Chronic lipid overconsumption, associated with the Western diet, causes excessive cardiac lipid accumulation, insulin resistance, and contractile dysfunction, altogether termed lipotoxic cardiomyopathy (LCM). Existing treatments for LCM are limited. Traditional Chinese Medicine (TCM) has been shown as beneficial in diabetes and its complications. The following compounds-Resveratrol, Quercetin, Berberine, Baicalein, and Isorhamnetin-derived from TCM and often used to treat type 2 diabetes. However, virtually nothing is known about their effects in the lipid-overexposed heart. Lipid-induced insulin resistance was generated in HL-1 cardiomyocytes and adult rat cardiomyocytes by 24 h exposure to high palmitate. Upon simultaneous treatment with each of the TCM compounds, we measured myocellular lipid accumulation, insulin-stimulated fatty acid and glucose uptake, phosphorylation levels of AKT and ERK1/2, plasma membrane appearance of GLUT4 and CD36, and expression of oxidative stress-/inflammation-related genes and contractility. In lipid-overloaded cardiomyocytes, all the selected TCM compounds prevented lipid accumulation. These compounds also preserved insulin-stimulated CD36 and GLUT4 translocation and insulin-stimulated glucose uptake in an Akt-independent manner. Moreover, all the TCM compounds prevented and restored lipid-induced contractile dysfunction. Finally, some (not all) of the TCM compounds inhibited oxidative stress-related SIRT3 expression, and others reduced inflammatory TNFα expression. Their ability to restore CD36 trafficking makes all these TCM compounds attractive natural supplements for LCM treatment.

BACKGROUND: Global longitudinal active strain energy density (GLASED) is an innovative method for assessing myocardial function and quantifies the work performed per unit volume of the left ventricular myocardium. The GLASED, measured using MRI, is the best prognostic marker currently available. This study aimed to evaluate the feasibility of measuring the GLASED using echocardiography and to investigate potential differences in the GLASED among athletes based on age and sex.
METHODS: An echocardiographic study was conducted with male controls, male and female young athletes, and male and female veteran athletes. GLASED was calculated from the myocardial stress and strain.
RESULTS: The mean age (in years) of the young athletes was 21.6 for males and 21.4 for females, while the mean age of the veteran athletes was 53.5 for males and 54.2 for females. GLASED was found to be highest in young male athletes (2.40 kJ/m3) and lowest in female veterans (1.96 kJ/m3). Veteran males exhibited lower values (1.96 kJ/m3) than young male athletes did (P < 0.001). Young females demonstrated greater GLASED (2.28 kJ/m3) than did veteran females (P < 0.01). However, no significant difference in the GLASED was observed between male and female veterans.
CONCLUSIONS: Our findings demonstrated the feasibility of measuring GLASED using echocardiography. GLASED values were greater in young male athletes than in female athletes and decreased with age, suggesting possible physiological differences in their myocardium. The sex-related differences observed in GLASED values among young athletes were no longer present in veteran athletes. We postulate that measuring the GLASED may serve as a useful additional screening tool for cardiac diseases in athletes, particularly for those with borderline phenotypes of hypertrophic and dilated cardiomyopathies.

Older adults are vulnerable to glucocorticoid-induced muscle atrophy and weakness, with sex potentially influencing their susceptibility to those effects. Aerobic exercise can reduce glucocorticoid-induced muscle atrophy in young rodents. However, it is unknown whether aerobic exercise can prevent glucocorticoid myopathy in aged muscle. The objectives of this study were to define the extent to which sex influences the development of glucocorticoid myopathy in aged muscle, and to determine the extent to which aerobic exercise training protects against myopathy development. Twenty-four-month-old female (n = 30) and male (n = 33) mice were randomized to either sedentary or aerobic exercise groups. Within their respective groups, mice were randomized to either daily treatment with dexamethasone (DEX) or saline. Upon completing treatments, the contractile properties of the triceps surae complex were assessed in situ. DEX marginally lowered muscle mass and soluble protein content in both sexes, which was attenuated by aerobic exercise only in females. DEX increased sub-tetanic force and rate of force development only in females, which was not influenced by aerobic exercise. Muscle fatigue was higher in both sexes following DEX, but aerobic exercise prevented fatigue induction only in females. The sex-specific differences to muscle function in response to DEX treatment coincided with sex-specific changes to the content of proteins related to calcium handling, mitochondrial quality control, reactive oxygen species production, and glucocorticoid receptor in muscle. These findings define several important sexually dimorphic changes to aged skeletal muscle physiology in response to glucocorticoid treatment and define the capacity of short-term aerobic exercise to protect against those changes. KEY POINTS: There are sexually dimorphic effects of glucocorticoids on aged skeletal muscle physiology. Glucocorticoid-induced changes to aged muscle contractile properties coincide with sex-specific differences in the content of calcium handling proteins. Aerobic exercise prevents glucocorticoid-induced fatigue only in aged females and coincides with differences in the content of mitochondrial quality control proteins and glucocorticoid receptors.

OBJECTIVE: Our study aimed to compare the immediate and prolonged effects of submaximal eccentric (ECC) and concentric (CON) fatiguing protocols on the etiology of hamstrings\' motor performance fatigue.
METHODS: On separate days, 16 males performed sets of 5 unilateral ECC or CON hamstrings\' contractions at 80% of their 1 Repetition Maximum (1 RM) until a 20% decrement in maximal voluntary isometric contraction (MVC) torque was reached. Electrical stimulations were delivered during and after MVCs at several time points: before, throughout, immediately after (POST) and 24 h (POST 24) after the exercise. Potentiated twitch torques (T100 and T10, respectively) were recorded in response to high and low frequency paired electrical stimulations, and hamstrings\' voluntary activation (VA) level was determined using the interpolated twitch technique. For statistical analysis, all indices of hamstrings\' motor performance fatigue were expressed as a percentage of their respective baseline value.
RESULTS: At POST, T100 (ECC: -13.3%; CON: -9.7%; p < 0.001), T10 (ECC: -5.1%; CON: -11.8%; p < 0.05) and hamstrings\' VA level (ECC: -3.0%; CON: -2.4%; p < 0.001) were significantly reduced from baseline, without statistical differences between fatigue conditions. At POST24, all indices of hamstrings\' motor performance fatigue returned to their baseline values.
CONCLUSIONS: These results suggest that the contribution of muscular and neural mechanisms in hamstrings\' motor performance fatigue may not depend on contraction type. This may have implications for practitioners, as ECC and CON strengthening could be similarly effective to improve hamstrings\' fatigue resistance.

Air pollution (gases and particulate matter -PM) and child undernutrition are globally recognized stressors with significant consequences. PM and its components breach the respiratory alveolar-capillary barrier, entering the vasculature transporting not only harmful particles and its mediators but, altering vascular paracrine and autocrine functions. The aim of this study was to investigate the effects of Residual Oil Fly Ash (ROFA), on the vasculature of young animals with nutritional growth retardation (NGR). Weanling rats were fed a diet restricted 20% (NGR) compared to ad libitum intake (control-C) for 4 weeks. Rats were intranasally instilled with 1 mg/kg BW of ROFA. After 24h exposure, histological and immunohistochemical, biochemical and contractile response to NA/ACh were evaluated in aortas. ROFA induced changes in the tunica media of the aorta in all groups regarding thickness, muscular cells and expression of Connexin-43. ROFA increased TGF-β1 and decreased eNOs levels and calcium channels in C and NGR animals. An increment in cytokines IL-6 and IL-10 was observed in C, with no changes in NGR. ROFA exposure altered the vascular contractile capacity. In conclusion, ROFA exposure could increase the risk for CVD through the alteration of vascular biochemical parameters, a possible step of the endothelial dysfunction.

BACKGROUND: Identifying the imaging method that best predicts all-cause mortality, cardiovascular adverse events and heart failure risk is crucial for tailoring optimal management. Potential prognostic markers include left ventricular myocardial mass, ejection fraction, myocardial strain, stroke work, contraction fraction, pressure-strain product and a new measurement called global longitudinal active strain density (GLASED).
OBJECTIVE: This study sought to compare the utility of 23 potential left ventricular prognostic markers of structure and contractile function in a community-based cohort.
METHODS: The impact of cardiovascular magnetic resonance image-derived markers extracted by machine learning algorithms was compared to the future risk of adverse events in a group of 44,957 UK Biobank participants.
RESULTS: Most markers, including the left ventricular ejection fraction, have limited prognostic value. GLASED was significantly associated with all-cause mortality and major adverse cardiovascular events, with the largest hazard ratio, highest ranking and differentiated risk in all three tertiles (P ≤ 0.0003).
CONCLUSIONS: GLASED predicted all-cause mortality and major cardiovascular adverse events better than conventional markers of risk and is recommended for assessing patient prognosis.

OBJECTIVE: This study compared commonly used methods for calculating left ventricular wall stress with the finite element analysis and evaluated different approaches to strain estimation. We sought to improve the accuracy of contractance estimation by developing a novel stress equation.
BACKGROUND: Multiple methods for calculating LV contractile stress and strain exist. Contractance is derived from stress and strain information and is a measure of myocardial work per unit volume of muscle. Precise stress and strain information are essential for its accurate evaluation.
RESULTS: We compared widely used methods for stress and strain calculations across diverse clinical scenarios representing distinct types of left ventricular myocardial disease. Our analysis revealed significant discrepancies in both the stress and strain values obtained with different methods. However, a newly developed modified version of the Mirsky equation demonstrated close agreement with the finite element analysis results for circumferential stress, while the Lamé method produced results close to those of finite element analysis for longitudinal stress and improved contractance accuracy.
CONCLUSIONS: This study highlights significant inconsistencies in stress and strain values calculated using different methods, emphasising the potential impact on contractance calculations and subsequent clinical interpretation. We recommend adopting the Lamé method for longitudinal stress assessment and the modified Mirsky equation for circumferential stress analysis. These methods offer a balance between accuracy and feasibility, making them advantageous for clinical practice. By adopting these recommendations, we can improve the accuracy of LV wall stress and strain estimates, leading to more dependable contractance calculations, better prognostication and improved clinical decisions.
UNASSIGNED: Accurately estimating myocardial stress and strain is of paramount significance in clinical practice because the calculation of the contractance, defined and quantified by myocardial active strain energy density, necessitates correct stress and strain data. Contractance, which assesses myocardial work per unit muscle volume, has emerged as a promising indicator of contractile function and a predictor of future risk. The new recommendations for calculating myocardial stress improve the reliability of calculating contractance and enhance the understanding of myocardial diseases.

BACKGROUND: 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.
RESULTS: We examined the effects of butyrate on (1) in vivo 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 in vivo. 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).
CONCLUSIONS: 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.

Goal: Contractile response and calcium handling are central to understanding cardiac function and physiology, yet existing methods of analysis to quantify these metrics are often time-consuming, prone to mistakes, or require specialized equipment/license. We developed BeatProfiler, a suite of cardiac analysis tools designed to quantify contractile function, calcium handling, and force generation for multiple in vitro cardiac models and apply downstream machine learning methods for deep phenotyping and classification. Methods: We first validate BeatProfiler\'s accuracy, robustness, and speed by benchmarking against existing tools with a fixed dataset. We further confirm its ability to robustly characterize disease and dose-dependent drug response. We then demonstrate that the data acquired by our automatic acquisition pipeline can be further harnessed for machine learning (ML) analysis to phenotype a disease model of restrictive cardiomyopathy and profile cardioactive drug functional response. To accurately classify between these biological signals, we apply feature-based ML and deep learning models (temporal convolutional-bidirectional long short-term memory model or TCN-BiLSTM). Results: Benchmarking against existing tools revealed that BeatProfiler detected and analyzed contraction and calcium signals better than existing tools through improved sensitivity in low signal data, reduction in false positives, and analysis speed increase by 7 to 50-fold. Of signals accurately detected by published methods (PMs), BeatProfiler\'s extracted features showed high correlations to PMs, confirming that it is reliable and consistent with PMs. The features extracted by BeatProfiler classified restrictive cardiomyopathy cardiomyocytes from isogenic healthy controls with 98% accuracy and identified relax90 as a top distinguishing feature in congruence with previous findings. We also show that our TCN-BiLSTM model was able to classify drug-free control and 4 cardiac drugs with different mechanisms of action at 96% accuracy. We further apply Grad-CAM on our convolution-based models to identify signature regions of perturbations by these drugs in calcium signals. Conclusions: We anticipate that the capabilities of BeatProfiler will help advance in vitro studies in cardiac biology through rapid phenotyping, revealing mechanisms underlying cardiac health and disease, and enabling objective classification of cardiac disease and responses to drugs.

UNASSIGNED: Our understanding of the factors associated with improvement of LVEF and a heart failure with improved EF (HFimpEF) phenotype remains incomplete.
UNASSIGNED: We conducted a retrospective study using a national database of patients followed in the Veterans Affairs (VA) health system with serial assessment of left ventricular ejection fraction (LVEF) by echocardiography. We identified US veterans with a new diagnosis of heart failure with: (i) LVEF of <40 % in the 12 months prior to diagnosis, and (ii) follow-up LVEF assessment at least 6 months after their diagnosis. We defined HFimpEF as a final LVEF of ≥40 %.
UNASSIGNED: Among the 106,414 US veterans with an initial LVEF of <40 % in this analysis, 39,994 (37.6 %) had a final EF of >40 % after a median follow up of 5 years. Multivariate regression analysis identified several factors that were independently associated with LVEF improvement including female sex, younger age, higher BMI, and a history of specific comorbid conditions such as hypertension, valve disease, atrial fibrillation, connective tissue disease, liver disease, and malignancy (p < 0.001). Conversely, a history of ischemic heart disease and peripheral arterial disease, as well as specific racial backgrounds (Black and Hispanic) were associated with lower rates of LVEF improvement. The model c-statistic for predicting LVEF improvement was 0.70.
UNASSIGNED: This large, detailed dataset facilitated an analysis of a large number of variables that significantly associated with HFimpEF; however, their combined discriminatory value for LVEF improvement remained modest, underscoring the complexity of the gene-environment-treatment interactions that govern LV function.