Left Ventricular Cardiac Function Research Articles

Pharmacokinetics and pharmacodynamics of JR-051, a biosimilar of agalsidase beta, in healthy adults and patients with Fabry disease: Phase I and II/III clinical studies

Fabry disease is a rare X-linked lysosomal disease, in which mutations in the gene encoding α-galactosidase A result in progressive cellular accumulation of globotriaosylceramide (GL-3) in various organs including the skin, kidney, and heart, often leading to life-threatening conditions. Enzyme replacement therapy is currently the standard therapy for the disease, to which two α-galactosidase A formulations have been approved: agalsidase α (Replagal®, Shire) and agalsidase β (Fabrazyme®, Sanofi). We have recently developed a biosimilar of agalsidase β, JR-051, and investigated its pharmacokinetics and pharmacodynamics to assess its bioequivalence to agalsidase β. In a randomized phase I study, healthy adult male volunteers were treated with JR-051 or agalsidase β and the pharmacokinetics of the drugs were compared. The ratio of geometric means (90% confidence interval [CI]) of the AUC0–24 and Cmax for JR-051 over agalsidase β were 0.91 (0.8294, 1.0082) and 0.90 (0.7992, 1.0125), respectively. In a 52-week, single-arm, phase II/III study, patients with Fabry disease switched therapy from agalsidase β to JR-051 to evaluate its pharmacodynamics. The mean (95% CI) plasma GL-3 concentrations at weeks 26 and 52 relative to pre-JR-051 administration were 1.03 (0.91, 1.15) and 0.96 (0.86, 1.06), respectively, which were within the pre-determined bioequivalence acceptance range (0.70, 1.43). The mean (95% CI) plasma globotriaosylsphingosine (lyso-GL-3) concentrations at weeks 26 and 52 relative to pre-JR-051 administration were 1.07 (0.92, 1.23) and 1.13 (1.03, 1.22), respectively. Estimated glomerular filtration rate and left ventricular mass index, as renal and cardiac function indicators, showed no notable changes from baseline throughout the study period, and no new safety concerns were identified. In conclusion, these studies demonstrated bioequivalence of JR-051 to agalsidase β in terms of its pharmacokinetics and pharmacodynamics. JR-051 offers a potential new treatment option for patients with Fabry disease.

Qi Dan Li Xin pill improves chronic heart failure by regulating mTOR/p70S6k-mediated autophagy and inhibiting apoptosis

Myocardial remodeling represents a key factor in chronic heart failure (CHF) development, and is characterized by chronic death of cardiomyocytes. Cardiac function changes may be attributed to inflammation, apoptosis and autophagy. This study assessed the effects of Qi Dan Li Xin Pill (QD) on heart function, inflammatory factors, autophagy and apoptosis in cardiac remodeling in CHF rats upon myocardial infarction (MI) induction. Male SD rats underwent a sham procedure or left anterior descending coronary artery (LADCA) ligation, causing MI. Twenty-eight days after modeling, the animals were treated daily with QD, valsartan and saline for 4 weeks. Echocardiography after 4 weeks of drug intervention revealed substantially improved left ventricular remodeling and cardiac function following QD treatment. As demonstrated by decreased IL-1β, IL-6 and TNF-α amounts, this treatment also inhibited the apoptotic process and protected the viability of the myocardium. These outcomes may be attributed to enhanced autophagy in cardiomyocytes, which further reduced pro-inflammatory and pro apoptotic effects. This process may be achieved by QD regulation of the mTOR/P70S6K signaling pathway, suggesting that the traditional Chinese medicine Qi Dan Li Xin pill is effective in heart protective treatment, and is worth further investigation.

Myristic Acid Conjugation Itself is Not Responsible for Robust Cardioprotective Effects Observed with Protein Kinase C Beta II Peptide Inhibitor in Ischemia‐Reperfusion Injury

Ischemia‐reperfusion (I/R) injury mediated by excessive reactive oxygen species (ROS) is a well‐known phenomenon causing paradoxical myocardial damage after cardio‐angioplasty, coronary bypass, or organ transplantation following ischemic injury. Protein kinase C beta II isoform (PKCβII) inhibition using a cell‐permeable myristic acid (myr‐) conjugated PKCβII peptide inhibitor (N‐myr‐SLNPEWNET; myr‐PKCβII−) given at reperfusion significantly attenuated ROS release in previous animal I/R studies. However, prior studies did not explore the possibility that myristic acid conjugation itself contributes to the attenuation of I/R injury. We hypothesize that myristic acid conjugation is not responsible for attenuation of ROS‐induced I/R damage and that myr‐PKCβII− will reduce infarct size and improve post‐reperfused cardiac function compared to scrambled myr‐PKCβII− peptide (N‐myr‐WNPESLNTE; myr‐PKCβII‐scram), myr‐PKCβII activator peptide (N‐myr‐SVEIWD; myr‐PKCβII+), and plasma controls. Hearts isolated from male Sprague‐Dawley rats (~300g) were subjected to 30 min of global ischemia and myr‐PKCβII− (20μM), myr‐PKCβII+ (20μM), myr‐PKCβII‐scram (20μM), or plasma (control) was given at initial reperfusion during the first five minutes. Thereafter, Krebs’ buffer was reperfused into hearts at a constant pressure (80 mmHg) throughout the remainder of reperfusion (50 min). Left ventricular (LV) cardiac function indices were measured using a pressure transducer, and infarct size of frozen post‐reperfused hearts was determined using 1% triphenyltetrazolium chloride staining comparing infarcted tissue vs. total tissue weight. Data were evaluated using ANOVA with Bonferroni‐Dunn post‐hoc analysis. Myr‐PKCβII‐significantly improved both post‐reperfused cardiac relaxation function indices compared to all groups (p<0.05). LV end diastolic pressure (LVEDP; mmHg) and the maximal rate of decline of LVEDP (mmHg/s) at 50 min post‐reperfusion significantly improved with myr‐PKCβII− (41±5 and 1088±84; n=16) compared to plasma‐control (61±4 and 731±95; n=14), myr‐PKCβII+ (58±4 and 716±84; n=13), or myr‐PKCβII‐scram (68±1 and 451±78; n=8) hearts. Additionally, myr‐PKCβII− significantly reduced infarct size (%) to 13±2 compared to either plasma‐control (24±4) or myr‐PKCβII‐scram (24±2; both p<0.05), whereas myr‐PKCβII+ (21±3) did not differ significantly from myr‐PKCβII‐scram or plasma‐control. Results suggest that myr‐conjugation is not responsible for the cardioprotective effects observed with myr‐PKCβII− in I/R injury. Myr‐PKCβII− may be an effective therapeutic to improve clinical outcomes after coronary bypass, cardio‐angioplasty, or organ transplantation.Support or Funding InformationThis research was supported by the Division of Research, Department of Biomedical Sciences, and the Center for Chronic Disorders of Aging at Philadelphia College of Osteopathic Medicine. Current research license is supported by Young Therapeutics, LLC. lindonyo@pcom.edu.

Atorvastatin alleviates left ventricular remodeling in isoproterenol-induced chronic heart failure in rats by regulating the RhoA/Rho kinase signaling pathway.

Chronic heart failure (CHF) is characterized by left ventricular dysfunction and altered autonomic control of cardiac function. This study aimed to investigate the effects of atorvastatin on left ventricular remodeling (LVR) and cardiac function in rats with isoproterenol-induced CHF and the possible mechanism. An isoproterenol-induced CHF model was established in rata, which were subsequently treated with atorvastatin. Echocardiography, hemodynamic, and left ventricular mass indexes were assessed. The mRNA expression of RhoA, Rho kinase, and endothelial nitric oxide synthase (eNOS) was determined by RT-qPCR. The protein expression of myosin-binding subunit (MBS), MBS-P, eNOS, phosphorylated-eNOS, RhoA, and Rho kinase was measured by Western blot analysis. The relative activity of NADPH oxidase, ROS, and NO was assessed by ELISA. Isoproterenol-induced CHF rats treated with atorvastatin exhibited decreased left ventricular end-systolic dimension, left ventricular end-diastolic dimension, left ventricular end-diastolic pressure, left ventricular mass index, maximum fall rate of change in left ventricular pressure, heart rate (p < 0.001), expression of RhoA, Rho kinase, MBS and MBS-P (p < 0.01), and relative activity of NADPH oxidase, ROS and NO (p < 0.05) and increased left ventricular short axis fractional shortening, left ventricular end-systolic pressure, maximum rise rate of change in left ventricular pressure (p < 0.001) and expression of eNOS, and phosphorylated-eNOS ser1177 (all p < 0.05) compared with those of rats with isoproterenol-induced CHF. We demonstrated that atorvastatin inhibits LVR and improves cardiac function in rats with isoproterenol-induced CHF through inhibition of the RhoA/Rho kinase signaling pathway.

Transfusion of Anaerobically or Conventionally Stored Blood After Hemorrhagic Shock.

ABSTRACTBackground:Resuscitation from hemorrhagic shock (HS) by blood transfusion restores oxygen (O2) delivery and provides hemodynamic stability. Current regulations allow red blood cells (RBCs) to be stored and used for up to 42 days. During storage, RBCs undergo many structural and functional changes. These storage lesions have been associated with adverse events and increased mortality after transfusion, increasing the need for improved RBC storage protocols. This study evaluates the efficacy of anaerobically stored RBCs to resuscitate rats from severe HS compared with conventionally stored RBCs.Methods and results:Rat RBCs were stored under anaerobic, anaerobic/hypercapnic, or conventional conditions for a period of 3 weeks. Hemorrhage was induced by controlled bleeding, shock was maintained for 30 min, and RBCs were transfused to restore and maintain blood pressure near the prhemorrhage level. All storage conditions met current regulatory 24-h posttransfusion recovery requirements. Transfusion of anaerobically stored RBCs required significantly less RBC volume to restore and maintain hemodynamics. Anaerobic or anaerobic/hypercapnic RBCs restored hemodynamics better than conventionally stored RBCs. Resuscitation with conventionally stored RBCs impaired indices of left ventricular cardiac function, increased hypoxic tissue staining and inflammatory markers, and affected organ function compared with anaerobically stored RBCs.Conclusions:Resuscitation from HS via transfusion of anaerobically stored RBCs recovered cardiac function, restored hemodynamic stability, and improved outcomes.

Metformin use in obese mothers is associated with improved cardiovascular profile in the offspring

Maternal obesity increases the risk for pregnancy complications and adverse neonatal outcome and has been associated with long-lasting adverse effects in the offspring, including increased body fat mass, insulin resistance, and increased risk for premature cardiovascular disease. Lifestyle interventions in pregnancy have produced no or modest effects in the reduction of adverse pregnancy outcomes in obese mothers. The Metformin in Obese Pregnant Women trial was associated with reduced adverse pregnancy outcomes and had no effect on birthweight. However, the long-term implications of metformin on the health of offspring remain unknown. The purpose of this study was to assess whether prenatal exposure to metformin can improve the cardiovascular profile and body composition in the offspring of obese mothers. In 151 children from the Metformin in Obese Pregnant Women trial, body composition, peripheral blood pressure, and arterial pulse wave velocity were measured. Central hemodynamics (central blood pressure and augmentation index) were estimated with the use of an oscillometric device. Left ventricular cardiac function and structure were assessed by echocardiography. Children were 3.9±1.0 years old, and 77 of them had been exposed to metformin prenatally. There was no significant difference in peripheral blood pressure, arterial stiffness, and body composition apart from gluteal and tricep circumferences, which were lower in the metformin group (P<.05). The metformin group, compared with the placebo group,had lower central hemodynamics (mean adjusted decrease, -0.707mmHg for aortic systolic blood pressure, -1.65 mm Hg for aortic pulse pressure, and -2.68% for augmentation index; P<.05 for all) and lower left ventricular diastolic function (adjusted difference in left atrial area, -0.525 cm2, in isovolumic relaxation time, -0.324 msec, and in pulmonary venous systolic wave, 2.97 cm/s; P<.05 for all). There were no significant differences in metabolic profile between the groups. Children of obese mothers who were exposed prenatally to metformin, compared with those who were exposed to placebo, had lower central hemodynamic and cardiac diastolic indices. These results suggest that the administration of metformin in obese pregnant women potentially may have a beneficial cardiovascular effect for their offspring.

Development of a new pharmacological chaperone therapeutic strategy for Fabry disease

Fabry disease is a rare X-linked lysosomal disease, in which mutations in the gene encoding α-galactosidase A result in progressive cellular accumulation of globotriaosylceramide (GL-3) in various organs including the skin, kidney, and heart, often leading to life-threatening conditions. Enzyme replacement therapy is currently the standard therapy for the disease, to which two α-galactosidase A formulations have been approved: agalsidase α (Replagal®, Shire) and agalsidase β (Fabrazyme®, Sanofi). We have recently developed a biosimilar of agalsidase β, JR-051, and investigated its pharmacokinetics and pharmacodynamics to assess its bioequivalence to agalsidase β. In a randomized phase I study, healthy adult male volunteers were treated with JR-051 or agalsidase β and the pharmacokinetics of the drugs were compared. The ratio of geometric means (90% confidence interval [CI]) of the AUC0–24 and Cmax for JR-051 over agalsidase β were 0.91 (0.8294, 1.0082) and 0.90 (0.7992, 1.0125), respectively. In a 52-week, single-arm, phase II/III study, patients with Fabry disease switched therapy from agalsidase β to JR-051 to evaluate its pharmacodynamics. The mean (95% CI) plasma GL-3 concentrations at weeks 26 and 52 relative to pre-JR-051 administration were 1.03 (0.91, 1.15) and 0.96 (0.86, 1.06), respectively, which were within the pre-determined bioequivalence acceptance range (0.70, 1.43). The mean (95% CI) plasma globotriaosylsphingosine (lyso-GL-3) concentrations at weeks 26 and 52 relative to pre-JR-051 administration were 1.07 (0.92, 1.23) and 1.13 (1.03, 1.22), respectively. Estimated glomerular filtration rate and left ventricular mass index, as renal and cardiac function indicators, showed no notable changes from baseline throughout the study period, and no new safety concerns were identified. In conclusion, these studies demonstrated bioequivalence of JR-051 to agalsidase β in terms of its pharmacokinetics and pharmacodynamics. JR-051 offers a potential new treatment option for patients with Fabry disease.

P948 Assessment of maternal cardiac remodeling and systolic function by 3D echocardiography in gestational hypertension and preeclampsia

Abstract Background It was recently showed that there is a difference between 3D and 2D evaluation of the left ventricular (LV) myocardial mass and cardiac function in gestational hypertension (GH) probably due to more pronounced heart shape changes in hypertensive pregnant women. It is also known that preeclampsia (PE) is associated with a deterioration in maternal cardiac function. Purpose: We were interested whether there was a difference in 3D morphological and functional parameters of the LV in relation to the blood pressure (BP) profile in GH, but also between GH and PE. Methods: 22 women and 55 with GH (28 with dipping pattern of BP, and 27 non-dippers) underwent 3D echocardiography and ambulatory blood pressure monitoring in the third trimester. LV mass index, LV volumes, SV index and parameters of systolic function of the LV: CO index, EF, longitudinal strain (LS), circumferential strain (CS), radial strain (RS) and area strain (AS) were estimated using 3D software. These three groups (PE, dippers and non-dippers) were each other"s control. Results: Groups did not differ in age and LV massi. SVi was significantly lower in non-dippers (p = 0,045) and PE (p = 0,031) compared with dippers, without significant difference between non-dippers and PE (p = 0,59). Similar results were obtained when we analyzed the EF in these three groups. COi was the lowest in PE (2,76 ± 0,3), compared with dippers (3,43 ± 0,5; p&amp;lt; 0,0005), with significant difference between non-dippers (2,97 ± 0,4; p&amp;lt; 0,0005) and dippers, and with a small difference between PE and non-dippers (p = 0,045). Evaluation of the systolic function by 3D strain, also showed that the systolic function was significantly lower in PE, but also in non-dippers compared to dippers (Table 1). Multivariate regression analysis revealed that nocturnal BP (p = 0,001; OR 1,106; 95% CI 1,029 - 1,142) and presence of proteinuria (p&amp;lt; 0,0005; OR 7,2; 95% CI 1,896 – 36,5) strongly predict preterm delivery. Conclusions: Deterioration of 3D systolic function is more pronaunced in PE, but also in non-dipping pattern of BP in GH compared with dippers, without significant difference in 3D LV massi between groups. Values od 3D strain in groups Dippers Non-dippers PE p1 p2 p3 LS -18,62 -16,99 -16,91 p&amp;lt; 0,0005 p&amp;lt; 0,0005 ns CS -18,22 -16,22 -16,21 p&amp;lt; 0,0005 p&amp;lt; 0,0005 ns RS 52,85 48,3 48,1 p&amp;lt; 0,0005 p&amp;lt; 0,0005 ns AS -31,77 -27,67 -27,98 p&amp;lt; 0,0005 p&amp;lt; 0,0005 ns p1 - difference between dippers and non-dippers; p2 - difference between dippers and PE; p3 - difference between non-dippers and PE

P196 Effect of tofogliflozin on systolic and diastolic cardiac function in type 2 diabetic patients

Abstract Funding Acknowledgements None Background Recent studies have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors have a favorable effect on cardiovascular events in diabetic patients. However, the underlying mechanism associated with favorable outcome has not been clearly identified. Purpose The purpose of this study was to investigate the effect of tofogliflozin, SGLT2 inhibitor, on systolic and diastolic cardiac function in patients with type 2 diabetes mellitus (T2DM). Methods We enrolled 26 consecutive T2DM out-patients on glucose-lowering drugs who initiated tofogliflozin and underwent echocardiogram before and ≥ 6 months after tofogliflozin administration. During this period, we also enrolled 162 T2DM out-patients taking other glucose-lowering drugs as a control group. Propensity score analysis was performed to match the patient characteristics. As a result, 40 patients (tofogliflozin group: 20 patients and control group: 20 patients) were finally used for analysis. Left ventricular systolic function was assessed by measuring 2D-echocardiographic left ventricular ejection fraction (LVEF) and diastolic cardiac function by pulsed wave Doppler derived early diastolic velocity (E/e’). Results There were no significant differences in patient characteristics and echocardiographic parameters at baseline. Follow-up E/e’ was significantly improved in tofogliflozin compared to control (11.7 ± 3.5 vs. 14.4 ± 4.5, p = 0.037). Moreover, the change in LVEF from baseline to follow up was 5.8± 7.2% in tofogliflozin group and 1.2 ± 6.9% in control group; difference significant: p = 0.047. Conclusions In addition to conventional oral glucose-lowering drugs, additional tofogliflozin administration had a favorable effect on left ventricular systolic and diastolic function in patients with T2DM.

Canstatin suppresses isoproterenol-induced cardiac hypertrophy through inhibition of calcineurin/nuclear factor of activated T-cells pathway in rats

Pathological cardiac hypertrophy associated with cardiac dysfunction is an independent risk factor for arrhythmia, myocardial infarction and sudden death. Canstatin, a C-terminal fragment of type IV collagen α2 chain, is abundantly expressed in normal heart tissue. We previously demonstrated that canstatin inhibits isoproterenol (ISO)-induced dephosphorylation of nuclear factor of activated T-cells (NFAT)c4, which plays an important role in cardiac hypertrophy, in differentiated H9c2 cardiomyoblasts. Thus, we investigated whether in vivo canstatin administration prevents ISO-induced cardiac hypertrophy through the inhibition of NFATc4 pathway. Rats were subcutaneously injected with ISO (5 mg/kg) or saline (Cont) for 7 days. Simultaneously, recombinant mouse canstatin (20 μg/kg) or vehicle was intraperitoneally administered. After left ventricular wall thickness and cardiac function were measured by echocardiography, the hearts were isolated and left ventricular weight (LVW) was weighed. Azan staining was performed to measure cross-sectional diameter of cardiomyocytes. Activity of calcineurin, which dephosphorylates NFATc4, was measured by calcineurin phosphatase activity assay. Immunohistochemical staining was performed to evaluate nuclear translocation of NFATc4. Intracellular Ca2+ concentration in neonatal rat cardiomyocytes (NRCMs) was measured by using a calcium indicator. Canstatin significantly inhibited ISO-induced increase of LVW, left ventricular posterior wall thickness at end-diastole and diameter of cardiomyocytes. Canstatin significantly inhibited ISO-induced activation of calcineurin, nuclear translocation of NFATc4, increased mRNA expression of β-myosin heavy chain and α-skeletal actin, and intracellular Ca2+ rise in NRCMs. In summary, we for the first time demonstrated that canstatin administration suppresses ISO-induced cardiac hypertrophy possibly through the blockade of calcineurin/NFATc4 pathway in rats.

Increased Hemoglobin Oxygen Affinity With 5-Hydroxymethylfurfural Supports Cardiac Function During Severe Hypoxia.

Acclimatization to hypoxia or high altitude involves physiological adaptation processes, to influence oxygen (O2) transport and utilization. Several natural products, including aromatic aldehydes and isothiocyanates stabilize the R-state of hemoglobin (Hb), increasing Hb-O2 affinity and Hb-O2 saturation. These products are a counter intuitive therapeutic strategy to increase O2 delivery during hypoxia. 5-Hydroxymethylfurfural (5-HMF) is well known Amadori compound formed during the Maillard reaction (the non-enzymatic browning and caramelization of carbohydrate-containing foods after thermal treatment), with well documented effects in Hb-O2 affinity. This study explores the therapeutic potential of 5-HMF on left ventricular (LV) cardiac function (LVCF) during hypoxia. Anesthetized Golden Syrian hamsters received 5-HMF i.v., at 100 mg/kg and were subjected to stepwise increased hypoxia (15, 10, and 5%) every 30 min. LVCF was assessed using a closed chest method with a miniaturized conductance catheter via continuous LV pressure-volume (PV) measurements. Heart hypoxic areas were studied using pimonidazole staining. 5-HMF improved cardiac indices, including stroke volume (SV), cardiac output (CO), ejection fraction (EF), and stroke work (SW) compared to the vehicle group. At 5% O2, SV, CO, EF, and SW were increased by 53, 42, 33, and 51% with 5-HMF relative to vehicle. Heart chronotropic activity was not statistically changed, suggesting that differences in LV-CF during hypoxia by 5-HMF were driven by volume dependent effects. Analysis of coronary blood flow and cardiac muscle metabolism suggest no direct pharmacological effects from 5-HMF, therefore these results can be attributed to 5-HMF-dependent increase in Hb-O2 affinity. These studies establish that naturally occurring aromatic aldehydes, such as 5-HMF, produce modification of hemoglobin oxygen affinity with promising therapeutic potential to increase O2 delivery during hypoxic hypoxia.

Microstructurally Motivated Constitutive Modeling of Heart Failure Mechanics

Heart failure (HF) is one of the leading causes of death worldwide. HF is associated with substantial microstructural remodeling, which is linked to changes in left ventricular geometry and impaired cardiac function. The role of myocardial remodeling in altering the mechanics of failing hearts remains unclear. Structurally based constitutive modeling provides an approach to improve understanding of the relationship between biomechanical function and tissue organization in cardiac muscle during HF. In this study, we used cardiac magnetic resonance imaging and extended-volume confocal microscopy to quantify the remodeling of left ventricular geometry and myocardial microstructure of healthy and spontaneously hypertensive rat hearts at the ages of 12 and 24 months. Passive cardiac mechanical function was characterized using left ventricular pressure-volume compliance measurements. We have developed a, to our knowledge, new structurally based biomechanical constitutive equation built on parameters quantified directly from collagen distributions observed in confocal images of the myocardium. Three-dimensional left ventricular finite element models were constructed from subject-specific in vivo magnetic resonance imaging data. The structurally based constitutive equation was integrated into geometrically subject-specific finite element models of the hearts and used to investigate the underlying mechanisms of ventricular dysfunction during HF. Using a single pair of material parameters for all hearts, we were able to produce compliance curves that reproduced all of the experimental compliance measurements. The value of this study is not limited to reproducing the mechanical behavior of healthy and diseased hearts, but it also provides important insights into the structure-function relationship of diseased myocardium that will help pave the way toward more effective treatments for HF.

Growth Hormone Secretagogues and the Regulation of Calcium Signaling in Muscle

Growth hormone secretagogues (GHS) are a family of synthetic molecules, first discovered in the late 1970s for their ability to stimulate growth hormone (GH) release. Many effects of GHS are mediated by binding to GHS-R1a, the receptor for the endogenous hormone ghrelin, a 28-amino acid peptide isolated from the stomach. Besides endocrine functions, both ghrelin and GHS are endowed with some relevant extraendocrine properties, including stimulation of food intake, anticonvulsant and anti-inflammatory effects, and protection of muscle tissue in different pathological conditions. In particular, ghrelin and GHS inhibit cardiomyocyte and endothelial cell apoptosis and improve cardiac left ventricular function during ischemia–reperfusion injury. Moreover, in a model of cisplatin-induced cachexia, GHS protect skeletal muscle from mitochondrial damage and improve lean mass recovery. Most of these effects are mediated by GHS ability to preserve intracellular Ca2+ homeostasis. In this review, we address the muscle-specific protective effects of GHS mediated by Ca2+ regulation, but also highlight recent findings of their therapeutic potential in pathological conditions characterized by skeletal or cardiac muscle impairment.

Effect of acupuncture on left ventricular configuration and cardiac function in patients with hypertension

To observe the related factors of left ventricular configuration in patients with mild to moderate hypertension, and to evaluate the influence of acupuncture on left ventricular configuration and cardiac function. Huoxue Sanfeng acupuncture regime formulated by academician SHI Xue-min was applied to 200 patients with mild to moderate hypertension. The treatment was given once a day, 5 times a week for 3 months. Blood pressure and blood lipid levels were measured before treatment. Before treatment and 3 months after treatment, the echocardiography was used to measured end-diastolic left ventricular diameter (LVIDd), end-diastolic left ventricular posterior wall thickness (LVPWTd), and end-diastolic interventricular septum thickness (IVSTd), ejection fraction (EF), left ventricular mass index (LVMI), etc.; the relevant influencing factors of different left ventricular configurations were analyzed. The patients with mild to moderate hypertension had left ventricular dysplasia (left ventricular remodeling, concentric hypertrophy, eccentric hypertrophy) reached 60%, and compared with the normal configuration group and the left ventricular remodeling group, there were significant differences in nighttime mean pulse pressure, total cholesterol, BMI and waist circumference in the eccentric hypertrophy group (P<0.05). LVMI was associated with nighttime pulse pressure, waist circumference, total cholesterol and BMI (P<0.05). Left ventricular relative wall thickness was associated with total cholesterol, BMI and waist circumference (P<0.05). The diastolic function from normal configuration to left ventricular remodeling, concentric hypertrophy and eccentric hypertrophy gradually decreased, but there were no significant difference (P>0.05). The systolic function in the concentric hypertrophy group and the eccentric hypertrophy group was significantly lower than that in the normal configuration group and the left ventricular remodeling group (P<0.05). There was no significant difference in left ventricular systolic function and diastolic function before and after acupuncture (P>0.05). Sixty percents of patients with mild to moderate hypertension have abnormal left ventricular configuration and are associated with total cholesterol, BMI, waist circumference and nighttime mean pulse pressure. Studies have not found that acupuncture can significantly improve the left ventricular configuration and left cardiac function.

Assessment of Left Ventricular Dyssynchrony and Cardiac Function in Patients with Different Pacing Modes Using Real-Time Three-Dimensional Echocardiography: Comparison with Tissue Doppler Imaging

Background: Previous studies revealed that right ventricle apex pacing with different modes may yield abnormal electrical activity and left ventricle dyssynchrony.Aim of the work: To evaluate systolic function of left ventricle and mechanical dyssynchrony with different modes of pacing using real time three dimensional echocardiography [the RT3DE] and tissue Doppler imaging [TDI].Patients and Methods: The study included thirty-five individuals with permanent dual chamber pacemaker with atrial leads placed in right atrial appendage and right ventricular leads placed in right ventricular apex, the pacemakers were programmed to different modes. Imaging parameters were obtained following pacing for 24 hours in each mode.Results: The results revealed that the RT3DE and TDI-derived dyssynchrony indices in the atrial demand pacing [AAI] mode were significantly lower than those in the dual chamber demand pacing [DDD] and ventricular demand pacing [VVI] modes; however, there was no significant difference between the DDD and VVI modes. Also, left ventricular ejection fraction [LVEF] during AAI and DDD modes was significantly higher than that during VVI mode; however, there was no significant difference between the DDD and AAI modes. There were negative correlations between LVEF and Ts-MD and Ts-SD, and there was positive strong correlation between RT3DE and TDI-derived dyssynchrony indices.Conclusions: Left ventricular systolic synchronicity in AAI mode was superior to that in DDD and VVI modes. Left ventricular ejection fraction in the AAI and DDD pacing modes are superior to that in the VVI mode.

Effect of Tofogliflozin on Systolic and Diastolic Cardiac Function in Type 2 Diabetic Patients.

Recent studies have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors have a favorable effect on cardiovascular events in diabetic patients. However, the underlying mechanism associated with a favorable outcome has not been clearly identified. The purpose of this study was to investigate the effect of tofogliflozin, SGLT2 inhibitor, on systolic and diastolic cardiac function in patients with type 2 diabetes mellitus (T2DM). We enrolled 26 consecutive T2DM out-patients on glucose-lowering drugs who initiated tofogliflozin and underwent echocardiography before and ≥ 6months after tofogliflozin administration. During this period, we also enrolled 162 T2DM out-patients taking other glucose-lowering drugs as a control group. Propensity score analysis was performed to match the patient characteristics. As a result, 42 patients (tofogliflozin group 21 patients and control group 21 patients) were finally used for analysis. Left ventricular systolic function was assessed by measuring 2D-echocardiographic left ventricular ejection fraction (LVEF) and diastolic cardiac function by pulsed wave Doppler-derived early diastolic velocity (E/e'). There were no significant differences in patient characteristics and echocardiographic parameters at baseline. The change in LVEF from baseline to follow-up was 5.0 ± 6.9% in the tofogliflozin group and - 0.6 ± 5.5% in the control group; difference significant, p = 0.006. The change in E/e' was - 1.7 ± 3.4 in the tofogliflozin group and 0.7 ± 4.1 in the control group; difference significant, p = 0.024. In addition to conventional oral glucose-lowering drugs, additional tofogliflozin administration had a favorable effect on left ventricular systolic and diastolic function in patients with T2DM.

C1q-TNF-related protein-3 attenuates pressure overload-induced cardiac hypertrophy by suppressing the p38/CREB pathway and p38-induced ER stress

C1q-tumor necrosis factor-related protein-3 (CTRP3) is an adipokine, which exerts protective function in ischemic or diabetic heart injury. However, the role of CTRP3 in cardiac hypertrophy remains unclear. The aim of this study was to investigate the pharmacological effects of CTRP3 on pathological cardiac hypertrophy induced by hypertension. Male C57BL/6 J wild-type (WT) mice, Ctrp3 knockout mice, and mice infected with lentivirus overexpressing mouse Ctrp3 underwent sham surgery or transverse aortic constriction (TAC) surgery. After 4 weeks, cardiac hypertrophy, fibrosis, and cardiac function were examined. Compared with WT mice, Ctrp3 deficiency substantially impaired contractile dysfunction, exacerbated the enlargement of cardiomyocytes and myocardial fibrosis, and reprogramed the expression of pathological genes after TAC. Conversely, CTRP3 overexpression played a role in restoring the left ventricular cardiac contractile function, alleviating cardiac hypertrophy and fibrosis, and inhibiting the expression of hypertrophic and fibrotic signaling in mice after TAC. Furthermore, CTRP3 regulated the expression of the p38/CREB pathway and of the primary modulating factors of the endoplasmic reticulum stress, i.e., GRP78 and the downstream molecules eukaryotic translation inhibition factor 2 submit α, C/EBP homologous protein, and inositol-requiring enzyme-1. Further, inhibition of p38 MAPK by SB203580 blunted the ER stress intensified by Ctrp3 deficiency. In vitro, CTRP3 protected neonatal rat cardiac myocytes against phenylephrine-induced cardiomyocyte hypertrophy. We conclude that CTRP3 protects the host against pathological cardiac remodeling and left ventricular dysfunction induced by pressure overload largely by inhibiting the p38/CREB pathway and alleviating p38-induced ER stress.

Reductions in gut microbiota‑derived metabolite trimethylamine N‑oxide in the circulation may ameliorate myocardial infarction‑induced heart failure in rats, possibly by inhibiting interleukin‑8 secretion.

Myocardial infarction (MI) is a common cause of chronic heart failure(HF). Increasing evidence has revealed that trimethylamine N‑oxide(TMAO), a gut‑microbiota‑derived metabolite, contributes to the pathogenesis of cardiovascular disease by promoting inflammation. Elevated levels of circulating TMAO have been reported in patients following MI and were associated with unfavorable outcomes. The present study examined whether reductions in circulating TMAO could attenuate the progression of HF in rats following MI. Sprague‑Dawley rats underwent coronary ligation to induce MI or a sham operation. Echocardiography confirmed MI and cardiac dysfunction one day following coronary ligation. MI and sham rats were then treated with either vehicle (tap water) or 1.0%3,3‑dimethyl‑1‑butanol (DMB, a trimethylamine formation inhibitor) in tap water, for 8weeks. At the end of the experiment, TMAO plasma levels were markedly elevated in vehicle‑treated MI rats compared with vehicle‑treated sham rats; however, TMAO plasma levels were reduced in DMB‑treated MI rats compared with vehicle‑treated MI rats. Both MI groups exhibited cardiac hypertrophy, lung congestion, left ventricular remodeling and impaired cardiac function, according to the results of anatomical analysis, echocardiography and left ventricular hemodynamics; however, these manifestations of MI‑induced HF were significantly improved in DMB‑treated MI rats compared with vehicle‑treated MI rats. The plasma levels of the chemokine interleukin (IL)‑8, and cardiac expression of IL‑8 and its receptors were significantly increased in vehicle‑treated MI rats compared with vehicle‑treated sham rats; however, these were normalized in DMB‑treated MI rats. In addition, elevated TMAO plasma level was positively correlated with increased IL‑8 plasma level in MI groups. Notably, DMB treatment of sham rats also reduced plasma TMAO, but did not alter other parameters. These results indicated that reducing circulating TMAO may ameliorate the development of chronic HF following MI in rats, potentially by inhibiting IL‑8 secretion. The results from the present study suggested that inhibition of TMAO synthesis may be considered as a novel therapeutic approach for the prevention and treatment of patients with chronic MI‑induced HF.

Prospective cardiac function monitoring in immunotherapy-treated patients.

e14157 Background: Immune checkpoint inhibitors (ICI) demonstrate activity and long-term benefit in melanoma and other cancers. While certain immune-related toxicities have been well described, cardiac toxicities remain poorly characterized. We sought to characterize changes in cardiac function in advanced melanoma patients (pts) starting ICI treatment. Methods: A prospective, observational, single institution trial was performed to monitor cardiac function in pts receiving ICI. Eligible pts were adults with stage III/IV melanoma and ECOG 0-1, determined safe to exercise and without unstable cardiac symptoms. Pts received PD-1 monotherapy or combination ipilimumab/pembrolizumab. Rest and exercise stress cardiac testing (EKG, echocardiography) was conducted at baseline, at 3 months (mo), and at 6 mo. Patient-reported surveys were administered at baseline and at 6 mo. Results: Between Feb 2018 to Jan 2019, we prospectively identified 8 pts who completed baseline cardiac testing. As of Feb 2019, 6 pts completed 3-mo testing, and 4 completed 6-mo testing. Mean age was 57 years (range 34-68). 5 pts received pembrolizumab or nivolumab monotherapy, and 3 received ipilimumab/pembrolizumab. Resting LVOT-VTI decreased from 23.1±2.8 cm at baseline to 20.7±2.8cm at 6 mo (p = 0.047). Maximum HR at peak exercise decreased over time from 149.7±13 bpm at baseline to 114±20.5 bpm at 6 mo (p = 0.085) with concurrent decrease in maximum BP. Enrollment is ongoing. Conclusions: These data suggest measurable changes in left ventricular cardiac function at rest over time, in a prospective cohort of ICI-treated advanced melanoma pts. Further, we observe progressive loss of chronotropic and blood pressure response to exercise. These data have important implications for cancer survivorship in the era of immunotherapy. Updated data to be presented at the meeting include correlation with patient-reported symptoms. [Table: see text]

The Effects of Nicotine on Cardiac Function and Structure

Nicotine is the addictive chemical in tobacco‐related products, such as cigarettes, water pipes, e‐cigs, and chewing tobacco. While the effects of smoke from cigarettes and cigars are well known, the rise in popularity of smokeless electronic cigarettes (e‐cigs) brings new questions about the effects of nicotine itself on the development of cardiovascular disease. These “smoke‐less” products have grown in popularity due to reduced costs, increased social acceptance, and a belief that e‐cigs are a less dangerous alternative to smoking.Nicotine use is associated with hypertension and may activate the renin‐angiotensin system when inhaled. The renin‐angiotensin system regulates blood pressure, and a major component of the system, angiotensin‐II (Ang‐II), can cause cardiac hypertrophy and fibrosis. However, most animal studies administer nicotine via infusion, and very little is known about the effects of chronically inhaled nicotine.Thus the goal of our study is to investigate the effects of chronic inhaled nicotine on cardiac function and structure.C57BL/6 male mice aged 8–12 weeks were used in this study. Mice were exposed to nicotine vapor in their home cage using an exposure system that provides control of chronicity and nicotine dosing. Mice were exposed for 12 hours/day corresponding with the dark cycle. Following 4 weeks of either nicotine or air exposure, subsets of these groups were implanted with osmotic mini‐pumps containing Ang‐II to induce hypertrophy and fibrosis. Cardiac function was assessed by ultrasound echocardiography and tissue samples collected for protein and mRNA analysis. While there was no significant change in left ventricular function, we found that nicotine blunted Ang‐II mediated hypertrophy in the posterior wall (0.83 ± 0.03 mm, n=19) compared to Ang‐II exposed mice (0.93 ± 0.02 mm, n=19, p&lt; 0.01). While there were no differences in collagen 1 and 3 mRNA expression between groups, our preliminary data showed an increase in collagen I protein expression in nicotine exposed mice compared to air controls (1.27 ± 0.05 vs. 1 ± 0.09, n=2–3 respectively).In conclusion, while nicotine does not appear to affect left ventricular cardiac function, nicotine does blunt Ang‐II mediated hypertrophy. In addition, there is also evidence for increased cardiac collagen deposition in nicotine exposed mice. Future studies to measure right ventricular function, cardiomyocyte size, hypertrophic pathways, and cardiac fibroblast activity are in progress.Support or Funding InformationNHLBI R01 HL135635NIH Grant #R25GM121189This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.