culture day 12 EEECT contractile response to the [beta]-adrenergic stimulation was less than culture day 9 EFCT (P < 0.05). Cyclic mechanical stretch stimulation induced myocardial hyperplasia in EEECT. Results indicate that EEECT retains the proliferative and contractile properties of developing embryonic myocardium and shows potential as a robust in vitro model of developing embryonic myocardium. cardiomyocyte; morphogenesis; growth and development; hyperplasia; tissue engineering

Pediatric patients with pulmonary arterial hypertension (PAH) are considered to be at risk for pulmonary hypertensive crisis (PHC) or even death during right heart catheterization (RHC). This retrospective study was designed to identify the risks and clinical characteristics associated with PHC in pediatric PAH patients. We included 163 consecutive procedures from 147 pediatric patients diagnosed with PAH who underwent diagnostic RHC in Beijing Anzhen Hospital between January 2007 and December 2020. The average patient age was 9.0 ±4.7 years and 84 (51.5%) were females. Before RHC, over 20% of patients were in New York Heart Association (NYHA) class III–IV. Sedation or general intravenous anesthesia was used in 103 procedures (63.2%), with spontaneous breathing in 93.2%. PHC occurred in 19 patients (11.7%), 5 (3.1%) required cardiac compression, and 1 died (0.6%). Compared to patients without PHC, those who experienced PHC were more likely to be in NYHA class III–IV (p=0.012) before RHC, require sedation (p=0.011), had echocardiographic indices of higher peak tricuspid regurgitation velocity (p=0.018), and right ventricle (RV) to left ventricle (LV) ratio (p< 0.001). Multivariate logistic regression for PHC identified the need for sedation and a higher RV/LV ratio as independent predictors. In conclusion, the risk of RHC remains significant in children with PAH, particularly in those with severe RV dilation who require sedation during cardiac catheterization. Comprehensive evaluation, close monitoring, and appropriate treatment before and during the procedure are essential for reducing mortality. [ABSTRACT FROM AUTHOR]

Mechanical load influences embryonic ventricular growth, morphogenesis, and function. However, little is known about changes in regional passive ventricular properties during the development of altered mechanical loading conditions in the embryo. We tested the hypothesis that regional mechanical loads are a critical determinant of embryonic ventricular passive properties. We measured biaxial passive right and left ventricular (RV and LV, respectively) stress-strain relations in chick embryos at Hamburger-Hamilton stages 21 and 27 after conotruncal banding (CTB) to increase biventricular pressure load or left atrial ligation (LAL) to reduce LV volume load and increase RV volume load. In the RV, wall strains at end-diastolic (ED) pressure normalized whereas ED stresses increased after either CTB or LAL during development. In the left ventricle, both ED strain and stress normalized after CTB, whereas both remained reduced with significantly increased myocardial stiffness after LAL. These results suggest that the embryonic ventricle adapts to chronically altered mechanical loading conditions by changing specific RV and LV passive properties. Thus regional mechanical load has a critical role during cardiogenesis. ventricle; cardiac morphogenesis; mechanical load

Research was conducted to examine the effects of acute alteration of loading condition to chick embryonic ventricular contractility using end-systolic myocardial stiffness based on the incremental elastic modulus concept. The embryonic end-systolic pressure-volume relations and maximum systolic stiffness were investigated during acute changes in ventricular preload, afterload and myofilament activation. Results indicate that normalized end-systolic myocardial stiffness is a load-independent index of ventricular contractility in the developing embryonic chick ventricle.

Herein, we define the role of ferroptosis in the pathogenesis of diabetic cardiomyopathy (DCM) by examining the expression of key regulators of ferroptosis in mice with DCM and a new ex vivo DCM model. Advanced glycation end-products (AGEs), an important pathogenic factor of DCM, were found to induce ferroptosis in engineered cardiac tissues (ECTs), as reflected through increased levels of Ptgs2 and lipid peroxides and decreased ferritin and SLC7A11 levels. Typical morphological changes of ferroptosis in cardiomyocytes were observed using transmission electron microscopy. Inhibition of ferroptosis with ferrostatin-1 and deferoxamine prevented AGE-induced ECT remodeling and dysfunction. Ferroptosis was also evidenced in the heart of type 2 diabetic mice with DCM. Inhibition of ferroptosis by liproxstatin-1 prevented the development of diastolic dysfunction at 3 months after the onset of diabetes. Nuclear factor erythroid 2-related factor 2 (NRF2) activated by sulforaphane inhibited cardiac cell ferroptosis in both AGE-treated ECTs and hearts of DCM mice by upregulating ferritin and SLC7A11 levels. The protective effect of sulforaphane on ferroptosis was AMP-activated protein kinase (AMPK)-dependent. These findings suggest that ferroptosis plays an essential role in the pathogenesis of DCM; sulforaphane prevents ferroptosis and associated pathogenesis via AMPK-mediated NRF2 activation. This suggests a feasible therapeutic approach with sulforaphane to clinically prevent ferroptosis and DCM. This study suggests that ferroptosis plays an essential role in the pathogenesis of diabetic cardiomyopathy. Sulforaphane prevents ferroptosis and associated pathogenesis via AMPK-mediated NRF2 activation. [Display omitted] [ABSTRACT FROM AUTHOR]

The prevalence of diabetes continues to increase world-wide and is a leading cause of morbidity, mortality, and rapidly rising health care costs. Although strict glucose control combined with good pharmacological and non-pharmacologic interventions can increase diabetic patient life span, the frequency and mortality of myocardial ischemia and infarction remain drastically increased in diabetic patients. Therefore, more effective therapeutic approaches are urgently needed. Over the past 15 years, cellular repair of the injured adult heart has become the focus of a rapidly expanding broad spectrum of pre-clinical and clinical research. Recent clinical trials have achieved favorable initial endpoints with improvements in cardiac function and clinical symptoms following cellular therapy. Due to the increased risk of cardiac disease, cardiac regeneration may be one strategy to treat patients with diabetic cardiomyopathy and/or myocardial infarction. However, pre-clinical studies suggest that the diabetic myocardium may not be a favorable environment for the transplantation and survival of stem cells due to altered kinetics in cellular homing, survival, and in situ remodeling. Therefore, unique conditions in the diabetic myocardium will require novel solutions in order to increase the efficiency of cellular repair following ischemia and/or infarction. This review briefly summarizes some of the recent advances in cardiac regeneration in non-diabetic conditions and then provides an overview of some of the issues related to diabetes that must be addressed in the coming years.

Research shows that the embryonic ventricular diastolic and systolic function in three-week old chick embryos is not affected by acute ventricular outflow tract occlusion. Experiments designed to measure ventricular-vascular dynamic coupling measurements using white Leghorn chicken eggs are described. Ventricular contractile reserver calculations are shown.

Developmental alterations in wave-propagation velocity (WPV) were determined by measuring both wave-front and phase velocities in chick embryos at stages 18-24 and correlated the results to other hemodynamic parameters by acute changes in the volume of circulating blood. Phase velocity was calculated employing fourier transform up to fourth harmonics while wave-front velocity was measured by threshold technique. It was observed that developmental changes in WPV were associated with the size of the vascular system, elastic elements and pressure range of the arterial wall in vasculogenesis.

It is possible to use lumped parameter circuit models to describe the embryonic and mature vascular systems. Researchers have been able to evaluate the accuracy of 18 different analog circuit models to describe embryonic arterial impedance within the restrictions of the existing measurement system. The most satisfactory representations of embryonic arterial load were achieved with the adaptation of the traditional three-element windkessel model to include a proximal inductance term.

The embryonic vascular system responds to changes in the volume of circulating blood by maintaining constant blood pressure levels. The artificial reduction of blood circulation increases the peripheral resistance of the blood vessels and produces constant levels of hydraulic pressure. This reaction is due to the efficient utilization of energy necessary for vascular development in the embryonic vasculatory system. The embryonic vasculature is also regulated by vasoactivators in the absence of autonomic control.

Measurement of atrial and ventricular blood pressure by micropressure system reveals a positive atrioventricular (AV) pressure gradient across the ventricular filling. The atrioventricular orifice and endocardial cushions act as flow resistance sites for diastolic pressure gradient. Ventricular end-diastolic pressure increases linearly from 0.18 + or - 0.03 to 0.55 + or - 0.04 mm Hg and the peak atrial pressure increases from 0.38 + or - 0.03 to 1.21 + or - 0.17 mm Hg. AV pressure gradient from 16-21 stage in terms of increasing AV flow reveals a reduction in AV orifice resistance.

Analysis of the effect of cycle length (CL) changes on the embryonic pressure and volume association to quantitate the correlation between ventricular functions, cardiac time and CL in fertile white Leghorn chick embryo reveals that stroke volume (SV), diastolic filling, isometric relaxation and systolic ejection time undergo linear modifications with CL changes. End-systolic pressure relates inversely to SV. Ventricular-vascular structures interact to mediate the CL change-induced optimization and the inverse correlation between heart rate and SV.

Cardiovascular diseases (CVDs) and cancer, which are the leading causes of mortality globally, have been viewed as two distinct diseases. However, the fact that cancer and CVDs may coincide has been noted by cardiologists when taking care of patients with CVDs caused by cancer chemotherapy; this entity is designated cardio‐oncology. More recently, patients with CVDs have also been found to have increased risk of cancers, termed reverse cardio‐oncology. Although reverse cardio‐oncology has been highlighted as an important disease state in recent studies, how the diseased heart affects cancer and the potential mediators of the crosstalk between CVDs and cancer are largely unknown. Here, we focus on the roles of cardiac‐specific microRNA‐208a (miR‐208a) in cardiac and cancer biology and explore its essential roles in reverse cardio‐oncology. Accumulating evidence has shown that within the heart, increased miR‐208a promotes myocardial injury, arrhythmia, cardiac remodeling, and dysfunction and that secreted miR‐208a in the circulation may have novel roles in promoting tumor proliferation and invasion. This review, therefore, provides insights into the novel roles of miR‐208a in reverse cardio‐oncology and strategies to prevent secondary carcinogenesis in patients with early‐ or late‐stage heart failure. [ABSTRACT FROM AUTHOR]

Right ventricular (RV) dysfunction is the main determinant of mortality in patients with pulmonary arterial hypertension (PAH) and while inflammation is pathogenic in PAH, there is limited information on the role of RV inflammation in PAH. Sulforaphane (SFN), a potent Nrf2 activator, has significant anti-inflammatory effects and facilitates cardiac protection in preclinical diabetic models. Therefore, we hypothesized that SFN might play a comparable role in reducing RV and pulmonary inflammation and injury in a murine PAH model. We induced PAH using SU5416 and 10% hypoxia (SuHx) for 4 wk in male mice randomized to SFN at a daily dose of 0.5 mg/kg 5 days per week for 4 wk or to vehicle control. Transthoracic echocardiography was performed to characterize chamber-specific ventricular function during PAH induction. At 4 wk, we measured RV pressure and relevant measures of histology and protein and gene expression. SuHx induced progressive RV, but not LV, diastolic and systolic dysfunction, and RV and pulmonary remodeling, fibrosis, and inflammation. SFN prevented SuHx-induced RV dysfunction and remodeling, reduced RV inflammation and fibrosis, upregulated Nrf2 expression and its downstream gene NQO1, and reduced the inflammatory mediator leucine-rich repeat and pyrin domain-containing 3 (NLRP3). SFN also reduced SuHx-induced pulmonary vascular remodeling, inflammation, and fibrosis. SFN alone had no effect on the heart or lungs. Thus, SuHx-induced RV and pulmonary dysfunction, inflammation, and fibrosis can be attenuated or prevented by SFN, supporting the rationale for further studies to investigate SFN and the role of Nrf2 and NLRP3 pathways in preclinical and clinical PAH studies. [ABSTRACT FROM AUTHOR]

The increasing prevalence of diabetic cardiomyopathy (DCM) is an important threat to health worldwide. While left ventricular (LV) dysfunction in DCM is well recognized, the accurate detection, diagnosis, and treatment of changes in right ventricular (RV) structure and function have not been well characterized. The pathophysiology of RV dysfunction in DCM may share features with LV diastolic and systolic dysfunction, including pathways related to insulin resistance and oxidant injury, although the RV has a unique cellular origin and composition and unique biomechanical properties and is coupled to the lower-impedance pulmonary vascular bed. In this review, we discuss potential mechanisms responsible for RV dysfunction in DCM and review the imaging approaches useful for early detection, protection, and intervention strategies. Additional data are required from animal models and clinical trials to better identify the onset and features of altered RV and pulmonary vascular structure and function during the onset and progression of DCM and to determine the efficacy of early detection and treatment of RV dysfunction on clinical symptoms and outcomes. [ABSTRACT FROM AUTHOR]

Right and left ventricular wall deformation patterns in normal and left heart hypoplasia chick embryos. Am J Physiol Heart Circ Physiol 279: H959-H969, 2000.--The vertebrate embryonic ventricle transforms from a smooth-walled single tube to trabeculated right ventricular (RV) and left ventricular (LV) chambers during cardiovascular morphogenesis. We hypothesized that ventricular contraction patterns change from globally isotropic to chamber-specific anisotropic patterns during normal morphogenesis and that these deformation patterns are influenced by experimentally altered mechanical load produced by chronic left atrial ligation (LAL). We measured epicardial RV and LV wall strains during normal development and left heart hypoplasia produced by LAL in Hamburger-Hamilton stage 21, 24, 27, and 31 chick embryos. Normal RV contracted isotropically until stage 24 and then contracted preferentially in the circumferential direction. Normal LV contracted isotropically at stage 21, preferentially in the longitudinal direction at stages 24 and 27, and then in the circumferential direction at stage 31. LAL altered both RV and LV strain patterns, accelerated the onset of preferential RV circumferential strain patterns, and abolished preferential LV longitudinal strain (P [is less than] 0.05 vs. normal). Mature patterns of anisotropic RV and LV deformation develop coincidentally with morphogenesis, and changes in these deformation patterns reflect altered cardiovascular function and/or morphogenesis. epicardial strain; embryonic heart; morphogenesis; hypoplastic left heart syndrome

Maturation of end-systolic stress-strain relations in chick embryonic myocardium. Am J Physiol Heart Circ Physiol 279: H216-H224, 2000.--The embryonic myocardium increases functional performance geometrically during cardiac morphogenesis. We investigated developmental changes in the in vivo end-systolic stress-strain relations of embryonic chick myocardium in stage 17, 21, and 24 white Leghorn chick embryos (n = 10 for each stage). End-systolic stress-strain relations were linear in all developmental stages. End-systolic strain decreased from 0.50 [+ or -] 0.02 to 0.31 [+ or -] 0.01 (mean [+ or -] SE, P [is less than] 0.05), while average end-systolic wall stress was similar at 3.29 [+ or -] 0.34 to 4.19 [+ or -] 0.43 mmHg (P = 0.14) from stage 17 to 24. Normalized end-systolic myocardial stiffness, a load-independent index of ventricular contractility, increased from 2.98 [+ or -] 0.19 to 6.03 [+ or -] 0.39 mmHg from stage 17 to 24 (P [is less than] 0.05). Zero-stress midwall volume increased from 0.024 [+ or -] 0.002 to 0.124 [+ or -] 0.004 [micro]l from stage 17 to 24 (P [is less than] 0.05). These results suggest that the embryonic ventricle increases normalized ventricular 'contractility' while maintaining average end-systolic wall stress over a relatively narrow range during cardiovascular morphogenesis. embryonic ventricle; cardiovascular development; end-systolic wall stress; end-systolic wall strain; contractility

Engineered cardiac tissues (ECTs) serve as robust in vitro models to study human cardiac diseases including cardiac toxicity assays due to rapid structural and functional maturation and the ability to vary ECT composition. Metallothionein (MT) has been shown to be cardioprotective for environmental toxicants including heavy metals. To date, studies on the role of cardiomyocyte (CM)-specific MT expression and function have occurred in dissociated single cell assays or expensive in vivo small animal models. Therefore, we generated 3D ECTs using neonatal mouse ventricular cells from wild-type (WT) and the CM-specific overexpressing MT-transgenic (MT-TG) to determine the effect of MT overexpression on ECT maturation and function. Because Cadmium (Cd) is an environmentally prevalent heavy metal toxicant with direct negative impact on cardiac structure and function, we then determined the effect of MT overexpression to reduce Cd mediated CM toxicity within ECTs. We found: (1) structural and functional maturation was similar in WT and MT-TG ECTs; (2) Cd exposure negatively impacted ECT cell survival, maturation, and function; and (3) MT-ECTs showed reduced Cd toxicity as defined by reduced cleaved caspase 3, reduced Bax/Bcl2 ratio, reduced TdT-mediated dUTP nick-end labeling positive cells, reduced CM loss after Cd treatment, and delayed onset of cardiac dysfunction after Cd treatment. Thus, neonatal murine ECTs can serve as a robust in vitro model for heavy metal toxicity screening and as a platform to evaluate the role cardioprotective mechanisms, such as the MT-TG model, on environmentally relevant toxicants. [ABSTRACT FROM AUTHOR]

An early manifestation of coronary artery disease in advanced age is the development of microvascular dysfunction leading to deficits in diastolic function. Our lab has previously shown that epicardial treatment with adipose-derived stromal vascular fraction (SVF) preserves microvascular function following coronary ischemia in a young rodent model. Follow-up studies showed intravenous (i.v.) delivery of SVF allows the cells to migrate to the walls of small vessels and reset vasomotor tone. Therefore we tested the hypothesis that the i.v. cell injection of SVF would reverse the coronary microvascular dysfunction associated with aging in a rodent model. Fischer 344 rats were divided into 4 groups: young control (YC), old control (OC), old + rat aortic endothelial cells (O+EC) and old + GFP+ SVF cells (O+SVF). After four weeks, cardiac function and coronary flow reserve (CFR) were measured via echocardiography, and hearts were explanted either for histology or isolation of coronary arterioles for vessel reactivity studies. In a subgroup of animals, microspheres were injected during resting and dobutamine-stimulated conditions to measure coronary blood flow. GFP+ SVF cells engrafted and persisted in the myocardium and coronary vasculature four weeks following i.v. injection. Echocardiography showed age-related diastolic dysfunction without accompanying systolic dysfunction; diastolic function was improved in old rats after SVF treatment. Ultrasound and microsphere data both showed increased stimulated coronary blood flow in O+SVF rats compared to OC and O+EC, while isolated vessel reactivity was mostly unchanged. I.v.-injected SVF cells were capable of incorporating into the vasculature of the aging heart and are shown in this study to improve CFR and diastolic function in a model of advanced age. Importantly, SVF injection did not lead to arrhythmias or increased mortality in aged rats. SVF cells provide an autologous cell therapy option for treatment of microvascular and cardiac dysfunction in aged populations. [ABSTRACT FROM AUTHOR]