Left Ventricular Systolic Pressure Research Articles

Twenty-four-hour Normothermic Ex Vivo Heart Perfusion With Low Flow Functional Assessment in an Adult Porcine Model.

Cold static storage and normothermic ex vivo heart perfusion are routinely limited to 6 h. This report describes intermittent left atrial (LA) perfusion that allows cardiac functional assessment in a working heart mode. Using our adult porcine model, general anesthesia was induced and a complete cardiectomy was performed following cardioplegic arrest. Back-table instrumentation was completed and normothermic ex vivo heart perfusion (NEHP) was initiated in a nonworking heart mode (Langendorff). After 1 h of resuscitation and recovery, LA perfusion was initiated and the heart was transitioned to a coronary flow-only working heart mode for 30 min. Baseline working heart parameters were documented and the heart was returned to nonworking mode. Working heart assessments were performed for 30 min every 6 h for 24 h. Twenty-four-hour NEHP on 9 consecutive hearts (280 ± 42.1 g) was successful and no significant differences were found between working heart parameters at baseline and after 24 h of perfusion. There was no difference between initial and final measurements of LA mean pressures (5.0 ± 3.1 versus 9.0 ± 6.5 mm Hg, P = 0.22), left ventricular systolic pressures (44.3 ± 7.2 versus 39.1 ± 9.0 mm Hg, P = 0.13), mean aortic pressures (30.9 ± 5.8 versus 28.1 ± 8.1 mm Hg, P = 0.37), and coronary resistance (0.174 ± 0.046 versus 0.173 ± 0.066 mL/min/g, P = 0.90). There were also no significant differences between lactate (2.4 ± 0.5 versus 2.6 ± 0.4 mmol/L, P = 0.17) and glucose (173 ± 75 versus 156 ± 70 mg/dL, P = 0.37). A novel model using intermittent LA perfusion to create a coronary flow-only working heart mode for assessment of ex vivo cardiac function has been successfully developed.

Interval training suppresses nod-like receptor protein 3 inflammasome activation to improve cardiac function in myocardial infarction rats by hindering the activation of the transforming growth factor-β1 pathway

ObjectiveMyocardial infarction (MI) -induced cardiac dysfunction can be attenuated by aerobic exercises. This study explored the mechanism of interval training (IT) regulating cardiac function in MI rats, providing some theoretical basis for clarifying MI pathogenesis and new ideas for clinically treating MI.MethodsRats were subjected to MI modeling, IT intervention, and treatments of the Transforming growth factor-β1 (TGF-β1) pathway or the nod-like receptor protein 3 (NLRP3) activators. Cardiac function and hemodynamic indicator alterations were observed. Myocardial pathological damage and fibrosis, reactive oxygen species (ROS) level, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities, MDA content, inflammasome-associated protein levels, and inflammatory factor levels were assessed. The binding between TGF-β1 and receptor was detected.ResultsMI rats exhibited decreased left ventricle ejection fraction (LVEF), left ventricle fractional shortening (LVFS), left ventricular systolic pressure (LVSP), positive and negative derivates max/min (dP/dt max/min) and increased left ventricular end-systolic pressure (LVEDP), a large number of scar areas in myocardium, disordered cell arrangement and extensive fibrotic lesions, increased TGF-β1 and receptor binding, elevated ROS level and MDA content and weakened SOD, CAT and GSH-Px activities, and up-regulated NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC) and cleaved-caspase-1 levels, while IT intervention caused ameliorated cardiac function. IT inactivated the TGF-β1 pathway to decrease oxidative stress in myocardial tissues of MI rats and inhibit NLRP3 inflammasome activation. Activating NLRP3 partially reversed IT-mediated improvement on cardiac function in MI rats.ConclusionIT diminished oxidative stress in myocardial tissues and suppressed NLRP3 inflammasome activation via inactivating the TGF-β1 pathway, thus improving the cardiac function of MI rats.

Short-Chain Fatty Acid Butyrate Is an Inotropic Agent With Vasorelaxant and Cardioprotective Properties.

The heart can metabolize the microbiota-derived short-chain fatty acid butyrate. Butyrate may have beneficial effects in heart failure, but the underlying mechanisms are unknown. We tested the hypothesis that butyrate elevates cardiac output by mechanisms involving direct stimulation of cardiac contractility and vasorelaxation in rats. We examined the effects of butyrate on (1) invivo hemodynamics using parallel echocardiographic and invasive blood pressure measurements, (2) isolated perfused hearts in Langendorff systems under physiological conditions and after ischemia and reperfusion, and (3) isolated coronary arteries mounted in isometric wire myographs. We tested Na-butyrate added to injection solutions or physiological buffers and compared its effects with equimolar doses of NaCl. Butyrate at plasma concentrations of 0.56 mM increased cardiac output by 48.8±14.9%, stroke volume by 38.5±12.1%, and left ventricular ejection fraction by 39.6±6.2%, and lowered systemic vascular resistance by 33.5±6.4% without affecting blood pressure or heart rate invivo. In the range between 0.1 and 5 mM, butyrate increased left ventricular systolic pressure by up to 23.7±3.4% in isolated perfused hearts and by 9.4±2.9% following ischemia and reperfusion, while reducing myocardial infarct size by 81.7±16.9%. Butyrate relaxed isolated coronary septal arteries concentration dependently with an EC50=0.57 mM (95% CI, 0.23-1.44). We conclude that butyrate elevates cardiac output through mechanisms involving increased cardiac contractility and vasorelaxation. This effect of butyrate was not associated with adverse myocardial injury in damaged hearts exposed to ischemia and reperfusion.

Mechanism of Qili Qiangxin Capsule for Heart Failure Based on miR133a-Endoplasmic Reticulum Stress.

To investigate the pharmacological mechanism of Qili Qiangxin Capsule (QLQX) improvement of heart failure (HF) based on miR133a-endoplasmic reticulum stress (ERS) pathway. A left coronary artery ligation-induced HF after myocardial infarction model was used in this study. Rats were randomly assigned to the sham group, the model group, the QLQX group [0.32 g/(kg·d)], and the captopril group [2.25 mg/(kg·d)], 15 rats per group, followed by 4 weeks of medication. Cardiac function such as left ventricular ejection fraction (EF), fractional shortening (FS), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), the maximal rate of increase of left ventricular pressure (+dp/dt max), and the maximal rate of decrease of left ventricular pressure (-dp/dt max) were monitored by echocardiography and hemodynamics. Hematoxylin and eosin (HE) and Masson stainings were used to visualize pathological changes in myocardial tissue. The mRNA expression of miR133a, glucose-regulated protein78 (GRP78), inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), X-box binding protein1 (XBP1), C/EBP homologous protein (CHOP) and Caspase 12 were detected by RT-PCR. The protein expression of GRP78, p-IRE1/IRE1 ratio, cleaved-ATF6, XBP1-s (the spliced form of XBP1), CHOP and Caspase 12 were detected by Western blot. TdT-mediated dUTP nick-end labeling (TUNEL) staining was used to detect the rate of apoptosis. QLQX significantly improved cardiac function as evidenced by increased EF, FS, LVSP, +dp/dt max, -dp/dt max, and decreased LVEDP (P<0.05, P<0.01). HE staining showed that QLQX ameliorated cardiac pathologic damage to some extent. Masson staining indicated that QLQX significantly reduced collagen volume fraction in myocardial tissue (P<0.01). Results from RT-PCR and Western blot showed that QLQX significantly increased the expression of miR133a and inhibited the mRNA expressions of GRP78, IRE1, ATF6 and XBP1, as well as decreased the protein expressions of GRP78, cleaved-ATF6 and XBP1-s and decreased p-IRE1/IRE1 ratio (P<0.05, P<0.01). Further studies showed that QLQX significantly reduced the expression of CHOP and Caspase12, resulting in a significant reduction in apoptosis rate (P<0.05, P<0.01). The pharmacological mechanism of QLQX in improving HF is partly attributed to its regulatory effect on the miR133a-IRE1/XBP1 pathway.

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.

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.

Chinese Medicine Supplementing Qi and Activating Blood Circulation Relieves the Progression of Diabetic Cardiomyopathy

Diabetic cardiomyopathy (DCM) is the leading cause of diabetic death as the final occurrence of heart failure and arrhythmia. Traditional Chinese medicine is usually used to treat various diseases including diabetes. This study sought to investigate the effects of Traditional Chinese medicine supplementing Qi and activating blood circulation (SAC) in DCM. After the construction of the DCM model by streptozotocin (STZ) injection and high glucose/fat diet feeding, rats were administered intragastrically with SAC. Then, cardiac systolic/diastolic function was evaluated by detecting left ventricular systolic pressure (LVSP), maximal rate of left ventricular pressure rise (+LVdp/dtmax), and fall (-LVdp/dtmax), heart rate (HR), left ventricular ejection fraction (EF), LV fractional shortening (FS) and left ventricular end-diastolic pressure (LVEDP). Masson’s and TUNEL staining were used to assess fibrosis and cardiomyocyte apoptosis. DCM rats exhibited impaired cardiac systolic/diastolic function manifested by decreasing LVSP, + LVdp/dtmax, -LVdp/dtmax, HR, EF and FS, and increasing LVEDP. Intriguingly, traditional Chinese medicine SAC alleviated the above-mentioned symptoms, indicating a potential role in improving cardiac function. Masson’s staining substantiated that SAC antagonized the increased collagen deposition and interstitial fibrosis area and the elevations in protein expression of fibrosis-related collagen I and fibronectin in heart tissues of DCM rats. Furthermore, TUNEL staining confirmed that traditional Chinese medicine SAC also attenuated cardiomyocyte apoptosis in DCM rats. Mechanically, DCM rats showed the aberrant activation of the TGF-β/Smad signaling, which was inhibited after SAC. SAC may exert cardiac protective efficacy in DCM rats via the TGF-β/Smad signaling, indicating a new promising therapeutic approach for DCM.

Sleeve gastrectomy improves cardiac function and glucose-lipid metabolism disorder in obese rats induced by a high-fat and high-sugar diet.

Obesity is affecting global health with multiple complications, including cardiac dysfunction. Currently, it is uncertain whether drug therapy should be applied in the early stages of obesity-induced cardiac dysfunction, with weight reduction as the first choice. Sleeve gastrectomy (SG) has been widely used to treat obesity and its complications, showing promising results. However, it remains unclear whether SG can alleviate obesity-induced cardiac dysfunction. A sudden decline in body weight and food intake was observed in both the obese and obese + SG groups, with a higher rate of increase observed in the Obese group. Elevated levels of plasma glucose, serum insulin, and glycated haemoglobin in obese rats were significantly reduced by SG. Markedly increased levels of alanine transaminase, aspartate transaminase, alkaline phosphatase albumin, total cholesterol, triglycerides, and low-density lipoprotein cholesterol levels, elevated values of heart rate, left ventricular end-systolic pressure, left ventricular end-diastolic pressure, systolic pressure, and end diastolic pressure, and decreased value of stroke volume were observed in obese rats, which were sharply reversed by SG. Furthermore, enhanced pathological changes, including inflammatory cell infiltration and loss of cytoplasm striations, enhanced oil red O staining, increased TUNEL-positive cells, upregulated Bax and cleaved-caspase-3, and downregulated Bcl-2, were observed in obese rats, which were notably alleviated by SG. Lastly, the increased levels of relative proteins observed in obese rats were significantly reduced by SG. In conclusion, SG improved cardiac function and glucose-lipid metabolism disorders in obese rats induced by a high-fat and high-sugar diet.

Virtual pacing of a patient's digital twin to predict left ventricular reverse remodelling after cardiac resynchronization therapy.

Identifying heart failure (HF) patients who will benefit from cardiac resynchronization therapy (CRT) remains challenging. We evaluated whether virtual pacing in a digital twin (DT) of the patient's heart could be used to predict the degree of left ventricular (LV) reverse remodelling post-CRT. Forty-five HF patients with wide QRS complex (≥130 ms) and reduced LV ejection fraction (≤35%) receiving CRT were retrospectively enrolled. Echocardiography was performed before (baseline) and 6 months after CRT implantation to obtain LV volumes and 18-segment longitudinal strain. A previously developed algorithm was used to generate 45 DTs by personalizing the CircAdapt model to each patient's baseline measurements. From each DT, baseline septal-to-lateral myocardial work difference (MWLW-S,DT) and maximum rate of LV systolic pressure rise (dP/dtmax,DT) were derived. Biventricular pacing was then simulated using patient-specific atrioventricular delay and lead location. Virtual pacing-induced changes ΔMWLW-S,DT and ΔdP/dtmax,DT were correlated with real-world LV end-systolic volume change at 6-month follow-up (ΔLVESV). The DT's baseline MWLW-S,DT and virtual pacing-induced ΔMWLW-S,DT were both significantly associated with the real patient's reverse remodelling ΔLVESV (r = -0.60, P < 0.001 and r = 0.62, P < 0.001, respectively), while correlation between ΔdP/dtmax,DT and ΔLVESV was considerably weaker (r = -0.34, P = 0.02). Our results suggest that the reduction of septal-to-lateral work imbalance by virtual pacing in the DT can predict real-world post-CRT LV reverse remodelling. This DT approach could prove to be an additional tool in selecting HF patients for CRT and has the potential to provide valuable insights in optimization of CRT delivery.

Therapeutic effects of the combination of moderate-intensity endurance training and MitoQ supplementation in rats with isoproterenol-induced myocardial injury: The role of mitochondrial fusion, fission, and mitophagy

IntroductionMitochondrial dysfunction causes myocardial disease. This study investigated the effects of MitoQ alone and in combination with moderate-intensity endurance training (EX) on cardiac function and content and mRNA expression of several proteins involved in mitochondrial quality control in isoproterenol (ISO)-induced heart injuries MethodsSeven groups of CTL, ISO, ISO-EX, ISO-MitoQ-125, ISO-MitoQ-250, ISO-EX+MitoQ-125, and ISO-EX+MitoQ-250 were assigned. Rats were trained on a treadmill, and the MitoQ groups received MitoQ in drinking water for 8 weeks, starting one week after the induction of heart injury. Arterial pressure and cardiac function indices, mRNA expression, protein content, oxidant and antioxidant markers, fibrosis, and histopathological changes were assessed by physiograph, Real-Time PCR, immunofluorescence, calorimetry, Masson’s trichrome, and H&E staining, respectively. ResultsThe impacts of MitoQ-125, EX+MitoQ-125, and EX+MitoQ-250 on arterial pressure and left ventricular systolic pressure were higher than MitoQ-250 or EX alone. ± dp/dt max were higher in ISO-EX+MitoQ-125 and ISO-EX+MitoQ-250 than ISO-MitoQ-125 and ISO-MitoQ-250 groups, respectively. Histopathological scores and fibrosis decreased in ISO-EX, ISO-MitoQ-125, ISO-EX+MitoQ-125, and ISO-EX+MitoQ-250 groups. The restoration of MFN2, PINK-1, and FIS-1 changes was higher in ISO-EX+MitoQ-125 and ISO-EX+MitoQ-250 than ISO-EX, ISO-MitoQ-125 and ISO-MitoQ-250 groups. The expression of MFN2 and PINK-1 was lower in ISO-MitoQ-125 and ISO-EX+MitoQ-125 than ISO and CTL groups. The expression of FIS-1 in ISO-EX and ISO-EX+MitoQ-250 increased compared to CTL and ISO groups. MDA decreased in ISO-MitoQ-125 and ISO-EX+MitoQ-125 groups. ConclusionExercise and MitoQ combination have additive effects on cardiac function by modulating cardiac mitochondria quality. This study provided a possible therapy to treat heart injuries.

Feature-Tracking-Derived Strain Analysis for Identification of Subendocardium-Involved Late Gadolinium Enhancement in Load-Induced Left Ventricular Hypertrophy: A Multicenter Study of Cardiac Magnetic Resonance Data.

Subendocardium-involved late gadolinium enhancement (SILGE) is a significant predictor of poor prognosis in patients with load-induced left ventricular hypertrophy (LVH). This multicenter study aimed to investigate whether the diagnostic performance of cardiac magnetic resonance feature-tracking (CMR-FT)-derived strain analysis for detecting subtle subendocardial injury would be influenced by its load dependence in patients with load-induced LVH. A total of 149 patients with load-induced LVH were recruited from three centers and underwent enhanced CMR imaging. The patients were divided into two groups based on the presence or absence of SILGE on CMR (SILGE+ group: n = 56; SILGE- group: n = 93). Clinical and CMR parameters were evaluated in both groups. The LV systolic pressure (LVSP) and LV end-diastolic pressure (LVEDP) in the SILGE+ group were higher than those in the SILGE- group (each with p < 0.05), and LVSP and LVEDP were correlated with the LV global longitudinal strain (GLS) (each with p < 0.05) in research center 1. The LV strain parameters were significantly lower in the SILGE+ group than those in the SILGE- group (each with p < 0.05). Logistic regression analysis identified GLS (OR 1.325; 95% CI 1.180 to 1.487, p < 0.001) as a predictive factor of SILGE in the patients with load-induced LVH. The receiver operating characteristic (ROC) curve analysis results indicated that the areas under the curve (AUC) of global radial strain (GRS), global circumferential strain (GCS), and GLS were 0.68, 0.69, and 0.76, respectively. De Long's test results implied that GLS had the best diagnostic performance for SILGE (p = 0.04). Despite the load dependency of CMR-FT-derived strain analysis, the GLS exhibits reasonable accuracy in the identification of SILGE and can potentially serve as a feasible alternative for detecting subendocardial involvement in patients with load-induced LVH who are contraindicated for LGE.

Sorafenib induces cardiotoxicity through RBM20-mediated alternative splicing of sarcomeric and mitochondrial genes

Sorafenib, a multi-targeted tyrosine kinase inhibitor, is a first-line treatment for advanced solid tumors, but it induces many adverse cardiovascular events, including myocardial infarction and heart failure. These cardiac defects can be mediated by alternative splicing of genes critical for heart function. Whether alternative splicing plays a role in sorafenib-induced cardiotoxicity remains unclear. Transcriptome of rat hearts or human cardiomyocytes treated with sorafenib was analyzed and validated to define alternatively spliced genes and their impact on cardiotoxicity. In rats, sorafenib caused severe cardiotoxicity with decreased left ventricular systolic pressure, elongated sarcomere, enlarged mitochondria and decreased ATP. This was associated with alternative splicing of hundreds of genes in the hearts, many of which were targets of a cardiac specific splicing factor, RBM20. Sorafenib inhibited RBM20 expression in both rat hearts and human cardiomyocytes. The splicing of RBM20’s targets, SLC25A3 and FHOD3, was altered into fetal isoforms with decreased function. Upregulation of RBM20 during sorafenib treatment reversed the pathogenic splicing of SLC25A3 and FHOD3, and enhanced the phosphate transport into mitochondria by SLC25A3, ATP synthesis and cell survival.We envision this regulation may happen in many drug-induced cardiotoxicity, and represent a potential druggable pathway for mitigating sorafenib-induced cardiotoxicity.

Ginsenoside Rg3 improves microcystin-induced cardiotoxicity through the miR-128-3p/MDM4 axis

Microcystin (MC) is the byproduct of cyanobacteria metabolism that is associated with oxidative stress and heart damage. This study aimed to investigate the effect of ginsenoside Rg3 on MC-induced cardiotoxicity. A mouse model of myocardial infarction was constructed by oral MC administration. H9C2 cells were used for in vitro analysis. Cellular oxidative stress, apoptosis, and the relationship between miR-128-3p and double minute 4 protein (MDM4) were analyzed. MiR-128-3p expression was upregulated in vitro and in vivo after MC treatment, which was downregulated after Rg3 treatment. Left ventricular ejection fraction (LVEF) and left ventricular systolic pressure (LVSP) were increased and left ventricular end–diastolic pressure (LVEDP) was decreased after Rg3 treatment. Moreover, Rg3 alleviated MC-induced pathological changes and apoptosis in myocardial tissues. Meanwhile, Rg3 treatment decreased the lactate dehydrogenase (LDH) and malondialdehyde (MDA) levels and inhabited cell apoptosis and oxidative stress in MC-treated myocardial cells. MiR-128-3p overexpression attenuated the protective effect of Rg3 on MC-induced cardiotoxicity. MiR-128-3p negatively regulated MDM4 expression. This study revealed that Rg3 alleviated MC-induced cardiotoxicity through the miR-128-3p/MDM4 axis, which emphasized the potential of Rg3 as a therapeutic agent for MC-induced cardiotoxicity, and miR-128-3p as a target for the Rg3 therapy.

Adjusting diffusing capacity for anemia in patients undergoing allogeneic HCT: a comparison of two methodologies

BackgroundDiffusing capacity (DLCO) measurements are affected by hemoglobin. Two adjustment equations are used: Cotes (recommended by ATS/ERS) and Dinakara (used in the hematopoietic stem cell transplantation comorbidity index [HCT-CI]). It is unknown how these methods compare, and which is better from a prognostication standpoint. Study designThis is a retrospective cohort of 1273 adult patients who underwent allogeneic HCT, completed a pre-transplant DLCO and had a concurrent hemoglobin measurement. Non-relapse mortality was measured using competing risk analysis. ResultsPatients had normal spirometry (FEV1 99.7% [IQR: 89.4–109.8%; FVC 100.1% [IQR: 91.0-109.6%] predicted), left ventricular ejection fraction (57.2[6.7]%) and right ventricular systolic pressure (30.1[7.0] mmHg). Cotes-DLCO was 85.6% (IQR: 76.5-95.7%) and Dinakara-DLCO was 103.6% (IQR: 90.7-117.2%) predicted. For anemic patients (Hb<10g/dL), Cotes-DLCO was 84.2% (IQR: 73.9–94.1%) while Dinakara-DLCO 111.0% (97.3–124.7%) predicted. Cotes-DLCO increased HCT-CI score for 323 (25.4%) and decreased for 4 (0.3%) patients. Cotes-DLCO was superior for predicting non-relapse mortality: for both mild (66-80% predicted, HR 1.55 [95%CI: 1.26-1.92, p < 0.001]) and moderate (<65% predicted, HR 2.11 [95%CI: 1.55-2.87, p<0.001]) impairment. In contrast, for Dinakara-DLCO, only mild impairment (HR 1.69 [95%CI 1.26-2.27, p < 0.001]) was associated with lower survival while moderate impairment was not (HR 1.44 [95%CI: 0.64-3.21, p = 0.4]). In multivariable analyses, after adjusting for demographics, hematologic variables, cardiac function and FEV1, Cotes-DLCO was predictive of overall survival at 1-year (OR 0.98 [95%CI: 0.97-1.00], p = 0.01), but Dinakara-DLCO was not (OR 1.00 [95%CI: 0.98-1.00], p = 0.20). ConclusionThe ERS/ATS recommended Cotes method likely underestimates DLCO in patients with anemia, whereas the Dinakara (used in the HCT-CI score) overestimates DLCO. The Cotes method is superior to the Dinakara method score in predicting overall survival and relapse-free survival in patients undergoing allogeneic HCT.

Non-invasive estimation of left ventricular systolic peak-pressure: a prerequisite to calculate of myocardial work in hypertrophic obstructive cardiomyopathy

Abstract Introduction Myocardial work (MW) is an echocardiographic parameter to estimate global and regional myocardial performance. This method utilizes pressure strain loops derived from global longitudinal strain (GLS) and left ventricular systolic pressure (LVSP) estimated by brachial blood pressure (BP). Purpose Since LVSP cannot be equated with BP in pts with HOCM, we investigated whether the LVSP can be calculated non-invasively by combining Doppler echo parameters and the BP. This estimation is mandatory to make MW applicable for HOCM-pts. Methods We studied 20 consecutive pts (8 women, 12 men; mean age 57.0±13.9 years; NYHA class 2.1±0.8) with indication for first alcohol septal ablation. 6 pts had hypertension and 2 pts unexplained syncope. 18 (90%) pts were in sinus rhythm. NTproBNP was 1431 pg/ml (1912 IQR). Echo baseline measurements showed subaortic septal (IVS) thickness of 21.0±5.0 mm and maximal IVS thickness of 24.7±6.3 mm. Pts showed high-normal left ventricular ejection fraction (70.4±10.1%). Left atrial (LA) volume was 101.2±26 ml. All measurements of pressures and gradients were performed in the catheterization laboratory after placement of a 5F Judkins JR4 in the ascending aorta and a 5.2F special pigtail catheter in the apex of LV beyond the obstruction. Simultaneous measurements of BP at left upper arm, echo intraventricular gradients (instantaneous and mean) with CW Doppler (GE Vivid E70), and invasive pressures and gradients (peak-to-peak and mean) of the LV and ascending aorta were performed. Echo and invasive gradients were averaged over 3 cardiac cycles. Finally, we tried to identify an estimation of invasively measured LV systolic pressure by combining systolic BP and echo measured gradients. Results Systolic BP was 143±21 mmHg. Max. CW Doppler gradient was 65±29 mmHg and mean gradient was 31±14 mmHg. Invasive simultaneous measurements at rest showed peak-to-peak gradient of 55±24 mmHg and mean gradient of 34±13 mmHg between apical LV and ascending aorta. Mean LVSP was 190±40 mmHg. Systolic pressure of the ascending aorta was 134±28 mmHg. Adding systolic peripheral BP and maximal echo-gradient mean value was 208±38 mmHg. Adding systolic peripheral BP and echo-mean gradient mean value was 174±26 mmHg. Correlating these values with the invasively measured systolic LV pressure we found a slightly higher correlation of the sum of systolic BP and mean-echo gradient (Pearson correlation coefficient: 0.867 p&amp;lt;0.001) compared with the sum of systolic BP and maximal echo-gradient (Pearson correlation coefficient: 0.851; p&amp;lt;0.001). Bland–Altman plots demonstrated good levels of agreements between invasively measured LVSP and both non-invasively estimated LVSP. Conclusions Non-invasive estimation of LVSP is feasible by combining conventional BP and CW Doppler measured mean LV outflow tract gradient in HOCM. Hereby estimation of MW in pts with HOCM is applicable.

Reduced left ventricular elastance as a novel marker of cardiac dysfunction in patients with severe liver disease

Abstract Introduction Left ventricular (LV) elastance reflects the contractility of the myocardium and is an index of cardiac performance. Liver cirrhosis is characterized by reduced systemic vascular resistance, leading to reduced afterload on the LV. This, combined with increased blood volume, results in increased preload, increased stroke volume and remodeling of the LV. The latter may result to alterations in end-systolic LV elastance (Ees) a parameter that has not been extensively studied in cirrhotics. Purpose To investigate the relationship between Ees and the severity of liver cirrhosis. Methods We conducted a cross-sectional study in which transthoracic echocardiography was performed in 75 patients with liver cirrhosis (mean age 58.9±8.5 years, 74.7% males). A verified noninvasive single-beat formula was used to calculate Ees. Specifically, Ees was calculated employing systolic and diastolic blood pressures, echo-derived stroke volume (SV), ejection fraction (LVEF) and the estimated normalized ventricular elastance at arterial end-diastole (ENd). The ENd was estimated from a group-averaged value adjusted for individual contractile/loading effects. The Model for End-Stage Liver Disease-Sodium (MELDNa) score, a widely used tool for assessing liver disease severity was also calculated. We compared Ees between patients with MELDNa scores above and below 15, which is the cutoff commonly used to indicate severe liver disease. Results Mean Ees in the cohort of the 75 patients was 2.34±0.81mmHg/ml. Ees was correlated with end-systolic LV volume (rho=-0.448, p&amp;lt;0.001), SV (rho=-0.568, p&amp;lt;0.001) and systolic blood pressure (rho=0.283, p=0.014), but not with LVEF. Mean MELDNa score was 15.5±7.3 and 32 (42.7%) of patients had MELDNa score ≥ 15. Mean Ees in patients with MELDNa score above 15 was significantly lower than in patients with MELDNa score below 15 (2.08±0.61mmHg/ml vs 2.54±0.89mmHg/ml, p=0.015). The association remained significant in a multivariate model after adjusting for age, sex, and body surface area (B=-0.426, p=0.015). Conclusion Our study demonstrates that patients with severe liver disease have lower Ees, indicating impaired LV function. Ees could be a useful marker for identifying patients with liver cirrhosis who are at increased risk of cardiovascular complications. Further research is needed to better understand the mechanisms underlying this association and to propose therapeutic interventions aimed at improving LV function in this special population.

Pharmacological inhibition of the cysteine protease cathepsin C improves graft function after heart transplantation in rats

BackgroundHeart transplantation (HTX) is the standard treatment for end-stage heart failure. However, reperfusion following an ischemic period can contribute to myocardial injury. Neutrophil infiltration, along with the subsequent release of tissue-degrading neutrophil elastase (NE)-related serine proteases and oxygen-derived radicals, is associated with adverse graft outcomes. The inhibition of cathepsin C (CatC) has been shown to block NE-related protease activation. We hypothesized that the CatC inhibitor BI-9740 improves graft function after HTX.MethodsIn a rat model of HTX, the recipient Lewis rats were orally administered with either a placebo (n = 12) or BI-9740 (n = 11, 20 mg/kg) once daily for 12 days. Donor hearts from untreated Lewis rats were explanted, preserved in a cardioplegic solution, and subsequently heterotopically implanted. In vivo left-ventricular (LV) graft function was assessed after 1 h of reperfusion. The proteolytic activity of neutrophil serine proteases was determined in bone marrow lysates from BI-9740-treated and control rats. Additionally, myocardial morphological changes were examined, and heart samples underwent immunohistochemistry and western blot analysis.ResultsThe NE-related proteolytic activity in bone marrow cell lysates was markedly decreased in the BI-9740-treated rats compared to those of the placebo group. Histopathological lesions, elevated CatC and myeloperoxidase-positive cell infiltration, and nitrotyrosine immunoreactivity with an increased number of poly(ADP-ribose) polymerase (PARP)-1-positive cells were lowered in the hearts of animals treated with BI-9740 compared to placebo groups. Regarding the functional parameters of the implanted graft, improvements were observed in both systolic function (LV systolic pressure 110 ± 6 vs 74 ± 6 mmHg; dP/dtmax 2782 ± 149 vs 2076 ± 167 mmHg/s, LV developed pressure, at an intraventricular volume of 200 µl, p < 0.05) and diastolic function in the hearts of BI-9740 treated animals compared with those receiving the only placebo. Furthermore, the administration of BI-9740 resulted in a shorter graft re-beating time compared to the placebo group. However, this study did not provide evidence of DNA fragmentation, the generation of both superoxide anions and hydrogen peroxide, correlating with the absence of protein alterations related to apoptosis, as evidenced by western blot in grafts after HTX.ConclusionsWe provided experimental evidence that pharmacological inhibition of CatC improves graft function following HTX in rats.

Abstract 16194: Relationship Between Change in Global Longitudinal Strain and Sustained Handgrip Induced Afterload as Assessed Using Invasive Left Ventricular Pressure Measurements and Machine Learning Analytics

Introduction: Global longitudinal strain (GLS) is a sensitive, quantitative measure of left ventricular (LV) systolic function and affected by afterload. We sought to compute the impact of LV systolic pressure (LVP) increase on GLS using handgrip stress during invasive LVP measurements. Methods: Patients undergoing left heart catheterization (n=51; mean age 64+/-11 years; 31% women; Table) for standard of care indications underwent echocardiography during handgrip stress with a catheter in the LV cavity. GLS and LVP were measured simultaneously over 15 seconds of continuous handgrip. GLS and LVP relationships were analyzed using linear regression and machine learning methods. Results: Sustained handgrip (HG) stress significantly increased LVP and reduced GLS. There was no significant correlation between resting and peak HG stress LVP and GLS (p= 0.32 &amp; 0.36, respectively). However, change in GLS was significantly correlated with change in LVP (p&lt;0.0001; Figure) with every 10 unit increase in LVP associated with a 0.6 reduction in GLS. The penalized maximum likelihood machine learning method was used to select key factors associated with the within subject slope of % change in GLS over % change in LVP (median slope -0.53; IQR-0.91 to -0.29). LV ejection fraction was identified as an important predictor of the GLS-LVP slope. LV ejection fraction was significantly associated with the slope (p=0.0005; Figure) with a 10 unit increase in LV ejection fraction corresponding to 0.22 increase in the slope. Conclusions: LV afterload is associated with significant decrements in GLS. LV ejection fraction is an important predictor of the GLS-LVP slope. These data provide the foundation to build models that would account for change in LVP during serial measurements of GLS thus allowing reliable comparison of repeated GLS measurements.

Abstract 15483: Mitoquinone Pretreatment Mitigates Dox-induced Systolic Dysfunction in Isolated Rat Hearts

Background: Doxorubicin (DOX) is a common and effective chemotherapeutic agent that can exert cardiotoxicity by inducing oxidative stress in mitochondria, compromising mitochondrial function, and inducing apoptosis. Currently, there is no treatment that targets this mechanism. We previously found that pretreatment with higher concentrations of mitoquinone (MQ), a mitochondrial antioxidant, exerts cardioprotection against DOX in myoblast H9C2 cells. Hypothesis: We hypothesize that MQ pretreatment would preserve cardiac function against DOX in isolated rat hearts. Methods: Cardiac parameters (heart rate (HR) and left ventricular end systolic pressure (LVESP)) were monitored before and after 60 min infusion of DOX, MQ, or DOX with MQ pretreatment (10-15 min) in a Langendorff preparation of male SD rat hearts. TUNEL assay was conducted on heart tissue slides to evaluate apoptosis. The ratio between the final and initial cardiac parameters was calculated and compared among experimental groups. Results: Higher dose DOX (25 μM, n=5) induced a higher reduction in the ratios of LVESP, to 39±5% than lower dose DOX infusion (20 μM, n=3; 74±3%). DOX had no effects on HR. A 60-minute perfusion of higher doses of MQ (1-5 μM, n=7) unexpectedly reduced the ratios of LVESP and HR to 73±12% and 66±5%, respectively. Higher dose MQ (1-2.5 μM, n=6) pretreatment showed similar improvement of LVESP ratio (68±9%) to lower dose MQ (0.25-0.5 μM, n=6; 71±11%). TUNEL assay showed that higher dose DOX caused a higher rate of apoptosis (number of TUNEL-positive nuclei) (326.3±6.4. n=3) than lower dose (214±29.5, n=3). Pretreatment with higher dose MQ prior to DOX 25 μM infusion resulted in a notable reduction of apoptosis (60.3±5, n=6) compared to DOX alone, while lower dose pretreatment reduced apoptosis to 70.5± 0.5 (n=4). Conclusion: This study suggests that infusion of DOX into the heart acutely attenuated cardiac systolic function accompanied with higher apoptotic cell damage. Although prolonged administration of higher doses of MQ suppressed cardiac function, MQ pretreatment for 10-15 minutes mitigated DOX-induced systolic dysfunction and reduced cardiomyocyte apoptosis. In summary, MQ pretreatment may mitigate DOX-induced cardiac damage.

Abstract 13349: The Effect of Chronic Standard Cigarette Smoke Exposure Compared to Chronic Electronic Cigarette Exposure With or Without Nicotine on Blood Pressure

Background: While the acute exposure to electronic cigarette (e-C) vapor has been associated with an increase in blood pressure, the chronic effect of e-C vapor on blood pressure compared to standard cigarette smoke has not been extensively studied. We determined the effect of chronic e-C exposure versus standard cigarette smoke on blood pressure and other cardiac functional measures. Methods: Sprague Dawley rats (both sexes) were randomly exposed to air (n=34), e-C with nicotine (e-Cn; n=30), e-C without nicotine (e-C; n= 28) or standard cigarette smoke (SCS; n=27) for 12 weeks. After 12 weeks of exposure hemodynamics were determined by Millar catheter, echocardiography, and thermodilution catheter, a few days after their last exposure. Results: As shown in the Table, SCS was associated with higher systolic, diastolic and mean blood pressures and peak LV systolic pressure compared to air or e-Cn or e-C groups. Neither fractional shortening or cardiac output differed among the groups. dp/dt min, a measure of diastolic LV function, was lowest in the e-C group. Tau, a measure of LV relaxation was worse in this group as well. Conclusions: Standard cigarette smoke exposure was associated with an increase in blood pressure when blood pressure was tested at 12 weeks. Neither electronic cigarette smoke with or without nicotine caused an increase in blood pressure compared to air. However, e-C was associated with worse diastolic function. Standard cigarettes may be associated with a greater sympathetic surge causing elevated blood pressure compared to electronic cigarettes.