Cardiac Structure Research Articles

Sex-specific effects on the heart from combined exposure to simulated galactic cosmic radiation and hindlimb unloading.

Future long duration space missions will expose astronauts to higher doses of galactic cosmic radiation (GCR) than those experienced on the international space station. Recent studies have demonstrated astronauts may be at risk for cardiovascular complications due to increased radiation exposure and fluid shift from microgravity. However, there is a lack of direct evidence on how the cardiovascular system is affected by GCR and microgravity since no astronauts have been exposed to exploratory mission relevant GCR doses. Therefore, we utilized a ground-based mouse model to determine the cardiovascular risks for space radiation exposure while the mice were simultaneously hindlimb suspended to mimic microgravity. 6-month-old male and female C57BL/6 mice were exposed to an absorbed dose of 0 Gy, 0.5 Gy, or 1.5 Gy simulated GCR (GCRsim) that comprised beams of 5 ions at NASA's Space Radiation Laboratory. Subcohorts of mice were hindlimb unloaded (HLU), starting 5 days before GCRsim until the completion of radiation exposure. GCRsim + HLU was performed over 8 hours (0.5 Gy) or 24 hours (1.5 Gy). After completion of GCRsim and HLU, mice were shipped to UAMS for long-term observation. Cardiac function was measured using high resolution ultrasound at 6 and 9 months after exposure. Tissues were collected after the final ultrasound and prepared for further analysis. Female mice exposed to 1.5 Gy + HLU demonstrated a significant increase in body weight compared to ground controls months after GCR exposure; however, there was no change in male body weights. Cardiac ultrasound revealed 0.5 Gy GCRsim decreased left ventricular (LV) mass, LV posterior wall thickness in diastole, and systole in males 6 months after exposure. In females, 1.5 Gy + HLU significantly increased LV posterior wall thickness in diastole and systole at 6 months. These changes in ultrasound measurements were no longer seen at 9 months. Moreover, at 9 months there was no change in total collagen content or density of the capillary network in the heart. Lastly, the combination of GCRsim and HLU influenced immune cell markers in the heart of female mice. These data suggest that combined simulated GCR and microgravity result in minor, yet statistically significant sex-dependent changes to body weight and cardiac structure.

BRD4 inhibition rewires cardiac macrophages toward a protective phenotype marked by low MHC class II expression.

Bromodomain and extraterminal domain (BET) proteins, including BRD4, bind acetylated chromatin and coactivate gene transcription. A BET inhibitor, JQ1, prevents and reverses pathological cardiac remodeling in preclinical models of heart failure. However, the underlying cellular mechanisms by which JQ1 improves cardiac structure and function remain poorly defined. Here, we demonstrate that BRD4 knockdown reduced expression of genes encoding CC chemokines in cardiac fibroblasts, suggesting a role for this epigenetic reader in controlling fibroblast-immune cell cross talk. Consistent with this, JQ1 dramatically suppressed recruitment of monocytes to the heart in response to stress. Normal mouse hearts were found to have approximately equivalent numbers of major histocompatibility complex (MHC-II)high and MHC-IIlow resident macrophages, whereas MHC-IIlow macrophages predominated following JQ1 treatment. Single-cell RNA-seq data confirmed that JQ1 treatment or BRD4 knockout in CX3CR1+ cells reduced MHC-II gene expression in cardiac macrophages, and studies with cultured macrophages further illustrated a cell autonomous role for BET proteins in controlling the MHC-II axis. Bulk RNA-seq analysis demonstrated that JQ1 blocked pro-inflammatory macrophage gene expression through a mechanism that likely involves repression of NF-κB signaling. JQ1 treatment reduced cardiac infarct size in mice subjected to ischemia/reperfusion. Our findings illustrate that BET inhibition affords a powerful pharmacological approach to manipulate monocyte-derived and resident macrophages in the heart. Such an approach has the potential to enhance the reparative phenotype of macrophages to promote wound healing and limit infarct expansion following myocardial ischemia.NEW & NOTEWORTHY BRD4 inhibition blocks stress-induced recruitment of pro-inflammatory monocytes to the heart. BRD4 inhibition reprograms resident cardiac macrophages toward a reparative phenotype marked by reduced NF-κB signaling and diminished MHC-II expression. BRD4 inhibition reduces infarct size in an acute model of ischemia/reperfusion injury in mice.

Active ingredients of traditional Chinese medicine inhibit NOD-like receptor protein 3 inflammasome: a novel strategy for preventing and treating heart failure

Heart failure (HF) has emerged as a significant global public health challenge owing to its high rates of morbidity and mortality. Activation of the NOD-like receptor protein 3 (NLRP3) inflammasome is regarded as a pivotal factor in the onset and progression of HF. Therefore, inhibiting the activation of the NLRP3 inflammasome may represent a promising therapeutic approach for preventing and treating HF. The active ingredients serve as the foundation for the therapeutic effects of traditional Chinese medicine (TCM). Recent research has revealed significant advantages of TCM active ingredients in inhibiting the activation of the NLRP3 inflammasome and enhancing cardiac structure and function in HF. The study aimed to explore the impact of NLRP3 inflammasome activation on the onset and progression of HF, and to review the current advancements in utilizing TCM active ingredients to inhibit the NLRP3 inflammasome for preventing and treating HF. This provides a novel perspective for the future development of precise intervention strategies targeting the NLRP3 inflammasome to prevent and treat HF.

Two Types of Double Chambered Left Ventricle: a case series

Abstract Background Double Chambered Left Ventricle (DCLV) is a rare anatomical variant of the left ventricular structure characterized by the division of the left ventricle into two distinct chambers due to abnormal muscle bundles or septa. This anomaly typically results in primary and secondary chambers within the left ventricle. Due to the lack of conspicuous clinical symptoms, DCLV is often overlooked. Case Summary The first patient was a 69-year-old male experiencing intermittent chest tightness for several weeks. Transthoracic echocardiography indicated the presence of Type A DCLV, which was subsequently confirmed by 3D echocardiography and cardiac magnetic resonance imaging. A few months later, during a routine transthoracic echocardiographic examination of a 48-year-old male, we unexpectedly discovered Type B DCLV. His unique cardiac structure was clearly demonstrated through 3D echocardiography. Discussion DCLV is a rare structural heart malformation often overlooked due to atypical symptoms. This paper presents two cases of DCLV within a six-month period, illustrating two distinct classifications. Comprehensive understanding of the imaging manifestations of DCLV is imperative for accurate clinical diagnosis.

Circulating growth differentiation factor-15 levels are associated with early echocardiographic signs of diastolic function impairment in the STANISLAS cohort: A 20-year follow-up study.

Early identification of healthy subjects prone to develop cardiac dysfunction may be instrumental to prevention strategies. Our study aimed to evaluate whether circulating levels of growth differentiation factor-15 (GDF-15) could predict adverse changes in echocardiographic indexes of cardiac structure and function in an initially healthy populational familial cohort with a long follow-up (STANISLAS cohort). We evaluated 1679 participants (49 ± 14 years, 48% males) included in the fourth visit (V4) of the STANISLAS cohort with available GDF-15 measurements (Olink proteomic analysis) and echocardiographic parameters. Among them, 1562 had also GDF-15 measurements at the first visit (V1) (18.2 ± 1.4 years before V4). We evaluated both prospective (GDF-15 at V1) and cross-sectional (GDF-15 at V4) associations between GDF-15 levels and echocardiographic variables. In adjusted analyses, higher baseline GDF-15 levels were associated with lower left ventricular (LV) end-diastolic volume and higher E/e' ratio nearly two decades later (both p ≤ 0.01). The cross-sectional analysis at V4 also found significant associations between GDF-15 and LV end-diastolic volume and higher E/e' ratio, further identifying significant associations with impaired LV strain. In the STANISLAS cohort, initial circulating GDF-15 levels were associated with echocardiographic signs of reduced LV size and increased filling pressure almost two decades later. This association was also confirmed by evaluating GDF-15 at the follow-up visit (V4). These findings suggest a potential role for GDF-15 as an easy screening and prognostic tool of diastolic dysfunction in the general population.

Vericiguat improves cardiac remodelling and function in rats with doxorubicin-induced cardiomyopathy.

Vericiguat, a soluble guanylate cyclase (sGC) stimulator, has been demonstrated effective in improving prognosis of patients with heart failure with reduced ejection fraction. However, there are limited data concerning the effect of vericiguat in patients with doxorubicin (DOX)-induced cardiomyopathy (DIC). In this study, we investigated the effects of vericiguat on cardiac structure and function in rats with DIC as well as their potential mechanisms of action. DIC rats were established by intraperitoneal injection of DOX (1mg/kg) twice a week for 6weeks, followed by intragastric administration of vericiguat 1mg/kg/day or an equal volume of normal saline for 8weeks. Cardiac histology and function, circulating levels of amino-terminal pro-B-type natriuretic peptide (NT-proBNP), nitric oxide (NO), and oxidative indices, as well as myocardial cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signalling, oxidative and apoptosis-associated protein were measured. Compared with the control group, rats treated with DOX exhibited significantly increased heart size, reduced systolic function and elevated plasma levels of NT-proBNP. Histological findings revealed myocardial cell atrophy, fibrosis and apoptosis. Vericiguat treatment effectively reversed DOX-induced cardiac remodelling and improved systolic function. Mechanistically, Vericiguat attenuated the inhibitory effects of DOX on the myocardial cGMP-PKG axis and nuclear factor erythroid 2-related factor 2 (Nrf2) protein, thereby alleviating oxidative stress and apoptosis. Vericiguat improved cardiac remodelling and contractile function in rats with DIC through upregulation of cGMP-PKG signalling and inhibition of oxidative stress and myocardial apoptosis.

Metabolomic Analysis of the Effects of Canagliflozin on HFpEF Rats and Its Underlying Mechanism.

Heart failure with preserved ejection fraction (HFpEF) represents a challenging cardiovascular condition characterized by normal systolic function but impaired diastolic performance. Despite its increasing prevalence, therapeutic options remain limited. This study investigated the metabolic effects of canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on cardiac function and energy metabolism in HFpEF. We established a rat model of HFpEF using Dahl salt-sensitive rats and evaluated three experimental groups: control (A), HFpEF (B), and canagliflozin-treated HFpEF (C). This study carried out comprehensive analyses of cardiac structure and function, metabolomic profiling, and detailed assessment of myocardial energy metabolism, including mitochondrial respiratory capacity and ATP synthesis. Additionally, we validated our findings using H9C2 cardiomyocytes under controlled conditions. Canagliflozin treatment significantly improved cardiac remodeling markers, including reduced myocardial volume and fibrosis area, while enhancing diastolic function (E/A ratio). Metabolomic analysis revealed normalization of hypermetabolic states, with significant reductions in key metabolites, including L-lysine, D-glucose, and uridine. The treatment restored balance in multiple metabolic pathways, particularly affecting β-alanine metabolism, pyrimidine metabolism, and the citrate cycle. Notably, canagliflozin enhanced mitochondrial respiratory function, increased ATP synthesis, and optimized fatty acid utilization, as evidenced by reduced free fatty acid content. Our findings demonstrated that canagliflozin exerts cardioprotective effects through multiple metabolic pathways, suggesting its potential as a therapeutic option for HFpEF. The ability of the drug to optimize energy metabolism and improve mitochondrial function represents a novel mechanism for treating this challenging condition.

Hepcidin, Incident Heart Failure and Cardiac Dysfunction in Older Adults: the ARIC Study.

Hepcidin regulates plasma and tissue iron levels. We studied the association of hepcidin levels with the risk of incident heart failure (HF) and cardiac dysfunction in older adults. We included adults from the ongoing, longitudinal Atherosclerosis Risk in Communities (ARIC) study who were free from prevalent anemia and HF at Visit 5 (2011-2013) and had available hepcidin and covariate data. Associations of plasma hepcidin levels with overall adjudicated incident HF, HF with reduced and HF with preserved ejection fraction (HFrEF and HFpEF) were assessed using multivariable Cox proportional hazards regression models. Cross-sectional associations of hepcidin with echocardiographic measures of cardiac structure and function were estimated using multivariable linear regression models. The mean age was 75±5 years old and 56% were women. In fully adjusted models, lower hepcidin levels were associated with a higher risk of overall incident HF (HR [95% CI] per 50% lower hepcidin: 1.15 [1.05-1.26]; P=0.003) and HFpEF (HR [95% CI]: 1.25 [1.10-1.42]; P=0.001). Plasma hepcidin level was not significantly associated with the risk of incident HFrEF (HR [95% CI]: 1.08 [0.94-1.24]; P=0.30). Lower hepcidin levels were associated with higher E wave (P=0.046), higher E/e' ratio (P=0.002), higher left atrial volume index (P=0.005) and higher pulmonary artery systolic pressure (P=0.02). In community-dwelling older adults without anemia, lower plasma hepcidin levels associate with a higher risk of incident HF (particularly HFpEF) and diastolic dysfunction. The findings imply the importance of monitoring iron metabolism dysregulation, even in absence of anemia, in late life.

Interleukin-10 exhibit dose-dependent effects on macrophage phenotypes and cardiac remodeling after myocardial infarction

IntroductionInterleukin-10 (IL-10) is a potent immunomodulatory cytokine widely explored as a therapeutic agent for diseases, including myocardial infarction (MI). High-dose IL-10 treatment may not achieve expected outcomes, raising the question of whether IL-10 has dose-dependency, or even uncharted side-effects from overdosing. We hypothesized that IL-10 has dose-dependent effects on macrophage (Mφ) phenotypic transition and cardiac remodeling after MI.MethodsUsing RAW264.7 monocyte models, we examined whether administering differential doses of exogenous IL-10 (0–1,000 ng/mL) perturbs classic M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes of polarized Mφ or even alters the phenotypic transition of prospective M1 and M2 polarization. We then investigated the impact of single intramyocardial IL-10 administration on cardiac function, structure, and inflammation post-MI, using a mouse MI model.ResultsCompared with 0-ng/mL control, 250-ng/mL IL-10 had the strongest overall effects in decreasing M1 and increasing M2 phenotypes on polarized Mφ while ≥500-ng/mL IL-10 dampened M1 polarization and augmented native IL-10 secretion more effectively than low doses in vitro. Echocardiography revealed that the 250-ng group had consistently higher contractile function and lower left ventricular (LV) dilatation than the saline control over 6 weeks while ≥1,000-ng groups exhibited transient lower LV ejection fraction at 5 days post-MI in vivo. Moreover, different doses of IL-10 differentially modulated myocardial gene expression, phagocytic cell infiltration at the infarct, LV fibrosis, and revascularization post-MI, with some, but not all, doses exerting beneficial effects.DiscussionOur study suggested that IL-10 has an effective dose range on Mφ phenotypes, and intramyocardial IL-10 treatment may trigger cardioprotective or unwanted effects post-MI in a dose-dependent manner.

Increased cardiac macrophages in Sorbs2-deficient hearts: revealing a potential role for macrophage in responding to embryonic myocardial abnormalities

Macrophages are known to support cardiac development and homeostasis, contributing to tissue remodeling and repair in the adult heart. However, it remains unclear whether embryonic macrophages also respond to abnormalities in the developing heart. Previously, we reported that the structural protein Sorbs2 promotes the development of the second heart field, with its deficiency resulting in atrial septal defects (ASD). In analyzing RNA-seq data, we noted an upregulation of macrophage-related genes in Sorbs2−/− hearts. Immunostaining and lineage-tracing confirmed an increase in macrophage numbers, underscoring a macrophage response to myocardial abnormalities. Partial depletion of macrophages led to downregulation of genes involved in lipid metabolism, muscle development and organ regeneration, alongside upregulation of genes associated with DNA damage-induced senescence and cardiomyopathy. Additionally, a non-significant increase in septal defects in macrophage-depleted Sorbs2−/− hearts suggests a potential reparative function for macrophages in maintaining structural integrity. Valve formation, however, remained unaffected. Our findings suggest that embryonic macrophages might sense abnormalities in embryonic cardiomyocytes and could adaptively support cardiac structure and function development in response to myocardial abnormalities.

YTHDF3-mediated FLCN/cPLA2 axis improves cardiac fibrosis via suppressing lysosomal function.

Cardiac fibrosis characterized by aberrant activation of cardiac fibroblasts impairs cardiac contractile and diastolic functions, inducing the progression of the disease towards its terminal phase, resulting in the onset of heart failure. Therefore, the inhibition of cardiac fibrosis has become a promising treatment for cardiac diseases. The ovarian follicle-stimulating hormone folliculin (FLCN) plays a significant role in various biological processes, such as lysosome function, mitochondrial synthesis, angiogenesis, ciliogenesis and autophagy. Severe heart failure was observed in FLCN knockout mice. In this study, we investigated the role of FLCN in cardiac fibrosis and its potential mechanisms. The mice were subjected to transverse aortic constriction (TAC) surgery. Myocardial fibrosis developed in the mice 8 weeks after surgery. We showed that the protein and mRNA expression levels of FLCN were significantly decreased in TAC mice. Similar results were observed in primary mouse cardiac fibroblasts treated with Ang-II, an in vitro cardiac fibrosis model, suggesting that FLCN is involved in the pathological process of cardiac fibrosis. We demonstrated that overexpression of FLCN inhibited lysosome function in cardiac fibroblasts. Furthermore, overexpression of FLCN protected the heart from TAC-induced pathological cardiac fibrosis. We revealed that FLCN bound to the cPLA2 protein, increased its activity, regulated lysosomal function, and promoted membrane permeabilisation in cardiac fibroblasts during cardiac fibrosis. Knockdown of cPLA2 blocked the antifibrotic effect of FLCN in cardiac fibrosis. In addition, we found that the reduced expression of FLCN in cardiac fibrosis resulted from the modulation of YTHDF3-regulated m6A methylation of FLCN mRNA. The overexpression of YTHDF3 alleviated the production of collagens and improved cardiac structure and function in TAC mice. YTHDF3 inhibited proliferation and differentiation and regulated lysosomal function in mouse cardiac fibroblasts, whereas these effects were abolished by FLCN knockdown. We conclude that FLCN undergoes YTHDF3-regulated m6A modification and interacts with cPLA2 to improve lysosomal function in cardiac fibroblasts, highlighting its role in myocardial fibrosis therapy. These results suggest that FLCN and YTHDF3 could serve as potential therapeutic targets for cardiac fibroblast treatment.

Cardiovascular magnetic resonance-estimated pulmonary capillary wedge pressure, congestion markers, and effect of empagliflozin in patients with heart failure with reduced ejection fraction and dysglycaemia (SUGAR-DM-HF).

A cardiovascular magnetic resonance (CMR) approach to non-invasively estimate left ventricular (LV) filling pressure was recently developed and shown to correlate with invasively measured pulmonary capillary wedge pressure (PCWP). We examined the association between CMR-estimated PCWP (CMR-PCWP) and other imaging and biomarker measures of congestion, and the effect of empagliflozin on these, in the SUGAR-DM-HF trial (NCT03485092). SUGAR-DM-HF enrolled 105 patients with heart failure with reduced ejection fraction (HFrEF) and pre-diabetes or type 2 diabetes who were randomly assigned to empagliflozin 10 mg or placebo once daily for 36 weeks. Transthoracic echocardiography (TTE) was performed at screening and physical examination, lung ultrasound (LUS), CMR, and blood sample collection at baseline and 36 weeks. The mean age of participants was 69 years, mean LV ejection fraction was 33%, and mean CMR-PCWP was 15.1 mmHg (standard deviation 2.5 mmHg). CMR-PCWP correlated with log N-terminal pro-B-type natriuretic peptide (Pearson's r = 0.31, p = 0.0012), total number of B-lines on LUS (Spearman's rho = 0.34, p < 0.001), TTE average E/e' (r = 0.22, p = 0.03) and CMR ventricular volumes (LV end-systolic volume: r = 0.51, p < 0.001; right ventricular end-systolic volume: r = 0.55, p < 0.001). Mean CMR-PCWP decreased from baseline to 36 weeks by -0.37 (95% confidence interval -0.78 to 0.05) mmHg and -0.17 (-0.69 to 0.36) mmHg in the empagliflozin and placebo groups, respectively; placebo-corrected difference -0.43 mmHg (-1.09 to 0.23, p = 0.20). Cardiovascular magnetic resonance-estimated PCWP correlates with clinical and ultrasound markers of congestion in HFrEF. CMR not only enables assessment of cardiac structure and function but also provides a non-invasive assessment of LV filling pressure.

Effect analysis of radiofrequency catheter ablation in the treatment of 7 children with atrial tachycardia-induced cardiomyopathy

BackgroundTachycardia-induced cardiomyopathy refers to changes in cardiac structure and function that result from rapid arrhythmia and can manifest as a continuous or recurrent event. Cardiomyopathy induced by atrial tachycardia is typically reversible if the arrhythmia is effectively controlled. There are few literature reports of atrial tachycardia-induced cardiomyopathy in children, and fewer cases have been effectively treated by radiofrequency catheter ablation in children.Objectivewe conducted a clinical summary of 7 cases of atrial tachycardia-induced cardiomyopathy in children in Wuhan Children’s Hospital to investigate the effectiveness and safety of radiofrequency catheter ablation for atrial tachycardia-induced cardiomyopathy.MethodsA total of 7 children (4 girls and 3 boys) diagnosed with atrial tachycardia-induced cardiomyopathy and admitted to Wuhan Children’s Hospital from January 2017 to April 2024 were selected. An intracardiac electrophysiological study was conducted on all 7 children to verify the origin of the atrial tachycardia and the presence of decreased cardiac function. All children were followed up for a period ranging from 2 to 12 months after RFCA or atrial appendectomy. During this follow-up, left ventricular end-diastolic diameter and left ventricular ejection fraction were monitored.ResultsThe age range was 3.6 to 13 years and the median age was 11.2 years. The weight range was from 15 to 92 kg, the average weight was 34 kg. The results of the intracardiac electrophysiological study of the 7 cases showed that the origin came from the right pulmonary vein in 2 cases, from the left pulmonary vein in 2 cases, from the left atrial appendage in one case, and from the right atrial appendage in 2 cases. Four cases of tachycardia-induced cardiomyopathy originating in the left and right pulmonary veins were successfully eliminated by radiofrequency catheter ablation (RFCA). The foci of atrial tachycardia were located in the atrial appendages of three children. For two of them, after precise positioning by the atrium three-dimensional electroanatomic mapping system and performing RFCA, the atrial tachycardia briefly stopped for approximately 24 h before reoccurring, and atrial appendectomy was subsequently performed. Nevertheless, in the other child, whose focus of atrial tachycardia was in the right atrial appendage, the lesion was successfully eliminated by RFCA. After RFCA or in combination with atrial appendectomy, 6 children were followed for more than 1 year and 1 child for 2 months. All children had sinus rhythm. At the same time, the left ventricular ejection fraction after RFCA or combined atrial appendectomy was significantly increased in 7 cases, indicating statistical significance (P = 0.018)), but the left ventricular end-diastolic diameter was not statistically significant in the treatment (P = 0.203)).ConclusionsSustained atrial tachycardia can lead to the occurrence of cardiomyopathy such as cardiac enlargement and heart failure. RFCA and combined atrial appendectomy can effectively stop tachycardia, eliminate the mechanism of tachycardia, and allow complete recovery of cardiac function.

Association between allostatic load and cardiac structural and functional abnormalities in young adults with serious mental disorders.

Allostatic load refers to the pathophysiological consequences of uncompensated adaptation to chronic stress. Few studies have investigated the effect of allostatic load on cardiac health in patients with serious mental disorders (SMDs), a population at high risk of cardiac mortality. Herein we evaluated associations between allostatic load and cardiac structure and function in young adults with SMDs. A total of 106 participants aged younger than 45years underwent echocardiographic study, blood biochemistry examination, and blood cell count analysis. Echocardiographic imaging was conducted in accordance with recommendations of the American Society of Echocardiography and European Association of Cardiovascular Imaging. Allostatic load index was calculated using 15 measures representing cardiovascular, metabolic, and inflammatory or oxidative stress markers. The SMD group exhibited a significantly higher allostatic load index than did control (Cohen's d=0.59). Additionally, they exhibited a greater left ventricular relative wall thickness (LVRWT, Cohen's d=0.39) and a less favorable mitral valve E/A ratio (Cohen's d=0.31), left ventricular ejection fraction (Cohen's d=0.51), and global longitudinal strain (Cohen's d=0.71). After demographic and clinical characteristics were adjusted for, multiple linear regression revealed that allostatic load index was positively associated with LVRWT (β=0.255) and negatively associated with mitral valve E/A ratio (β=-0.247) in the SMD group. This is the first study to suggest that allostatic load may play a critical role in accelerated adverse cardiac remodeling among young patients with SMDs. Future studies should elucidate the underlying mechanisms.

Mineralocorticoid axis activity and cardiac remodeling in patients with ACTH-dependent Cushing's syndrome.

Arterial hypertension and left ventricular hypertrophy and remodeling are independent cardiovascular risk factors in patients with Cushing's syndrome. Changes in the renin-angiotensin system and in the mineralocorticoid axis activity could be involved as potential mechanisms in their pathogenesis, in addition to cortisol excess. In this ancillary study of our previous study prospectively investigating patients with ACTH-dependent Cushing's syndrome by cardiac magnetic resonance imaging (NCT02202902), 11 patients without any interfering medication were cross-sectionally compared to 20 control subjects matched for age, sex and body mass index. Angiotensin metabolites and adrenal steroids were measured by liquid chromatography tandem mass spectrometry, and their relation to blood pressure and cardiac structure was evaluated. Concentrations of angiotensin I and angiotensin II were comparable, but the angiotensin-converting enzyme activity was significantly lower (2.19 (1.67; 3.08) vs 4.07 (3.1; 5.6); P < 0.001) in patients compared to controls. Aldosterone concentrations were significantly lower (6.9 (6.9; 124.1) vs 239.9 (181.4; 321.9) pmol/L; P < 0.001) in the group of patients, but adrenal aldosterone precursor metabolites were comparable between patients and controls. Inverse correlations were observed for 24 h urinary free cortisol and aldosterone with the ratio of left ventricular mass to end-diastolic volume (r = 0.470, P = 0.012 and r = -0.367, P = 0.046, respectively). We describe a disease-specific profile of angiotensin metabolites in patients with ACTH-dependent Cushing's syndrome. Low levels of aldosterone in the presence of unchanged precursor metabolites indicate a direct inhibitory action of cortisol excess on the aldosterone synthase. Furthermore, glucocorticoid excess per se drives cardiac muscle remodeling.

Imperatorin's Effect on Myocardial Infarction Based on Network Pharmacology and Molecular Docking.

Purpose: Myocardial infarction (MI), a severe cardiovascular disease, is the result of insufficient blood supply to the myocardium. Despite the improvements of conventional therapies, new approaches are needed to improve the outcome post-MI. Imperatorin is a natural compound with multiple pharmacological properties and potential cardioprotective effects. Therefore, this work investigated imperatorin's therapeutic effects and its mechanism of action in an MI mouse model. Methods: Network pharmacology, molecular docking, and experimental validation were performed for exploring the pharmacokinetic properties, therapeutic effects, and molecular targets of imperatorin in MI. Permanent ligation of the left anterior descending artery was performed in male C57BL/6 mice to induce MI before treatment with imperatorin once per day for 1 week. Echocardiography, heart histology, RNA sequencing, and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) as well as western blotting were carried out for evaluating cardiac function and structure, as well as gene and protein expression. Results: Imperatorin significantly improved cardiac function, preserved cardiac structure, attenuated cardiac remodeling and fibrosis, and reduced cardiomyocyte apoptosis in MI mice. Eight differentially expressed genes overlapping with key target genes were found, two upregulated and six downregulated. A key target in signaling pathways associated with imperatorin effect in MI was angiotensin-converting enzyme (ACE). Imperatorin inhibited ACE-angiotensin II (Ang II)-angiotensin II Type 1 receptor (AT1R) axis in MI mice. Conclusion: Imperatorin attenuated MI by inhibiting the ACE-Ang II-AT1R axis. Thus, imperatorin might be considered a potential therapeutic agent to cure MI.

Pathophysiological characterization of the ApoE-/-;db/db mouse: A model of diabetes and atherosclerosis.

The high prevalence of type 2 diabetes and atherosclerosis makes essential the availability of in vivo experimental models that accurately replicate the pathophysiological mechanisms of these diseases. Apolipoprotein E knockout mice (ApoE-/-) have been used in atherosclerosis studies, and the db/db mice show hyperphagia and obesity. Mice harbouring both alterations (i.e., ApoE-/-;db/db) are expected to develop combined features of type 2 diabetes, obesity and accelerated atherosclerosis. To deepen into their pathophysiological profile and further assess their potential as an experimental model, we studied their mortality and their pancreatic, cardiac, and renal phenotype. We analysed during 6months the glycemic and lipid profile, pancreatic, cardiac and renal structure and function and atherosclerosis in ApoE-/-;db/db mice. ApoE-/-;db/db mice show increases in plasma glucose (although without statistical significance) and glucagon levels, total cholesterol, triglycerides and HDL-cholesterol and in both insulin-producing β and glucagon producing α cells, and in the tissue expression of both hormones with respect to control (C57BL/6) mice; they show a remarkably high degree of atherosclerosis, higher left ventricular ejection fraction. Although renal function is normal, glucose, sodium and albumin excretion and urinary flow are increased with respect to control mice. Summarizing, ApoE-/-;db/db mice constitute a suitable experimental model for the study of type 2 diabetes associated with atherosclerosis.

The impact of common and rare genetic variants on bradyarrhythmia development

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD, while others were more specific for SND or DCD. SND and DCD showed a moderate genetic correlation (rg = 0.63). Cardiomyocyte-expressed genes were enriched for contributions to DCD heritability. Rare-variant analyses implicated LMNA for all bradyarrhythmia phenotypes, SMAD6 and SCN5A for DCD and TTN, MYBPC3 and SCN5A for PM. These results show that variation in multiple genetic pathways (for example, ion channel function, cardiac developmental programs, sarcomeric structure and cellular homeostasis) appear critical to the development of bradyarrhythmias.

The prognostic and diagnostic significance of echocardiographic parameters on acute ischemic stroke.

To comprehensively explore the prognostic significance of transthoracic echocardiography (TTE) and three-dimensional speckle-tracking echocardiography (3D STE) parameters in AIS and their role in distinguishing cardioembolic stroke. 301 acute ischemic stroke (AIS) patients were enrolled. TTE and 3D STE were employed to evaluate cardiac function and structure, also left atrial strain. Patients were categorized into two groups based on functional outcome at discharge and 3 months post-stroke, respectively. Models combining variables related to unfavorable outcome were established, and their predictive efficacy was assessed using receiver operating characteristic (ROC) curves. Additionally, AIS patients were stratified into cardioembolic and non-cardioembolic stroke groups. Logistic regression identified predictors for cardioembolic stroke, and ROC curves assessed their diagnostic performance. We found that a decrease in early diastolic peak velocity of the mitral valve (E value) was independently associated with adverse outcomes at both discharge (P = 0.014, OR = 0.126, 95% CI 0.024-0.657) and 3 months post-stroke in AIS patients (P = 0.004, OR = 0.054, 95% CI 0.007-0.403). Adding E value significantly improved predictive ability for adverse outcome at discharge and 3 months post-onset (0.807 vs. 0.794; 0.834 vs. 0.815). Moreover, left atrial diameter (LAD) [area under the curve (AUC) = 0.705] was the most valuable TTE parameter, and left atrial reservoir circumferential strain (LASr-c) (AUC = 0.766) was the most valuable STE parameter, even among all echocardiographic parameters for prediction of cardioembolic stroke. This study indicates reduced E value was associated with unfavorable outcome at discharge and 3 months post-onset of AIS patients. LAD, especially LASr-c exhibited optimal diagnostic performance on cardioembolic stroke.

Elevated Septal Native T1 Time in CMR Imaging Suggesting Myocardial Fibrosis in Young Kidney Transplant Recipients.

Patients after kidney transplantation (KTx) in childhood show a high prevalence of cardiac complications, but the underlying mechanism is still poorly understood. In adults, myocardial fibrosis detected in cardiac magnetic resonance (CMR) imaging is already an established risk factor. Data for children after KTx are not available. This study aimed to explore cardiac function and structure with focus on myocardial fibrosis and associated risk factors in KTx recipients. 46 KTx recipients (mean age 16.0 ± 3.5 years) and 46 age- and sex-matched healthy controls were examined with non-contrast CMR imaging. Native T1 time (nT1), a marker for myocardial fibrosis, was measured at the interventricular septum. Other parameters comprised left ventricular mass index (LVMI), ejection fraction (LVEF), and global longitudinal strain (GLS). Multivariable linear regression analyses were used to explore associations with nT1. Mean nT1 was significantly higher in KTx recipients than in controls (1198.1±48.8ms vs. 1154.4±23.4ms, p<0.0001). Twenty-one (46%) had a nT1 above above the upper limit of the normal range (mean + 2SD of controls). KTx recipients showed higher LVMI z-scores (0.1±1.1 vs. -0.3±0.7, p=0.026), higher LVEF (67.3±3.8% vs. 65.3±3.6%, p=0.012), and lower GLS (-19.0±2.1% vs. -20.3±2.7%, p=0.010). Higher systolic blood pressure (SBP; ß=1.284, p=0.001), LVMI (ß=1.542, p<0.001), and LVEF (ß=3.535, p=0.026) were associated with longer nT1 only in KTx recipients, but not in controls. Only two KTx recipients exhibited left ventricular hypertrophy, however, a total of 18 displayed elevated nT1 with LVMI z-score within the normal range. Our data suggest the presence of cardiac remodeling with myocardial fibrosis in a significant proportion of young KTx recipients. Non-contrast CMR imaging has the potential to visualize early structural cardiac changes and could become an important diagnostic adjunct in the follow-up of KTx recipients. Longitudinal studies are needed to further evaluate the importance of nT1 in early identification of those at high risk for sudden cardiac death allowing to integrate preventive strategies.