The compound NS5806 is a Kv4 channel modulator. This study investigated the chronic effects of NS5806 on cardiac hypertrophy induced by transverse aortic constriction (TAC) in mice in vivo and on neonatal rat ventricular cardiomyocyte hypertrophy induced by endothelin-1 (ET-1) in vitro. Four weeks after TAC, NS5806 was administered by gavage for 4 weeks. Echocardiograms revealed pronounced left ventricular (LV) hypertrophy in TAC-treated mice compared with sham mice. NS5806 attenuated LV hypertrophy, as manifested by the restoration of LV wall thickness and weight and the reversal of contractile dysfunction in TAC-treated mice. NS5806 also blunted the TAC-induced increases in the expression of cardiac hypertrophic and fibrotic genes, including ANP, BNP and TGF-β. Electrophysiological recordings revealed a significant prolongation of action potential duration and QT intervals, accompanied by an increase in susceptibility to ventricular arrhythmias in mice with cardiac hypertrophy. However, NS5806 restored these alterations in electrical parameters and thus reduced the incidence of mouse sudden death. Furthermore, NS5806 abrogated the downregulation of the Kv4 protein in the hypertrophic myocardium but did not influence the reduction in Kv4 mRNA expression. In addition, NS5806 suppressed in vitro cardiomyocyte hypertrophy. The results provide novel insight for further ion channel modulator development as a potential treatment option for cardiac hypertrophy.

BACKGROUND: Cardiovascular disease is a leading cause of death worldwide. Rates of cardiovascular disease vary both across the lifespan and between sexes. While multiple factors, including adverse life experiences, impact the development and progression of cardiovascular disease, the potential interactions of biological sex and stress history on the aged heart are unknown. To this end, we examined sex- and stress-specific impacts on left ventricular hypertrophy (VH) after aging. We hypothesized that early-life chronic stress exposure impacts behavioral and physiologic responses that predict cardiac remodeling in a sex-specific manner.
METHODS: Histological analysis was conducted on hearts of male and female rats previously exposed to chronic variable stress during the late adolescent period (postnatal days 43-62). These animals were challenged with a forced swim test and a glucose tolerance test before aging to 15 months and again being challenged. Predictive analyses were then used to isolate factors that relate to cardiac remodeling among these groups.
RESULTS: Early-life chronic stress impacted cardiac remodeling in a sex-specific manner. Among rats with a history of chronic stress, females had increased concentric VH. However, there were few associations within the female groups among individual behavioral and physiologic parameters and cardiac remodeling. While males as a group did not have VH after chronic stress, they exhibited multiple individual associations with cardiac susceptibility. Passive coping in young males and active coping in aged males related to VH in a stress history-dependent manner. Moreover, baseline corticosterone positively correlated with VH in unstressed males, while chronically-stressed males had positive correlations between VH and visceral adiposity.
CONCLUSIONS: These results indicate that females as a group are uniquely susceptible to the effects of early-life stress on cardiac remodeling later in life. Conversely, males have more individual differences in vulnerability, where susceptibility to cardiac remodeling relates to endocrine, metabolic, and behavioral measures depending on stress history. These results ultimately support a framework for assessing cardiovascular risk based on biological sex and prior adverse experiences.
Cardiovascular disease is the leading cause of death worldwide. Multiple factors influence the incidence and severity of cardiovascular disease including adverse life experiences, biological sex, and age. Alterations of heart structure predict negative cardiovascular health by impacting blood circulation; however, the potential interactions of stress history and biological sex on the aged heart are unknown. In this study, we examined how chronic stress exposure impacts heart structure in male and female rats after aging. Adolescent male and female rats were chronically stressed and then acutely challenged to examine behavioral, endocrine, and metabolic parameters both immediately following chronic stress and after aging. Heart morphology was quantified to examine how behavioral and physiological responses related to cardiac remodeling. Our results indicate that, as a group, female rats previously exposed to chronic stress were uniquely susceptible to inward remodeling of the heart. Subjects were further divided into sub-groups based on the level of inward remodeling of the ventricle. While male rats did not exhibit group effects on heart structure, individual variability in male heart morphology related to endocrine and metabolic parameters in a stress history-dependent manner. Here, there were interactions with multiple systems including coping behavior, stress hormones, and body composition. Moreover, males without a prior history of chronic stress had correlations between stress hormones and the degree of heart remodeling. However, males that were exposed to chronic stress had correlations between heart structure and abdominal fat. Overall, our results indicate that biological sex and stress history interact to predict cardiovascular susceptibility.

BACKGROUND: Left ventricular hypertrophy (LVH) is a critical factor in heart failure and cardiovascular event-related mortality. While the prevalence of LVH in diabetic patients is well-documented, its occurrence and risk factors in non-diabetic populations remain largely unexplored. This study addresses this issue by investigating the independent risk factors of LVH in non-diabetic individuals.
METHODS: This cross-sectional study, conducted meticulously, utilized data from a robust and comprehensive source, DATADRYAD, in the Sierra Leone database, collected between October 2019 and October 2021, including LVH and various variables. All variables were described and screened using univariate analysis, Spearman correlation, and principal component analysis (PCA). The lipid profile, including total cholesterols (TC), triglycerides (TG), high-density lipoprotein (HDL-C), non-high-density lipoprotein (Non-HDL-C), and low-density lipoprotein cholesterol (LDL-C), TC/HDL-C ratio, TG/HDL-C ratio, Non-HDL-C /HDL-C ratio and LDL-C/HDL-C ratio, which quartiles were treated as categorical variables, with the lowest quartile serving as the reference category. Three adjusted models were constructed to mitigate the influence of other variables. To ensure the robustness of the model, receiver operating characteristic (ROC) curves were used to calculate the cutoff values by analyzing the ROC curves. A sensitivity analysis was performed to validate the findings further.
RESULTS: The dataset encompasses information from 2092 individuals. After adjusting for potential factors that could influence the results, we found that TC (OR = 2.773, 95%CI: 1.805-4.26), Non-HDL-C (OR = 2.74, 95%CI: 1.7723-4.236), TC/HDL-C ratio (OR = 2.237, 95%CI: 1.445-3.463), Non-HDL-C/HDL-C ratio (OR = 2.357, 95%CI: 1.548-3.588), TG/HDL-C ratio (OR = 1.513, 95%CI: 1.02-2.245) acts as independent risk factors of LVH. ROC curve analysis revealed the predictive ability of blood lipids for LVH, with Non-HDL-C exhibiting area under the curve (AUC = 0.6109), followed by TC (AUC = 0.6084).
CONCLUSIONS: TC, non-HDL-C, TC/HDL-C ratio, Non-HDL-C/HDL-C ratio, and TG/HDL-C ratio were independent risk factors of LVH in non-diabetic people. Non-HDL-C and TC were found to be essential indicators for predicting the prevalence of LVH.

UNASSIGNED: Left ventricular (LV) hypertrophy occurs in both aortic stenosis (AS) and systemic hypertension (HTN) in response to wall stress. However, differentiation of hypertrophy due to these 2 etiologies is lacking. The aim was to study the 3-dimensional geometric remodeling pattern in severe AS pre- and postsurgical aortic valve replacement and to compare with HTN and healthy controls.
UNASSIGNED: Ninety-one subjects (36 severe AS, 19 HTN, and 36 healthy controls) underwent cine cardiac magnetic resonance. Cardiac magnetic resonance was repeated 8 months post-aortic valve replacement (n=18). Principal component analysis was performed on the 3-dimensional meshes reconstructed from 109 cardiac magnetic resonance scans of 91 subjects at end-diastole. Principal component analysis modes were compared across experimental groups together with conventional metrics of shape, strain, and scar.
UNASSIGNED: A unique AS signature was identified by wall thickness linked to a LV left-right axis shift and a decrease in short-axis eccentricity. HTN was uniquely linked to increased septal thickness. Combining these 3 features had good discriminative ability between AS and HTN (area under the curve, 0.792). The LV left-right axis shift was not reversible post-aortic valve replacement, did not associate with strain, age, or sex, and was predictive of postoperative LV mass regression (R2=0.339, P=0.014).
UNASSIGNED: Unique remodeling signatures might differentiate the etiology of LV hypertrophy. Preliminary findings suggest that LV axis shift is characteristic in AS, is not reversible post-aortic valve replacement, predicts mass regression, and may be interpreted to be an adaptive mechanism.

BACKGROUND: Beta 2-microglobulin (β2-MG) is a component of the class I major histocompatibility complex (MHCI) and has recently been reported to be involved in type 2 diabetes mellitus (T2DM) and cardiovascular disease. However, the association of β2-MG with left ventricular hypertrophy (LVH) in T2DM patients remains unknown. This study aims to investigate the correlation between serum β2-MG and LVH in T2DM patients.
METHODS: The retrospective analysis included 4602 eligible T2DM patients, divided into LVH and non-LVH groups based on echocardiography results. Serum β2-MG levels were measured, and participants were categorized into four groups (Q1-Q4) by their serum β2-MG quartile. The relationship of serum β2-MG level with LVH was evaluated using logistic regression, restricted cubic spline (RCS), subgroup analysis, and machine learning.
RESULTS: The prevalence of LVH in T2DM patients was 31.12%. Each standard deviation increase in serum β2-MG level corresponded to a 1.17-fold increase in the prevalence of LVH [OR = 1.17, (95% CI: 1.05-1.31); p = 0.006]. When considering β2-MG as a categorical variable (quartile), Q3 [OR = 1.36, (95% CI: 1.09-1.69); p = 0.007] and Q4 [OR = 1.77, (95% CI: 1.36-2.31); p < 0.001] had a significantly higher prevalence of LVH than Q1. RCS analysis found a nonlinear association between β2-MG and LVH prevalence (p for nonlinearity <0.05). Additionally, machine learning results confirmed the importance of β2-MG for LVH in T2DM patients.
CONCLUSIONS: Elevated serum β2-MG levels were likely to be associated with an increased prevalence of LVH in T2DM patients, suggesting its potential role in LVH development.

Hypertrophic cardiomyopathy (HCM) is a genetic disease characterized by unexplained left ventricular hypertrophy (LVH), diastolic dysfunction, and increased sudden-death risk. Early detection of the phenotypic expression of the disease in genetic carriers without LVH (Gen+/Phen-) is crucial for emerging therapies. This clinical study aims to identify echocardiographic predictors of phenotypic development in Gen+/Phen-. Sixteen Gen+/Phen- (one subject with troponin T, six with myosin heavy chain-7, and nine with myosin-binding protein C3 mutations), represented the study population. At first and last visit we performed comprehensive 2D speckle-tracking strain echocardiography. During a follow-up of 8 ± 5 years, five carriers developed LVH (LVH+). At baseline, these patients were older than those who did not develop LVH (LVH-) (30 ± 8 vs. 15 ± 8 years, p = 0.005). LVH+ had reduced peak global strain rate during the isovolumic relaxation period (SRIVR) (0.28 ± 0.05 vs. 0.40 ± 0.11 1/s, p = 0.048) and lower global longitudinal strain (GLS) (-19.8 ± 0.4 vs. -22.3 ± 1.1%; p < 0.0001) than LVH- at baseline. SRIVR and GLS were not correlated with age (overall, p > 0.08). This is the first HCM study investigating subjects before they manifest clinically significant or relevant disease burden or symptomatology, comparing at baseline HCM Gen+/Phen- subjects who will develop LVH with those who will not. Furthermore, we identified highly sensitive, easily obtainable, age- and load-independent echocardiographic predictors of phenotype development in HCM gene carriers who may undergo early preventive treatment.

BACKGROUND: This study evaluated the effects of concurrent isolated training (T) or training combined with the antioxidant N-acetylcysteine (NAC) on cardiac remodeling and oxidative stress in spontaneously hypertensive rats (SHR).
METHODS: Six-month-old male SHR were divided into sedentary (S, n = 12), concurrent training (T, n = 13), sedentary supplemented with NAC (SNAC, n = 13), and concurrent training with NAC supplementation (TNAC, n = 14) groups. T and TNAC rats were trained three times a week on a treadmill and ladder; NAC supplemented groups received 120 mg/kg/day NAC in rat chow for eight weeks. Myocardial antioxidant enzyme activity and lipid hydroperoxide concentration were assessed by spectrophotometry. Gene expression of NADPH oxidase subunits Nox2, Nox4, p22 phox, and p47 phox was evaluated by real time RT-PCR. Statistical analysis was performed using ANOVA and Bonferroni or Kruskal-Wallis and Dunn.
RESULTS: Echocardiogram showed concentric remodeling in TNAC, characterized by increased relative wall thickness (S 0.40 ± 0.04; T 0.39 ± 0.03; SNAC 0.40 ± 0.04; TNAC 0.43 ± 0.04 *; * p < 0.05 vs T and SNAC) and diastolic posterior wall thickness (S 1.50 ± 0.12; T 1.52 ± 0.10; SNAC 1.56 ± 0.12; TNAC 1.62 ± 0.14 * mm; * p < 0.05 vs T), with improved contractile function (posterior wall shortening velocity: S 39.4 ± 5.01; T 36.4 ± 2.96; SNAC 39.7 ± 3.44; TNAC 41.6 ± 3.57 * mm/s; * p < 0.05 vs T). Myocardial lipid hydroperoxide concentration was lower in NAC treated groups (S 210 ± 48; T 182 ± 43; SNAC 159 ± 33 *; TNAC 110 ± 23 *# nmol/g tissue; * p < 0.05 vs S, # p < 0.05 vs T and SNAC). Nox 2 and p22 phox expression was higher and p47 phox lower in T than S [S 1.37 (0.66-1.66); T 0.78 (0.61-1.04) *; SNAC 1.07 (1.01-1.38); TNAC 1.06 (1.01-1.15) arbitrary units; * p < 0.05 vs S]. NADPH oxidase subunits did not differ between TNAC, SNAC, and S groups.
CONCLUSIONS: N-acetylcysteine supplementation alone reduces oxidative stress in untreated spontaneously hypertensive rats. The combination of N-acetylcysteine and concurrent exercise further decreases oxidative stress. However, the lower oxidative stress does not translate into improved cardiac remodeling and function in untreated spontaneously hypertensive rats.

BACKGROUND: In this study, we examine the association between the hyperuricemia(HU) and hypertension(HTN) in Chinese young adults. Besides, the correlation between the occurrence of thickened left ventricular wall and HU was identified in patients with HTN.
METHODS: In all, 360 patients with HTN and 1991 young adults with normal blood pressure(NBP) were enrolled in the study. Participant characteristics were collected. Univariable and multivariable logistic regression tests were utilized to identify the correlation between the presence of HU and HTN, and the correlation between the occurrence of thickened ventricular septum and HU in patients with HTN.
RESULTS: The prevalence of HU in Chinese young adults with HTN was significantly higher than young adults with NBP(36.39% vs. 16.93%). Univariable analyses revealed that 8 factors were related with the presence of HTN with p value < 0.001, including HU, male, body mass index(BMI) ≥ 24 kg/m2, total cholesterol(TC) > 5.17mmol/L, triglyceride(TG) > 1.70mmol/L, high density lipoprotein cholesterol(HDL-C) < 1.0mmol/L, fasting blood glucose(FBG) > 6.10mmol/L and fatty liver. After adjusting these covariates, multivariable analysis revealed that HU[odds ratio(OR):1.47, 95% confidence interval(CI): 1.10-1.95, p = 0.008] remained independent association with HTN in young adults. Additionally, univariable and multivariable logistic analyses revealed that HU kept the independent effect on the presence of thickened interventricular septum(adjusted OR = 1.81, 95% CI: 1.05-3.11, P = 0.03) and thickened left ventricular posterior wall(adjusted OR = 2.28, 95% CI: 1.28-4.08, P = 0.005) in young adults with HTN.
CONCLUSIONS: HU was independently associated with HTN in young adults. HU was independently correlated with thickened left ventricular wall, including interventricular septum and left ventricular posterior wall, in young adults with HTN.

Background and Objectives: Left ventricular hypertrophy (LVH) represents a significant cardiovascular risk in patients undergoing chronic hemodialysis (CHD). A large inferior vena cava diameter (IVCD), potentially indicative of fluid overload and a contributing factor to elevated cardiovascular risk, has not been sufficiently explored. Therefore, our study aims to gain further insights into this aspect. Materials and Methods: A retrospective cohort study enrolled patients receiving CHD in a single medical center with available echocardiography from October to December 2018. They were categorized into four groups based on LVH geometry and IVCD. Cox proportional hazard models assessed the risk of major adverse cardiovascular effects (MACEs) and cardiovascular and overall mortality after multivariate adjustments. Kaplan-Meier analysis depicted MACE-free events and survival during the follow-up time. Results: Of the 175 CHD patients, 38, 42, 45, and 50 exhibited small IVCD with eccentric and concentric LVH and large IVCD with eccentric and concentric LVH, respectively. Compared to small IVCD and eccentric LVH, large IVCD and eccentric LVH had the highest risk of MACEs, followed by large IVCD and concentric LVH (aHR: 4.40, 3.60; 95% CI: 1.58-12.23, 1.28-10.12, respectively). As for cardiovascular mortality, large IVCD and concentric LVH had the highest risk, followed by large IVCD and eccentric LVH, and small IVCD and concentric LVH. (aHR: 14.34, 10.23, 8.87; 95% CI: 1.99-103.35, 1.41-74.33; 1.01-77.87). The trend in overall mortality risk among the groups was similar to that of cardiovascular mortality. Conclusions: LVH geometry and IVCD co-modify the risk of MACEs and cardiovascular and overall mortality in CHD patients. The highest risk of MACEs is associated with large IVCD and eccentric LVH, while the highest risk of cardiovascular and overall mortality is linked with large IVCD and concentric LVH.

OBJECTIVE: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have beneficial effects in heart failure (HF), including reverse remodelling, but the mechanisms by which these benefits are conferred are unclear. Inflammation is implicated in the pathophysiology of heart failure (HF) and there are some pre-clinical data suggesting that SGLT2 inhibitors may reduce inflammation. There is however a lack of clinical data. The aim of our study was to investigate whether improvements in cardiac remodelling caused by dapagliflozin in individuals with type 2 diabetes (T2D) and left ventricular hypertrophy (LVH) were associated with its effects on inflammation.
METHODS: We measured C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin 6 (IL-6), and interleukin 10 (IL-10) and neutrophil-to-lymphocyte ratio (NLR) in plasma samples of 60 patients with T2D and left ventricular hypertrophy (LVH) but without symptomatic HF from the DAPA-LVH trial in which participants were randomised dapagliflozin 10 mg daily or placebo for 12 months and underwent cardiac magnetic resonance imaging (CMR) at baseline and end of treatment. The primary analysis was to investigate the effect of dapagliflozin on inflammation and to assess the relationships between changes in inflammatory markers and LV mass and global longitudinal strain (GLS) and whether the effect of dapagliflozin on LV mass and GLS was modulated by baseline levels of inflammation.
RESULTS: Following 12 months of treatment dapagliflozin significantly reduced CRP compared to placebo (mean difference of -1.96; 95% CI -3.68 to -0.24, p = 0.026). There were no significant statistical changes in other inflammatory markers. There were modest correlations between improvements in GLS and reduced inflammation (NLR (r = 0.311), IL-1β (r = 0.246), TNF-α (r = 0.230)) at 12 months.
CONCLUSIONS: Dapagliflozin caused a significant reduction in CRP compared to placebo. There were correlations between reductions in inflammatory markers including IL-1β and improvements in global longitudinal strain (but not reduced LV mass). Reductions in systemic inflammation might play a contributory role in the cardiovascular benefits of dapagliflozin.
BACKGROUND: Clinicaltrials.gov NCT02956811 (06/11/2016).