Ventricular Pressure Research Articles

Structured Weaning From the Impella Left Ventricular Micro-Axial Pump in Acute Myocardial Infarction With Cardiogenic Shock and Protected Percutaneous Coronary Intervention: Experience From a Non-Cardiac Surgical Centre

The Impella (Abiomed, Danvers, MA, USA) temporary percutaneous left ventricular assist device is increasingly used as mechanical circulatory support in patients with acute myocardial infarction-cardiogenic shock (AMICS) or those undergoing high-risk protected percutaneous coronary intervention (PCI). The optimal weaning regimen remains to be defined. We implemented a structured weaning protocol in a series of 10 consecutive patients receiving Impella support for protected PCI or AMICS treated with PCI in a high volume non-cardiac surgery centre. Weaning after revascularisation was titrated to native heart recovery using both haemodynamic and echocardiographic parameters. Ten patients (eight male, two female; aged 43-70 years) received Impella support for AMICS (80%) or protected PCI (20%). Cardiogenic shock was of Society for Cardiac Angiography & Interventions grade C-E of severity in 80%, and median left ventricular end-diastolic pressure was 31 mmHg. Protocol implementation allowed successful weaning in eight of 10 patients with a median support time of 29 hours (range, 4-48 hours). Explantation was associated with an increase in heart rate (81 vs 88 bpm; p=0.005), but no significant change in Cardiac Index (2.9 vs 2.9 L/min/m2), mean arterial pressure (79 vs 82 mmHg), vasopressor requirement (10% vs 10%), or serum lactate (1.0 vs 1.0). Median durations of intensive care and hospital stay were 3 and 6 days, respectively. At 30 days, the mortality rate was 20%, with median left ventricular ejection fraction of 40%. A structured and dynamic weaning protocol for patients with AMICS and protected PCI supported by the Impella device is feasible in a non-cardiac surgery centre. Larger studies are needed to assess generalisability of such a weaning protocol.

Reversal of Pulmonary Hypertension in a Human-Like Model: Therapeutic Targeting of Endothelial DHFR.

Pulmonary hypertension (PH) is a progressive disorder characterized by remodeling of the pulmonary vasculature and elevated mean pulmonary arterial pressure, resulting in right heart failure. Here, we show that direct targeting of the endothelium to uncouple eNOS (endothelial nitric oxide synthase) with DAHP (2,4-diamino 6-hydroxypyrimidine; an inhibitor of GTP cyclohydrolase 1, the rate-limiting synthetic enzyme for the critical eNOS cofactor tetrahydrobiopterin) induces human-like, time-dependent progression of PH phenotypes in mice. Critical phenotypic features include progressive elevation in mean pulmonary arterial pressure, right ventricular systolic blood pressure, and right ventricle (RV)/left ventricle plus septum (LV+S) weight ratio; extensive vascular remodeling of pulmonary arterioles with increased medial thickness/perivascular collagen deposition and increased expression of PCNA (proliferative cell nuclear antigen) and alpha-actin; markedly increased total and mitochondrial superoxide production, substantially reduced tetrahydrobiopterin and nitric oxide bioavailabilities; and formation of an array of human-like vascular lesions. Intriguingly, novel in-house generated endothelial-specific dihydrofolate reductase (DHFR) transgenic mice (tg-EC-DHFR) were completely protected from the pathophysiological and molecular features of PH upon DAHP treatment or hypoxia exposure. Furthermore, DHFR overexpression with a pCMV-DHFR plasmid transfection in mice after initiation of DAHP treatment completely reversed PH phenotypes. DHFR knockout mice spontaneously developed PH at baseline and had no additional deterioration in response to hypoxia, indicating an intrinsic role of DHFR deficiency in causing PH. RNA-sequencing experiments indicated great similarity in gene regulation profiles between the DAHP model and human patients with PH. Taken together, these results establish a novel human-like murine model of PH that has long been lacking in the field, which can be broadly used for future mechanistic and translational studies. These data also indicate that targeting endothelial DHFR deficiency represents a novel and robust therapeutic strategy for the treatment of PH.

Blockade of ZFX Alleviates Hypoxia-Induced Pulmonary Vascular Remodeling by Regulating the YAP Signaling.

High expression of the zinc finger X-chromosomal protein (ZFX) correlates with proliferation, aggressiveness, and development in many types of cancers. In the current report, we investigated the efficacy of ZFX in mouse pulmonary artery smooth muscle cells (PASMCs) proliferation during pulmonary arterial hypertension (PAH). PASMCs were cultured in hypoxic conditions. Real-time PCR and western blotting were conducted to detect the expression of ZFX. Cell proliferation, apoptosis, migration, and invasion were, respectively, measured by CCK-8, flow cytometry, wound scratchy, and transwell assays. Glycolytic ability was validated by the extracellular acidification rate and oxygen consumption rate. Transcriptome sequencing technology was used to explore the genes affected by ZFX knockdown. Luciferase and chromatin immunoprecipitation assays were utilized to verify the possible binding site of ZFX and YAP1. Mice were subjected to hypoxia for 21days to induce PAH. The right ventricular systolic pressure (RVSP) was measured and ratio of RV/LV + S was calculated. The results show that ZFX was increased in hypoxia-induced PASMCs and mice. ZFX knockdown inhibited the proliferation, migration, and invasion of PASMC. Using RNA sequencing, we identify glycolysis and YAP as a key signaling of ZFX. ZFX knockdown inhibited Glycolytic ability. ZFX strengthened the transcription activity of YAP1, thereby regulating the YAP signaling. YAP1 overexpression reversed the effect of ZFX knockdown on hypoxia-treated PASMCs. In conclusion, ZFX knockdown protected mice from hypoxia-induced PAH injury. ZFX knockdown dramatically reduced RVSP and RV/(LV + S) in hypoxia-treated mice.

Curcumin alleviates myocardial inflammation, apoptosis, and oxidative stress induced by acute pulmonary embolism by regulating microRNA-145-5P/insulin receptor substrate 1 axis.

The treatment of patients with acute pulmonary embolism (APE) is extremely challenging due to the complex clinical presentation and prognosis of APE related to the patient's hemodynamic status and insufficient arterial blood flow and right ventricular overload. Protective efficacy against cardiovascular diseases of curcumin, a common natural polyphenolic compound, which has antithrombotic properties and reduces platelet accumulation in the circulation by inhibiting thromboxane synthesis has been demonstrated. However, the direct effect of curcumin on APE has rarely been studied. Therefore, the present study aimed to investigate the therapeutic potential of curcumin in APE and associated myocardial injury to provide new insights into curcumin as a promising competitive new target for the treatment of APE. A suspension of 12 mg/kg microspheres was injected intravenously into rats. An APE rat model was built. Before modeling, intragastric 100 mg/kg curcumin was given, and/or lentiviral plasmid vector targeting microRNA-145-5p or insulin receptor substrate 1 (IRS1) was injected. Pulmonary artery pressure was measured to assess right ventricular systolic pressure (RVSP). Hematoxylin and eosin (H&E) staining was performed on liver tissues and myocardial tissues of APE rats. TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling) staining and immunohistochemical (IHC) staining were conducted to measure apoptosis and CyPA-CD147 expression in the myocardium, respectively. Inflammatory indices interleukin-1beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were measured by ELISA in cardiac tissues. RT-qPCR and Western blot were performed to determine the expression levels of related genes. In addition, by dual luciferase reporter assay and RIP assay, the relationship between microRNA-145-5p and insulin receptor substrate 1 (IRS1) was confirmed. In results: curcumin improved APE-induced myocardial injury, reduced myocardial tissue edema, and thrombus volume. It attenuated APE-induced myocardial inflammation and apoptosis, as well as reduced lung injury and pulmonary artery pressure. Curcumin promoted microRNA-145-5p expression in APE rat myocardium. MicroRNA-145-5p overexpression protected against APE-induced myocardial injury, and microRNA-145-5p silencing abolished the beneficial effects of curcumin in APE-induced myocardial injury. IRS1 was targeted by microRNA-145-5p. IRS1 silencing attenuated APE-induced myocardial injury, and enhanced therapeutic effect of curcumin on myocardial injury in APE rats. In conclusion, curcumin alleviates myocardial inflammation, apoptosis, and oxidative stress induced by APE by regulating microRNA-145-5p/IRS1 axis.

Human Stem Cell-Derived Cardiomyocytes Integrate Into the Heart of Monkeys With Right Ventricular Pressure Overload.

Cardiac ventricular pressure overload affects patients with congenital heart defects and can cause cardiac insufficiency. Grafts of stem cell-derived cardiomyocytes are proposed as a complementary treatment to surgical repair of the cardiac defect, aiming to support ventricular function. Here, we report successful engraftment of human induced pluripotent stem cell-derived cardiac lineage cells into the heart of immunosuppressed rhesus macaques with a novel surgical model of right ventricular pressure overload. The human troponin+ grafts were detected in low-dose (2 × 106 cells/kg) and high-dose (10 × 106 cells/kg) treatment groups up to 12 weeks post-injection. Transplanted cells integrated and progressively matched the organization of the surrounding host myocardium. Ventricular tachycardia occurred in five out of 16 animals receiving cells, with episodes of incessant tachycardia observed in two animals; ventricular tachycardia events resolved within 19 days. Our results demonstrate that grafted cardiomyocytes mature and integrate into the myocardium of nonhuman primates modeling right ventricular pressure overload.

Hypoxia Attenuates Pressure Overload-Induced Heart Failure.

Alveolar hypoxia is protective in the context of cardiovascular and ischemic heart disease; however, the underlying mechanisms are incompletely understood. The present study sought to test the hypothesis that hypoxia is cardioprotective in left ventricular pressure overload (LVPO)-induced heart failure. We furthermore aimed to test that overlapping mechanisms promote cardiac recovery in heart failure patients following left ventricular assist device-mediated mechanical unloading and circulatory support. We established a novel murine model of combined chronic alveolar hypoxia and LVPO following transverse aortic constriction (HxTAC). The HxTAC model is resistant to cardiac hypertrophy and the development of heart failure. The cardioprotective mechanisms identified in our HxTAC model include increased activation of HIF (hypoxia-inducible factor)-1α-mediated angiogenesis, attenuated induction of genes associated with pathological remodeling, and preserved metabolic gene expression as identified by RNA sequencing. Furthermore, LVPO decreased Tbx5 and increased Hsd11b1 mRNA expression under normoxic conditions, which was attenuated under hypoxic conditions and may induce additional hypoxia-mediated cardioprotective effects. Analysis of samples from patients with advanced heart failure that demonstrated left ventricular assist device-mediated myocardial recovery revealed a similar expression pattern for TBX5 and HSD11B1 as observed in HxTAC hearts. Hypoxia attenuates LVPO-induced heart failure. Cardioprotective pathways identified in the HxTAC model might also contribute to cardiac recovery following left ventricular assist device support. These data highlight the potential of our novel HxTAC model to identify hypoxia-mediated cardioprotective mechanisms and therapeutic targets that attenuate LVPO-induced heart failure and mediate cardiac recovery following mechanical circulatory support.

Echocardiographic estimation of left ventricular filling pressures in heart transplant recipients

BackgroundEchocardiographic estimation of left ventricular filling pressure in heart transplant (HTx) recipients is challenging. The ability of echocardiography to detect elevated left ventricular end-diastolic pressure (LVEDP) in HTx patients was assessed in this study.ResultsThis descriptive cross-sectional study included 39 HTx recipients who were candidates for endomyocardial biopsy as a part of their routine post-transplantation surveillance. Doppler transthoracic echocardiography was done before the procedure, and left heart catheterization was done during the endomyocardial biopsy. Thirty-nine patients (15 female, 24 male), with a mean age of 39.6 years (range 13–70), were enrolled. A strong relation was observed between lateral E/e′ and LVEDP (R = 0.64, P value < 0.001) and average E/e′ and LVEDP (R = 0.6, P value < 0.001). The best cutoff value for LVEDP prediction was the average E/e′ ≥ 6.8 with a sensitivity of 96.15% and specificity of 68.5% for the prediction of LVEDP more than or equal to 20 mmHg. Two predictive models comprising age, gender, and lateral E/e′ or average E/e′ were also proposed. A significant relationship was also found between LVEDP and left ventricular global longitudinal strain (R = − 0.31, P value < 0.01).ConclusionsLateral E/e′ was the best predictor of LVEDP. The cutoff of average E/e′ had the best validity for the estimation of LVEDP. Despite the strong observed association, echocardiographic parameters cannot be considered a surrogate for invasive LVEDP measurements when seeking information about left ventricle filling pressure on heart transplant recipients.

Diagnosis of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) currently causes about half of the heart failure related hospitalizations. With the aging of the population and increasing prevalence of risk factors and comorbidities, such as arterial hypertension, diabetes mellitus and obesity, HFpEF prevalence is expected to increase as well. With regards to quality of life, overall morbidity, and mortality, HFpEF patients have a similarly adverse prognosis as patients with heart failure with reduced ejection fraction. The leading symptoms of exertional dyspnea and exercise intolerance with concomitant clinical signs of heart failure should, therefore, prompt diagnostic tests to exclude or confirm HFpEF. Considering the main pathophysiological mechanisms, echocardiography is crucial to non-invasively identify signs of left ventricular (LV) hypertrophy, impaired myocardial relaxation, and elevated filling pressures. Elevated NT-proBNP may furthermore indicate increased LV wall stress and volume overload. If the results of these investigations are inconclusive, parameters of elevated filling pressures can be measured invasively by right or left heart catheterization. High pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) may confirm a HFpEF diagnosis. Ongoing studies are investigating potential distinct phenotypes within the HFpEF patient group.

Jagged 2 inhibition attenuates hypoxia-induced mitochondrial damage and pulmonary hypertension through Sirtuin 1 signaling.

Notch pathway has played a significant role in the pathophysiology of pulmonary hypertension (PH). However, the role of Jagged 2 (Jag2), one ligand of Notch, remains to be elucidated.Therefore, determining the contribution of Jag2 to PH and its impact on pulmonary artery smooth muscle cells (PASMCs) was the aim of this investigation. Adeno-associated virus-mediated Jag2 inhibition was used to explore the role of Jag2 in peripheral pulmonary vascular remodeling assessed in a rat model of chronic hypoxia (10% O2, 4 weeks) induced pulmonary hypertension. In vitro, the effect of Jag2 silencing on hypoxia (1% O2, 24h) induced rat PASMCs was determined. Group differences were assessed using a 2-sided unpaired Student's t-test for two groups and one-way ANOVA for multiple groups. Jag2 upregulation was first confirmed in rats with sustained hypoxia-induced PH using publicly available gene expression data, experimental PH rat models and hypoxia induced rat PASMCs. Jag2 deficiency decreased oxidative stress injury, peripheral pulmonary vascular remodeling (0.276±0.020 vs. 0.451±0.033 μm, P<0.001, <50μm), and right ventricular systolic pressure (36.8±3.033 vs. 51.8±4.245 mmHg, P<0.001) in the chronic hypoxia-induced rat model of PH. Moreover, Jag2 knockdown decreased proliferation (1.227±0.051 vs. 1.45±0.07, P = 0.012), increased apoptosis (16.733%±0.724% vs. 6.56%±0.668%, P<0.001), and suppressed mitochondrial injury in hypoxia-treated rat PASMCs. Jag2 inhibition restored the activity of the Nrf2/HO-1 pathway, which was abolished by Sirtuin 1 deficiency. These findings show that Jag2 is essential for modulating pulmonary vascular dysfunction and accelerating PH, and that inhibition of Jag2 expression suppresses the progression and development of PH.

The protective effects of gallic acid and SGK1 inhibitor on cardiac damage and genes involved in Ca2+ homeostasis in an isolated heart model of ischemia/reperfusion injury in rat.

Serum and glucocorticoid-induced kinase 1 (SGK1) is an enzyme that may play a vital role in myocardial ischemia/reperfusion (I/R) injury. This enzyme may affect sarcoplasmic reticulum Ca2+ ATPase (SERCA2), ryanodine receptor (RyR2) and sodium/calcium exchanger (NCX1) during myocardial ischemia/reperfusion injury. The objective of this investigation was to analyze theeffects ofthe combination of GSK650394 (SGK1 inhibitor) and gallic acid on the calcium ions regulation, inflammation, and cardiac dysfunction resulting from ischemia/reperfusion (I/R) injury in the heart. Sixty male Wistar rats were randomly divided into six groups, pretreated with gallic acid or vehicle for 10 days. Then the heart was isolated and exposed to I/R. In the SGK1 inhibitor groups, GSK650394 was infused 5 min before ischemia induction. After that, Ca2+ homeostasis, inflammatory factors, cardiac function, antioxidant activity, and myocardial damage were evaluated. The findings suggested that the use of two drugs in combination therapy produced more significant improvements in left ventricular end diastolic pressure, left ventricular systolic pressure, RR-interval, ST-elevation, inflammation factors, and antioxidant enzymes activity as compared to the use of each drug. Despite this, there was a significant decrease observed in heart marker enzymes (including lactate dehydrogenase (LDH), troponin-I (cTn-I), creatine kinase-MB (CK-MB) and creatine phosphokinase (CPK) when compared to the ischemic group. Additionally, the expression of RyR2, NCX1, and SERCA2 genes showed a noteworthy increase as compared to the ischemic group. The findings of this study propose that using both of these agents on myocardial I/R injury could have superior advantages compared to using only one of them.

Induced pluripotent stem cell-derived exosomes attenuate vascular remodelling in pulmonary arterial hypertension by targeting HIF-1α and Runx2.

Pulmonary arterial hypertension (PAH) is characterized by extensive pulmonary arterial remodelling. Although mesenchymal stem cell (MSC)-derived exosomes provide protective effects in PAH, MSCs exhibit limited senescence during in vitro expansion compared with the induced pluripotent stem cells (iPSCs). Moreover, the exact mechanism is not known. In this study, we used murine iPSCs generated from mouse embryonic fibroblasts with triple factor (Oct4, Klf4, and Sox2) transduction to determine the efficacy and action mechanism of iPSC-derived exosomes (iPSC-Exo) in attenuating PAH in rats with monocrotaline (MCT)-induced pulmonary hypertension. Both early and late iPSC-Exo treatment effectively prevented the wall thickening and muscularization of pulmonary arterioles, improved the right ventricular systolic pressure, and alleviated the right ventricular hypertrophy in MCT-induced PAH rats. Pulmonary artery smooth muscle cells (PASMC) derived from MCT-treated rats (MCT-PASMC) developed more proliferative and pro-migratory phenotypes, which were attenuated by the iPSC-Exo treatment. Moreover, the proliferation and migration of MCT-PASMC were reduced by iPSC-Exo with suppression of PCNA, cyclin D1, MMP-1, and MMP-10, which are mediated via the HIF-1α and P21-activated kinase 1/AKT/Runx2 pathways. IPSC-Exo are effective at reversing pulmonary hypertension by reducing pulmonary vascular remodelling and may provide an iPSC-free therapy for the treatment of PAH.

An altered plasma lipidome-phenome network characterizes heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a multifactorial, multisystemic syndrome that involves alterations in lipid metabolism. This study aimed to test whether distinct plasma lipid profiles or lipid entities or both are associated with clinical and functional echocardiographic parameters in HFpEF. We examined the human plasma lipidome in HFpEF patients (n=18) with left ventricular ejection fraction ≥50% and N-terminal pro-brain natriuretic peptide (NT-proBNP) >125pg/mL and control subjects (n=12) using mass spectrometry-based shotgun lipidomics. The cohort included 8 women and 22 men with average age of 67.8±8.6 SD. The control and disease groups were not significantly different with respect to age, body mass index, systolic and diastolic blood pressure, and waist-to-hip ratio. The disease group experienced more fatigue (P<0.001), had more often coronary artery disease (P=0.04), and received more medications (beta-blockers, P<0.001). The disease group had significantly different levels of HFpEF-relevant parameters, including NT-proBNP (P<0.001), left ventricular mass index (P=0.005), left atrial volume index (P=0.001), and left ventricular filling index (P<0.001), and lower left ventricular end-diastolic diameter (P=0.014), with no difference in left ventricular ejection fraction. Significant differences in lipid profiles between HFpEF patients and controls could not be detected, including no significant differences in abundance of circulating lipids binned by carbon chain length or by double bonds, nor at the level of individual lipid species. However, there was a striking correlation between selected lipids with smoking status that was independent of disease status, as well as between specific lipids and hyperlipidaemia [with corresponding significance of either false discovery rate (FDR) <0.1 or FDR<0.01]. In an exploratory network analysis of correlations, we observed significantly stronger correlations within the HFpEF group between individual lipids from the cholesterol ester and phosphatidylcholine (PC) classes and clinical/echocardiographic parameters such as left atrial volume index, left ventricular end-diastolic diameters, and heart rate (FDR<0.1). In contrast, the control group showed significantly stronger negative correlations (FDR<0.1) between individual species from the PC and sphingomyelin classes and left ventricular mass index or systolic blood pressure. We did not find significant direct associations between plasma lipidomic parameters and HFpEF and therefore could not conclude that any specific lipids are biomarkers of HFpEF. The validation in larger cohort is needed to confidently conclude the absence of first-order associations.

Mitral Annulus Calcium Score in Patients With Calcific Mitral Stenosis Undergoing Invasive Hemodynamic Assessment.

Aortic valve calcium score is associated with hemodynamic severity of aortic stenosis. Whether this association is present in calcific mitral stenosis remains unknown. This study was a retrospective analysis of consecutive patients with mitral stenosis secondary to mitral annular calcification (MAC) undergoing transseptal catheterization. All patients underwent invasive mitral valve assessment via direct left atrial and left ventricular pressure measurement. Computed tomography within 1 year of cardiac catheterization and with adequate visualization of the mitral annulus was included. MAC calcium score quantification by Agatston method was obtained offline using dedicated software (Aquarius, TeraRecon, V.4). Median patient age was 66.9±11.2 years, 47% of patients were women, 50% had coronary artery disease, 40% had atrial fibrillation, 47% had prior cardiac surgery, and 33% had prior chest radiation. Median diastolic mitral valve gradient was 9.4±3.4 mm Hg on echocardiography and 8.5±4 mm Hg invasively. Invasive median mitral valve area using the Gorlin formula was 1.87±0.9 cm2. Median MAC calcium score for the cohort was 7280±7937 Hounsfield units. MAC calcium score correlated with the presence of atrial fibrillation (P=0.02) but was not associated with other comorbidities. There was no correlation between MAC calcium score and mitral valve area (r=0.07; P=0.6) or mitral valve gradient (r=-0.03; P=0.8). MAC calcium score did not correlate with invasively measured mitral valve gradient and mitral valve area in patients with MAC-related mitral stenosis, suggesting that calcium score should not be used as a surrogate for invasive hemodynamic parameters.

Salidroside protects pulmonary artery endothelial cells against hypoxia-induced apoptosis via the AhR/NF-κB and Nrf2/HO-1 pathways

BackgroundThe apoptosis of pulmonary artery endothelial cells (PAECs) is an important factor contributing to the development of pulmonary hypertension (PH), a serious cardio-pulmonary vascular disorder. Salidroside (SAL) is a bioactive compound derived from an herb Rhodiola, but the potential protective effects of SAL on PAECs and the underlying mechanisms remain elusive. PurposeThe objective of this study was to determine the role of SAL in the hypoxia-induced apoptosis of PAECs and to dissect the underlying mechanisms. Study designMale Sprague-Dawley (SD) rats were subjected to hypoxia (10% O2) for 4 weeks to establish a model of PH. Rats were intraperitoneally injected daily with SAL (2, 8, and 32 mg/kg/d) or vehicle. To define the molecular mechanisms of SAL in PAECs, an in vitro model of hypoxic cell injury was also generated by exposed PAECs to 1% O2 for 48 h. MethodsVarious techniques including hematoxylin and eosin (HE) staining, immunofluorescence, flow cytometry, CCK-8, Western blot, qPCR, molecular docking, and surface plasmon resonance (SPR) were used to determine the role of SAL in rats and in PAECs in vitro. ResultsHypoxia stimulation increases AhR nuclear translocation and activates the NF-κB signaling pathway, as evidenced by upregulated expression of CYP1A1, CYP1B1, IL-1β, and IL-6, resulting in oxidative stress and inflammatory response and ultimately apoptosis of PAECs. SAL inhibited the activation of AhR and NF-κB, while promoted the nuclear translocation of Nrf2 and increased the expression of its downstream antioxidant proteins HO-1 and NQO1 in PAECs, ameliorating the hypoxia-induced oxidative stress in PAECs. Furthermore, SAL lowered right ventricular systolic pressure, and decreased pulmonary vascular remodeling and right ventricular hypertrophy in hypoxia-exposed rats. ConclusionsSAL may attenuate the apoptosis of PAECs by suppressing NF-κB and activating Nrf2/HO-1 pathways, thereby delaying the progressive pathology of PH.

Biological Activity of a Coumarin Derivative on Heart Failure Using an Ischemia/Reperfusion Injury Model.

Heart failure is a health problem worldwide. There are some drugs for it, including digoxin, spironolactone, captopril, and valsartan, but some of these drugs can produce secondary effects, such as arrhythmia, cough, hyperkalemia, hyponatremia and hypotension. The aim of this research was to evaluate the biological activity of coumarin (2H-chromen-2-one) and its derivatives (3BrAcet-C, 3-4Br-Ph-C, 4-CN-7D-C, 4-Me-7-Ph-C and 6Br-3-D-C) against ischemia/reperfusion injury as a therapeutic alternative for heart failure. In addition, the biological activity of the coumarin derivative 4-Me-7-Ph-C on left ventricular pressure (LVP) was determined in the absence or presence of ouabain and nifedipine at a dose of 1 nM using an isolated rat heart model. The results showed that i) the coumarin derivative 4-Me-7-Ph-C significantly decreased the infarct area (p+=+0.05) compared with 3BrAcet-C, 3-4Br-Ph-C, 4-CN-7D-C, and 6Br-3-D-C; and ii) 4-Me-7-Ph-C increased LVP in a dose-dependent manner, which effect was inhibited by nifedipine. These data suggest that coumarin 4-Me-7-Ph-C may act as a type-L calcium channel activator, so it could be a good agent to treat heart failure.

Left atrial deformation analysis in patients with non-ischaemic dilated cardiomyopathy in atrial fibrillation.

Atrial fibrillation (AF) is a common comorbidity in non-ischaemic dilated cardiomyopathy (NIDCM) affecting conventional measures of left atrial (LA) function. We aimed to determine whether LA function analysis could identify patients at higher risk of major cardiovascular events (MACEs). A retrospective study of patients with NIDCM in AF referred to a single centre for transthoracic echocardiography (TTE) between 2015 and 2019. Peak atrial longitudinal strain (PALS) was measured along with LA emptying fraction and LA filling index (LAFI = E wave/PALS). Cox regression analysis was conducted. A total of 153 patients were included [median age 74 years, left ventricular ejection fraction (LVEF) 35%], and 57 (37.3%) had MACE after a median follow-up of 3.2 years. LAFI was the only independent TTE parameter associated with MACE after adjustment for age, diabetes, LVEF, left ventricular global longitudinal strain (LV-GLS), and LA volume index [adjusted hazard ratio (HR) = 1.02 per point increase, P = 0.024], with the best cut-off at ≥15. LAFI ≥15 predicted each of MACE components when separately analysed: MACE HR = 1.95, 95% confidence interval (CI) 1.16-3.30; cardiovascular death HR = 3.68, 95% CI 1.41-9.56, heart failure admission HR = 2.13, 95% CI 1.19-3.80, and ventricular arrhythmia HR = 4.72, 95% CI 1.52-14.67. Higher LAFI was associated with worsening LV-GLS, E/e', systolic pulmonary artery (PA) pressure, tricuspid annular plane systolic excursion, and right ventricular to PA coupling. LA deformation analysis is feasible in patients with NIDCM presenting with AF. LAFI may identify patients at higher risk of MACE and correlates with higher pulmonary pressures and worse right ventricular function, suggesting an elevation of left-sided ventricular pressures in patients with higher LAFI.

Cardiac effects of 5F-Cumyl-PEGACLONE

Synthetic cannabinoids become increasingly popular as a supposedly safe and legal alternative to cannabis. In order to circumvent the German New Psychoactive Substances Law, producers of so-called herbal mixtures rapidly design new substances with structural alterations that are not covered by the law. Acting as full agonists not only at the cannabinoid receptors 1 and 2, synthetic cannabinoids might have not only desired mental but also serious physical adverse effects. However, knowledge of adverse effects of specific substances is sparse and incomplete. This also accounts for 5F-Cumyl-PEGACLONE, a synthetic cannabinoid, which has been detected regularly in Germany in recent years. By using an animal model, the isolated perfused Langendorff heart, the study at hand aimed on finding out more about possible cardiovascular adverse effects of 5F-Cumyl-PEGACLONE. Hearts of male Wistar rats, which were excised postmortem, were exposed to two different concentrations of 5F-Cumyl-PEGACLONE: 13 hearts were exposed to 50 ng/ml and 12 hearts were exposed to 100 ng/ml. Thirteen control hearts were merely exposed to an additional amount of buffer solution. Functional parameters heart rate, minimal and maximum left ventricular pressure and coronary flow were documented at pre-defined time points during and after the administration of 5F-Cumyl-PEGACLONE/additional buffer solution. Electrocardiograms (ECGs) were documented throughout the experiments and evaluated afterwards. Kruskal–Wallis analysis was performed for each functional parameter as well as for the duration of the QRS complexes and the duration of RR intervals as derived from the ECGs. Furthermore, a multivariate analysis, comprising all functional and ECG parameters, was performed. Kruskal–Wallis analysis revealed only single significant p-values for QRS duration and minimum left ventricular pressure that did not pass a Bonferroni test. The results of the multivariate approach were also comparably homogeneous, but still the model correctly recognized hearts exposed to 100 ng/ml of 5F-Cumyl-PEGACLONE more often than hearts exposed to the low concentration of 5F-Cumyl-PEGACLONE or additional buffer solution. Evaluation of the ECGs presented single cases of ST depression and QT prolongation. Though certainly not unambiguous, these findings support the assumption that 5F-Cumyl-PEGACLONE can cause severe, if not lethal, cardiac adverse effects like arrhythmias or myocardial infarctions especially if it is consumed in combination with other drugs like alcohol or if the consumer suffers from pre-existing heart diseases.

Sex-Based Differences in LPS-induced Rapid Myocardial Dysfunction

Background: Previous studies have indicated better myocardial responses with preserved cardiac function in female animals compared to males after LPS challenge; however, the mechanisms remain incompletely understood. Our published studies have revealed that TNFa substantially increased in heart tissue and serum following LPS. Females experienced less cardiac dysfunction than males during equivalent dose of TNFa infusion. Therefore, sex-related disparities in myocardial impairment could be due to an indirect/secondary outcome from LPS-induced inflammatory cytokines, like TNFa. To dissect the potential mechanism underlying myocardial reactions between males and females, we aim to determine any sex differences in LPS-caused direct effects on cardiac function using coronary infusion of LPS.&#x0D; &#x0D; Methods: Isolated hearts from aged-matched adult male and female mice were subjected to LPS infusion via Langendorff after &gt;20-min equilibration (Eq), with left ventricular developed pressure (LVDP) continuously recorded. Dose responsive experiments with LPS at 2.5, 5.0, and 7.5 mg/kg of body weight were performed in male hearts. Significant depression of LVDP (&gt;20% drop) after LPS infusion was considered rapid response to LPS. Female estrous cycle was determined via vaginal smear.&#x0D; &#x0D; Results: Male hearts infused with 5.0 and 7.5 mg/kg of LPS demonstrated significant depression of LV function. Males also experienced worse outcomes of LV function than females following 5.0 mg/kg of LPS infusion. A trend of earlier response to LPS occurred in male hearts compared to females. However, there were no significant differences in cardiac function between female groups in different estrous phases.&#x0D; &#x0D; Conclusion and Potential Impact: Our data demonstrates that male hearts exhibit higher sensitivity to LPS-induced rapid cardiac dysfunction compared to females, but estrogen may have little influence on LPS-induced rapid functional depression. The insight from our data can be used to better understand the differences between male and female outcomes to cardiac pathologies and insult.

Left Ventricular Pressure Strain Loops for Evaluation of Myocardial Work in Type 2 Diabetic Patients with Hypertension.

Type 2 diabetes mellitus (T2DM) and hypertension (HT) are the two most common underlying diseases worldwide, and they often coexist. The long-term existence of both may lead to left ventricular dysfunction. Therefore, evaluating the cardiac function of T2DM patients with HT is vital to guide treatment and improve prognosis. Left ventricular pressure strain loops (LVPSL) combine left ventricular strain and afterload, which can quantify left ventricular energy expenditure and detect left ventricular subclinical systolic dysfunction. Many studies have focused on myocardial work (MW) in uncomplicated T2DM patients or simple HT patients, but a few have focused on T2DM patients with HT. The study aimed to evaluate the MW changes in T2DM patients with HT using LVPSL and to find independent related factors of MW parameters. 40 T2DM patients, 35 HT patients, 40 T2DM patients with HT (T2DM+HT group), and 35 controls were enrolled. The differences between clinical data, conventional ultrasound parameters, and MW parameters were analyzed among the four groups. The global longitudinal strain (GLS) of the T2DM group, HT group, and T2DM+HT group was lower than the control group (P<0.05). The global work index (GWI) and global constructive work (GCW) in the T2DM group were lower than other groups (P<0.05). The GWI of the HT group was higher than other groups (P<0.05), while GCW was only higher than the T2DM group and T2DM+HT group (P<0.05). The GWI and GCW of the T2DM+HT group were higher than the T2DM group and were lower than the HT group(P<0.05), while there was no significant difference with the control group. HT group and T2DM+HT group had higher global work waste (GWW) (P<0.05). The global work efficiency (GWE) of the T2DM+HT group was lower than other groups (P<0.05). Systolic blood pressure (SBP) and glycosylated hemoglobin (HbA1c) were independent factors of each MW parameter. LVPSL can recognize left ventricular subclinical systolic dysfunction early in patients with T2DM and HT. Compared to simple T2DM or HT, the combination of T2DM and HT had greater damage to left ventricular systolic function. SBP and HbA1c are two factors that have a considerable impact on MW parameters. The impact of afterload on MW parameters should be paid more attention to.

Clinical Effect of the Modified Morrow Septal Myectomy Procedure for Biventricular Hypertrophic Cardiomyopathy.

Right ventricular involvement in hypertrophic cardiomyopathy is uncommon. This study aimed to evaluate clinical outcomes of the modified septal myectomy in patients diagnosed with biventricular hypertrophic cardiomyopathy (BHCM), a subject seldom explored in the literature. We conducted a retrospective cohort study from January 2019 to January 2023, enrolling 12 patients with BHCM. Each patient underwent a modified septal myectomy and was followed postoperatively. Clinical data and echocardiographic parameters, including the ventricular outflow tract peak pressure gradient and maximum interventricular septum thickness, were collected and analyzed. The study cohort had a median age of 43.0 (interquartile range 14.5-63.0) years at surgery, with four patients (33.3%) being children. Two patients (16.7%) previously underwent percutaneous transluminal septal myocardial ablation. Surgical relief of biventricular outflow tract obstruction (BVOTO) was achieved in five patients (41.7%), aside from those managed solely for left ventricular outflow tract obstruction. In five instances, three-dimensional (3D) printing technology assisted in surgical planning. The postoperative interventricular septum thickness was significantly reduced (21.0 mm preoperative vs. 14.5 mm postoperative, p 0.001), effectively eliminating residual ventricular outflow tract obstruction. There were no severe complications, such as septal perforation or third-degree atrioventricular block. During a mean follow up of 21.2 15.3 months, no sudden deaths, residual outflow tract obstruction, permanent pacemaker implantation, recurrent systolic anterior motion, or reoperations were reported. Our findings affirm that the modified septal myectomy remains the gold standard treatment for BHCM, improving patient symptoms and quality of life. BVOTO relief can be safely and effectively achieved through septal myectomy via transaortic and pulmonary valve approaches in selected patients. For intricate cases, the application of 3D printing technology as a preoperative planning tool is advised to optimize surgical precision and safety.