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Diabetic cardiomyopathy (DCM) is a common cardiovascular complication of diabetes, which may threaten the quality of life and shorten life expectancy in the diabetic population. However, the molecular mechanisms underlying the diabetes cardiomyopathy are not fully elucidated. We analyzed two datasets from Gene Expression Omnibus (GEO). Differentially expressed and weighted gene correlation network analysis (WGCNA) was used to screen key genes and molecules. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and protein–protein interaction (PPI) network analysis were constructed to identify hub genes. The diagnostic value of the hub gene was evaluated using the receiver operating characteristic (ROC). Quantitative real-time PCR (RT-qPCR) was used to validate the hub genes. A total of 13 differentially co-expressed modules were selected by WGCNA and differential expression analysis. KEGG and GO analysis showed these DEGs were mainly enriched in lipid metabolism and myocardial hypertrophy pathway, cytomembrane, and mitochondrion. As a result, six genes were identified as hub genes. Finally, five genes (Pdk4, Lipe, Serpine1, Igf1r, and Bcl2l1) were found significantly changed in both the validation dataset and experimental mice with DCM. In conclusion, the present study identified five genes that may help provide novel targets for diagnosing and treating DCM. [ABSTRACT FROM AUTHOR]

The myocardium is a highly oxidative tissue in which mitochondria are essential to supply the energy required to maintain pump function. When pathological hypertrophy develops, energy consumption augments and jeopardizes mitochondrial capacity. We explored the cardiac consequences of chronic swimming training, focusing on the mitochondrial network, in spontaneously hypertensive rats (SHR). Male adult SHR were randomized to sedentary or trained (T: 8-week swimming protocol). Blood pressure and echocardiograms were recorded, and hearts were removed at the end of the training period to perform molecular, imaging, or isolated mitochondria studies. Swimming improved cardiac midventricular shortening and decreased the pathological hypertrophic marker atrial natriuretic peptide. Oxidative stress was reduced, and even more interesting, mitochondrial spatial distribution, dynamics, function, and ATP were significantly improved in the myocardium of T rats. In the signaling pathway triggered by training, we detected an increase in the phosphorylation level of both AKT and glycogen synthase kinase-3 β, key downstream targets of insulin-like growth factor 1 signaling that are crucially involved in mitochondria biogenesis and integrity. Aerobic exercise training emerges as an effective approach to improve pathological cardiac hypertrophy and bioenergetics in hypertension-induced cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Cardiac hypertrophy (CH) is an adaptive response to maintain cardiac function; however, persistent stress responses lead to contractile dysfunction and heart failure. Although inflammation is involved in these processes, the mechanisms that control cardiac inflammation and hypertrophy still need to be clarified. The NLRP3 inflammasome is a cytosolic multiprotein complex that mediates IL-1β production. The priming step of NLRP3 is essential for increasing the expression of its components and occurs following NF-κB activation. Hyperthyroidism triggers CH, which can progress to maladaptive CH and even heart failure. We have shown in a previous study that thyroid hormone (TH)-induced CH is linked to the upregulation of S100A8, leading to NF-κB activation. Therefore, we aimed to investigate whether the NLRP3 inflammasome is involved in TH-induced CH and its potential role in CH pathophysiology. Hyperthyroidism was induced in NLRP3 knockout (NLRP3-KO), Caspase-1-KO and Wild Type (WT) male mice of the C57Bl/6J strain, aged 8–12 weeks, by triiodothyronine (7 μg/100 g BW, i.p.) administered daily for 14 days. Morphological and cardiac functional analysis besides molecular assays showed, for the first time, that TH-induced CH is accompanied by reduced NLRP3 expression in the heart and that it occurs independently of the NLRP3 inflammasome and caspase 1-related pathways. However, NLRP3 is important for the maintenance of basal cardiac function since NLRP3-KO mice had impaired diastolic function and reduced heart rate, ejection fraction, and fractional shortening compared with WT mice. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) and cardiac dysfunction are established comorbidities of congenital diaphragmatic hernia (CDH). However, there is very little data focusing on arterial hypertension in CDH. This study aims to investigate the incidence of arterial hypertension in neonates with CDH at hospital discharge. Archived clinical data of 167 CDH infants who received surgical repair of the diaphragmatic defect and survived for > 60 days were retrospectively analyzed. Blood pressure (BP) values were averaged for the last 7 days before discharge and compared to standard BP values for sex, age, and height provided by the AHA in 2004. BP values reaching or extending the 95th percentile were defined as arterial hypertension. The use of antihypertensive medication was analyzed at discharge and during hospitalization. Arterial hypertension at discharge was observed in 19 of 167 infants (11.3%) of which 12 (63%) were not receiving antihypertensive medication. Eighty patients (47.9%) received antihypertensive medication at any point during hospitalization and 28.9% of 152 survivors (n = 44) received antihypertensive medication at discharge, although in 45.5% (n = 20) of patients receiving antihypertensive medication, the indication for antihypertensive medication was myocardial hypertrophy or frequency control. BP was significantly higher in ECMO compared to non-ECMO patients, despite a similar incidence of arterial hypertension in both groups (13.8% vs. 10.1%, p = 0.473). Non-isolated CDH, formula feeding, and minimal creatinine in the first week of life were significantly associated with arterial hypertension on univariate analysis. Following multivariate analysis, only minimal creatinine remained independently associated with arterial hypertension. Conclusion: This study demonstrates a moderately high incidence of arterial hypertension in CDH infants at discharge and an independent association of creatinine values with arterial hypertension. Physicians should be aware of this risk and include regular BP measurements and test of renal function in CDH care and follow-up. What is Known: • Due to decreasing mortality, morbidity is increasing in surviving CDH patients. • Pulmonary hypertension and cardiac dysfunction are well-known cardiovascular comorbidities of CDH. What is New: • There is a moderately high incidence of arterial hypertension in CDH infants at discharge even in a population with frequent treatment with antihypertensive medication. • A more complicated hospital course (ECMO, higher degree of PH, larger defect size) was associated with a higher risk for arterial hypertension. [ABSTRACT FROM AUTHOR]

Emerging evidence has documented that circadian rhythm disorders could be related to cardiovascular diseases. However, there is limited knowledge on the direct adverse effects of circadian misalignment on the heart. This study aimed to investigate the effect of chronic circadian rhythm disorder on heart homeostasis in a mouse model of consistent jetlag. The jetlag model was induced in mice by a serial 8-h phase advance of the light cycle using a light-controlled isolation box every 4 days for up to 3 months. Herein, we demonstrated for the first time that chronic circadian rhythm disorder established in the mouse jetlag model could lead to HFpEF-like phenotype such as cardiac hypertrophy, cardiac fibrosis, and cardiac diastolic dysfunction, following the attenuation of the Clock-sGC-cGMP-PKG1 signaling. In addition, clock gene knock down in cardiomyocytes induced hypertrophy via decreased sGC-cGMP-PKG signaling pathway. Furthermore, treatment with an sGC-activator riociguat directly attenuated the adverse effects of jetlag model-induced cardiac hypertrophy, cardiac fibrosis, and cardiac diastolic dysfunction. Our data suggest that circadian rhythm disruption could induce HFpEF-like phenotype through downregulation of the clock-sGC-cGMP-PKG1 signaling pathway. sGC could be one of the molecular targets against circadian rhythm disorder-related heart disease. [ABSTRACT FROM AUTHOR]

Introduction: Thiazolidinediones (TZDs), represented by pioglitazone and rosiglitazone, are a class of cost-effective oral antidiabetic agents posing a marginal hypoglycaemia risk. Nevertheless, observations of heart failure have hindered the clinical use of both therapies. Objective: Since the mechanism of TZD-induced heart failure remains largely uncharacterised, this study aimed to explore the as-yet-unidentified mechanisms underpinning TZD cardiotoxicity using a toxicometabolomics approach. Methods: The present investigation included an untargeted liquid chromatography–mass spectrometry-based toxicometabolomics pipeline, followed by multivariate statistics and pathway analyses to elucidate the mechanism(s)of TZD-induced cardiotoxicity using AC16 human cardiomyocytes as a model, and to identify the prognostic features associated with such effects. Results: Acute administration of either TZD agent resulted in a significant modulation in carnitine content, reflecting potential disruption of the mitochondrial carnitine shuttle. Furthermore, perturbations were noted in purine metabolism and amino acid fingerprints, strongly conveying aberrations in cardiac energetics associated with TZD usage. Analysis of our findings also highlighted alterations in polyamine (spermine and spermidine) and amino acid (L-tyrosine and valine) metabolism, known modulators of cardiac hypertrophy, suggesting a potential link to TZD cardiotoxicity that necessitates further research. In addition, this comprehensive study identified two groupings – (i) valine and creatine, and (ii) L-tryptophan and L-methionine – that were significantly enriched in the above-mentioned mechanisms, emerging as potential fingerprint biomarkers for pioglitazone and rosiglitazone cardiotoxicity, respectively. Conclusion: These findings demonstrate the utility of toxicometabolomics in elaborating on mechanisms of drug toxicity and identifying potential biomarkers, thus encouraging its application in the toxicological sciences. (245 words) [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the role of circSlc8a1 in cardiac hypertrophy (CH), a pathological change in various cardiovascular diseases. Methods: An in vitro CH model was established using angiotensin II (AngII) treated H9c2 cells, followed by western blotting and RT-qPCR for detecting relative expressions. Cell viability and proliferation were analyzed using CCK-8 and EdU assays, while lactate dehydrogenase (LDH), reactive oxygen species (ROS), glutathione (GSH), and iron levels were determined using corresponding kits. Moreover, dual-luciferase reporter and RNA pull-down assays were performed to demonstrate whether miR-673-5p is bound to circSlc8a1 or transferrin receptor (TFRC). Results: The results indicated that the expressions of circSlc8a1 and TFRC were increased, while miR-673-5p was decreased in the AngII treated H9c2 cells. The ferroptosis inhibitor treatment decreased the atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-major histocompatibility complex (β-MHC) protein expressions, and circSlc8a1 expressions. Knocking down of circSlc8a1 inhibited promoted the cell viability and proliferation, increased the GSH content, glutathione peroxidase 4, and solute carrier family 7 member 11 protein expressions, and decreased the LDH, ROS, iron levels, and RAS protein expressions. The MiR-673-5p inhibitor antagonized the role of si-circSlc8a1, and the over-expressed TFRC reversed the miR-673-5p mimicking effects in AngII treated H9c2 cells. Conclusion: CircSlc8a1 promoted the ferroptosis in CH via regulating the miR-673-5p/TFRC axis. [ABSTRACT FROM AUTHOR]

Background: The development of left ventricular (LV) remodeling has been associated with an increased cardiovascular risk and cardiogenic death, and different patterns of remodeling result in varying levels of prognosis. Objective: To investigate the association between different patterns of LV remodeling and clinical outcomes in the preclinical stage of patients with Duchenne muscular dystrophy (DMD). Materials and methods: A total of 148 patients with DMD and 43 sex- and age-matched healthy participants were enrolled. We used the four-quadrant analysis method to investigate LV remodeling based on cardiac magnetic resonance (MR) imaging. Kaplan-Meier curves were generated to illustrate the event-free survival probability stratified by the LV remodeling pattern. Cox regression models were constructed and compared to evaluate the incremental predictive value of the LV remodeling pattern. Results: During the median follow-up period of 2.2 years, all-cause death, cardiomyopathy, and ventricular arrhythmia occurred in 5, 35, and 7 patients, respectively. LV concentric hypertrophy (hazard ratio 2.91, 95% confidence interval 1.47–5.75, P=0.002) was an independent predictor of composite endpoint events. Compared to the model without LV concentric hypertrophy, the model with LV concentric hypertrophy had significant incremental predictive value (chi-square value 33.5 vs. 25.2, P=0.004). Conclusion: Age and late gadolinium enhancement positivity were positively correlated with clinical outcomes according to the prediction models. LV concentric hypertrophy was also an independent predictor for risk stratification and provided incremental value for predicting clinical outcomes in the preclinical stage of patients with DMD. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate whether deep learning–based detection algorithms (DLD)–based triaging can reduce outpatient chest radiograph interpretation workload while maintaining noninferior sensitivity. Methods: This retrospective study included patients who underwent initial chest radiography at the outpatient clinic between June 1 and June 30, 2017. Readers interpreted radiographs with/without a commercially available DLD that detects nine radiologic findings (atelectasis, calcification, cardiomegaly, consolidation, fibrosis, nodules, pneumothorax, pleural effusion, and pneumoperitoneum). The reading order was determined in a randomized, crossover manner. The radiographs were classified into negative and positive examinations. In a 50% worklist reduction scenario, radiographs were sorted in descending order of probability scores: the lower half was regarded as negative exams, while the remaining were read with DLD by radiologists. The primary analysis evaluated noninferiority in sensitivity between radiologists reading all radiographs and simulating a 50% worklist reduction, with the inferiority margin of 5%. The specificities were compared using McNemar's test. Results: The study included 1964 patients (median age [interquartile range], 55 years [40–67 years]). The sensitivity was 82.6% (195 of 236; 95% CI: 77.5%, 87.3%) when readers interpreted all chest radiographs without DLD and 83.5% (197 of 236; 95% CI: 78.8%, 88.1%) in the 50% worklist reduction scenario. The difference in sensitivity was 0.8% (95% CI: − 3.8%, 5.5%), establishing noninferiority of 50% worklist reduction (p = 0.01). The specificity increased from 86.7% (1498 of 1728) to 90.4% (1562 of 1728) (p < 0.001) with DLD-based triage. Conclusion: Deep learning–based triaging may substantially reduce workload without lowering sensitivity while improving specificity. Clinical relevance statement: Substantial workload reduction without lowering sensitivity was feasible using deep learning–based triaging of outpatient chest radiograph; however, the legal responsibility for incorrect diagnoses based on AI-standalone interpretation remains an issue that should be defined before clinical implementation. Key Points: • A 50% workload reduction simulation using deep learning–based detection algorithm maintained noninferior sensitivity while improving specificity. • The CT recommendation rate significantly decreased in the disease-negative patients, whereas it slightly increased in the disease-positive group without statistical significance. • In the exploratory analysis, the noninferiority of sensitivity was maintained until 70% of the workload was reduced; the difference in sensitivity was 0%. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a large class of endogenous single-stranded covalently closed RNA molecules. High-throughput RNA sequencing and bioinformatic algorithms have identified thousands of eukaryotic circRNAs characterized by high stability and tissue-specific expression pattern. Recent studies have shown that circRNAs play an important role in the regulation of physiological processes in the norm and in various diseases, including cardiovascular disorders. The review presents current concepts of circRNA biogenesis, structural features, and biological functions, describes the methods of circRNA analysis, and summarizes the results of studies on the role of circRNAs in the pathogenesis of hypertrophic cardiomyopathy, the most common inherited heart disease. [ABSTRACT FROM AUTHOR]

The aim of the present study is to investigate the ameliorative potential of the aqueous extract of Indigofera tinctoria (IT) in aging-induced inflammation and its associated cardiac hypertrophy and fibrosis. Young (3-month-old) and aged (24–26-month-old) male Wistar albino rats were grouped into young control, aged control, aged + IT, and young + IT. The animals in the supplementary groups received 200 mg/kg BWT of aqueous extract of IT orally once a day for 21 days. Aged animals showed prolonged QT interval and increased weight and volume of the heart with a thickening ventricular wall. Infiltration of leukocytes and increased cardiomyocyte diameter and decreased numerical density along with cardiomyocyte apoptosis and increased collagen accumulation were also seen in aged myocardium when compared to the young. The expression profile of various pro-inflammatory cytokines such as IL-6, IL-1β, TNF-α, NFκB, and iNOS was increased with a concomitant reduction in IL-10 expression in the aged compared to the young. In addition, a marked increase in ROS generation, TGF-β, and α-SMA levels is evident in the aged myocardium. These pathological changes were greatly reversed in aged animals supplemented with IT. Furthermore, the aged + IT group showed repression of pro-inflammatory markers with a subsequent increase in IL-10 expression. Contrarily, no marked changes were observed between young and young + IT groups. Taken together, it is concluded that the aqueous extract of Indigofera tinctoria suppresses cardiac fibrosis and hypertrophy by repressing the inflammation and its associated activation of TGFβ and myofibroblast conversion. [ABSTRACT FROM AUTHOR]

Cardiac ventricular dimensions measured at postmortem examination are used to assess whether there is hypertrophy of the heart chambers. However, there is no clear consensus on where these measurements should be taken. Some have proposed this should be measured at the mid-ventricular level, but others advocate it should be measured at a set distance (e.g. 20 mm) from the base of the heart. Twenty consecutive adult hearts were examined and showed the ventricular dimensions were significantly higher (mean: 5–15 mm, p < 0.01) when measured at a level 20 mm from the base of the heart compared to the mid-ventricular level. Of clinical significance is that in slightly less than half the cases, normal ventricular dimensions at mid ventricle level fell within the criteria considered pathological (> 40 mm) when measured at 20 mm from the base of the heart. In terms of actual ventricular dimensions, only the left ventricle diameter measured at 20 mm from the base of the heart correlated significantly (albeit moderately) with heart weight, suggesting it can be a predictor for cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Cardiac hypertrophy (CH) is an adaptational enlargement of the myocardium, in exposure to altered stress conditions or in case of injury which can lead to heart failure and death. MicroRNAs (miRNAs) are non-coding RNAs that play a significant role in modulating gene expression. Here, we aimed to identify new miRNAs effective in an experimental CH model and to find an epigenetic biomarker that could demonstrate therapeutic targets responsible for the pathology of heart tissue and serum. In this study, Sprague–Dawley male rats were divided into the training group (TG, n=9) and the control group (CG, n=6). Systolic and diastolic dimensions of the left ventricle and myocardial wall thickness were measured by echocardiography to assess CH. After the exercise program of the rats, miRNA expression measurements and histological analyses were performed. The 25,000 genes in the rat genome were searched using microarray analysis. A total of 128 miRNAs were selected according to the fold change rates, and nine miRNAs were validated for expression analysis. The terminal deoxynucleotidyl transferase dUTP nick (TUNEL) method was used to detect apoptotic cells. Cell proliferation was evaluated by the proliferative cell nuclear antigen (PCNA) method. Necrosis, bleeding, and intercellular edema were detected in TG. The mean histopathological score was higher in TG (p=0.03). There were rarely positive cells for apoptosis of both groups in cardiomyocytes. In the receiver characteristic curve analysis (ROC), the heart tissue rno-miR-290 had an area under the curve (AUC) of 0.920 with 100% sensitivity and 89.90% specificity (p=0.045), rno-miR-194-5p had AUC of 0.940 with 83.33% sensitivity and 100% specificity (p=0.003), and the serum rno-miR-132-3p AUC was 0.880 with 66.67% sensitivity and 100% specificity (p=0.004) in TG. miR-194-5p was used as a therapeutic target for remodeling the cardiac process. While miR-290 contributes to CH as a negative regulator, miR-132 in serum is effective in the pathological and physiological cardiac remodeling process and is a candidate biomarker. [ABSTRACT FROM AUTHOR]

The aim of the present study is to investigate the ameliorative potential of the aqueous extract of Indigofera tinctoria (IT) in aging-induced inflammation and its associated cardiac hypertrophy and fibrosis. Young (3-month-old) and aged (24–26-month-old) male Wistar albino rats were grouped into young control, aged control, aged + IT, and young + IT. The animals in the supplementary groups received 200 mg/kg BWT of aqueous extract of IT orally once a day for 21 days. Aged animals showed prolonged QT interval and increased weight and volume of the heart with a thickening ventricular wall. Infiltration of leukocytes and increased cardiomyocyte diameter and decreased numerical density along with cardiomyocyte apoptosis and increased collagen accumulation were also seen in aged myocardium when compared to the young. The expression profile of various pro-inflammatory cytokines such as IL-6, IL-1β, TNF-α, NFκB, and iNOS was increased with a concomitant reduction in IL-10 expression in the aged compared to the young. In addition, a marked increase in ROS generation, TGF-β, and α-SMA levels is evident in the aged myocardium. These pathological changes were greatly reversed in aged animals supplemented with IT. Furthermore, the aged + IT group showed repression of pro-inflammatory markers with a subsequent increase in IL-10 expression. Contrarily, no marked changes were observed between young and young + IT groups. Taken together, it is concluded that the aqueous extract of Indigofera tinctoria suppresses cardiac fibrosis and hypertrophy by repressing the inflammation and its associated activation of TGFβ and myofibroblast conversion. [ABSTRACT FROM AUTHOR]

Regulation of RNA stability and translation by RNA-binding proteins (RBPs) is a crucial process altering gene expression. Musashi family of RBPs comprising Msi1 and Msi2 is known to control RNA stability and translation. However, despite the presence of MSI2 in the heart, its function remains largely unknown. Here, we aim to explore the cardiac functions of MSI2. We confirmed the presence of MSI2 in the adult mouse, rat heart, and neonatal rat cardiomyocytes. Furthermore, Msi2 was significantly enriched in the heart cardiomyocyte fraction. Next, using RNA-seq data and isoform-specific PCR primers, we identified Msi2 isoforms 1, 4, and 5, and two novel putative isoforms labeled as Msi2 6 and 7 to be expressed in the heart. Overexpression of Msi2 isoforms led to cardiac hypertrophy in cultured cardiomyocytes. Additionally, Msi2 exhibited a significant increase in a pressure-overload model of cardiac hypertrophy. We selected isoforms 4 and 7 to validate the hypertrophic effects due to their unique alternative splicing patterns. AAV9-mediated overexpression of Msi2 isoforms 4 and 7 in murine hearts led to cardiac hypertrophy, dilation, heart failure, and eventually early death, confirming a pathological function for Msi2. Using global proteomics, gene ontology, transmission electron microscopy, seahorse, and transmembrane potential measurement assays, increased MSI2 was found to cause mitochondrial dysfunction in the heart. Mechanistically, we identified Cluh and Smyd1 as direct downstream targets of Msi2. Overexpression of Cluh and Smyd1 inhibited Msi2-induced cardiac malfunction and mitochondrial dysfunction. Collectively, we show that Msi2 induces hypertrophy, mitochondrial dysfunction, and heart failure. [ABSTRACT FROM AUTHOR]

During autopsies, weighing the heart is a standard procedure. In addition to myocardial pathologies, heart size, and ventricular wall thickness, heart weight is a common parameter to describe cardiac pathology and should be recorded as accurately as possible. To date, there exists no standard for recording heart weight at autopsy, although some authors recommend weighing the heart after dissection and removal of blood and blood clots. In the study presented, the hearts of 58 decedents were weighed after being dissected out of the pericardial sac (a), after dissection using the short-axis or inflow-outflow method with manual removal of blood and blood clots (b), and after rinsing and drying (c). Depending on the dissection method, the heart weight was 7.8% lower for the inflow-outflow method and 11.6% lower for the short-axis method after dissection compared to before and correspondingly 2.9% to 5% lower again after rinsing and drying respectively. Accordingly, the heart should be dissected, blood and blood clots removed, rinsed with water, and dried with a surgical towel after dissection, before weighing. [ABSTRACT FROM AUTHOR]

Ventricular remodeling is one of the main causes of mortality from heart failure due to hypertension. Exploring its mechanism and finding therapeutic targets have become urgent scientific problems to be solved. A number of studies have shown that Mas, as an Ang-(1-7) specific receptor, was significantly reduced in myocardial tissue of rats undergoing hypertensive ventricular remodeling. It has been reported that Mas receptor levels are significantly downregulated in myocardium undergoing ventricular remodeling, but studies focused on intracellular and post-translational modifications of Mas are lacking. The results of this research are as follows: (1) PDZK1 interacts with the carboxyl terminus of Mas through its PDZ1 domain; (2) the expression of PDZK1 and Mas is decreased in rats undergoing hypertensive ventricular remodeling, and PDZK1 upregulation can ameliorate hypertensive myocardial fibrosis and myocardial hypertrophy; (3) PDZK1 enhances the stability of Mas protein through the proteasome pathway, and the proteasome inhibitor MG132 promotes hypertensive ventricular remodeling. PDZK1 improves ventricular remodeling in hypertensive rats by regulating Mas receptor stability. This study provides a scientific basis for the prevention and treatment of ventricular remodeling. [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy (HCM) is a complicated, heterogeneous genetic condition that causes left ventricular hypertrophy, fibrosis, hypercontractility, and decreased compliance. Despite the advances made over the past 3 decades in understanding the molecular and cellular mechanisms aggravating HCM, the relationship between pathophysiological stress stimuli and distinctive myocyte growth profiles is still imprecise. Currently, mavacamten, a selective and reversible inhibitor of cardiac myosin ATPase, is the only drug approved by the US FDA for the treatment of HCM. Thus, there is an unmet need for developing novel disease-specific therapeutic approaches. This article provides an overview of emerging therapeutic targets for the treatment of HCM based on various molecular pathways and novel developments that are hopefully soon to enter the clinical study. These newly discovered targets include the dual specificity tyrosine-phosphorylation-regulated kinase 1B, the absence of the melanoma 1 inflammasome, the leucine-rich repeat kinase 2 enzyme, and the cluster of differentiation 147. [ABSTRACT FROM AUTHOR]

Population aging combined with higher susceptibility to cardiovascular diseases in older adults is increasing the incidence of conditions such as atherosclerosis, myocardial infarction, heart failure, myocardial hypertrophy, myocardial fibrosis, arrhythmia, and hypertension. sodium–glucose cotransporter 2 inhibitors (SGLT2i) were originally developed as a novel oral drug for patients with type 2 diabetes mellitus. Unexpectedly, recent studies have shown that, beyond their effect on hyperglycemia, SGLT2i also have a variety of beneficial effects on cardiovascular disease. Experimental models of cardiovascular disease have shown that SGLT2i ameliorate the process of aging-related cardiovascular disease by inhibiting inflammation, reducing oxidative stress, and reversing endothelial dysfunction. In this review, we discuss the role of SGLT2i in aging-related cardiovascular disease and propose the use of SGLT2i to prevent and treat these conditions in older adults. [ABSTRACT FROM AUTHOR]

Friedreich's ataxia (FRDA) is the most common inherited recessive ataxia. Cardiomyopathy (CM) with myocardial hypertrophy is the predominant cause of death. The presence of CM is variable and the risk factors for cardiac involvement are not entirely clear. Markers of collagen degradation, such as C-terminal cross-linked telopeptide of type I collagen (CTX-I), seem to be associated with unfavorable cardiovascular outcomes. The aim of our study was to measure serum CTX-I as a marker of cardiac fibrosis in FRDA patients. We measured serum CTX value in twenty-five FRDA patients (mean age, 31.3 ± 14.7 years) and nineteen healthy controls (mean age, 34.0 ± 13.5 years). Patients underwent echocardiography and SARA scale evaluation. CTX values were significantly higher in the patients than in the control group (31.82 ± 2.27 vs 16.44 ± 1.6 μg/L; p = 0.006). CTX-I was inversely correlated with age (R = − 0,535; n = 44; p < 0.001). The regression model identified disease duration and TT3 levels to be independent predictors of CTX-I (model R2 = 0.938; intercept − 64.0, p = 0.071; disease duration coefficient = − 2.34, p = 0.005; TT3 coefficient = 127.17, p = 0.011). CTX-I, a biomarkers of collagen turnover, is elevated in FRDA and should provide complementary information to identify patients with high cardiological risk even if longitudinal studies are needed to define the role of this serologic marker of collagen metabolism in the natural history of cardiomyopathy in FRDA patients. [ABSTRACT FROM AUTHOR]

Background: Cardiac hypertrophy, which develops in middle-aged and older individuals as a consequence of hypertension and obesity, is an established risk factor for sudden cardiac death (SCD). However, it is sometimes difficult to differentiate SCD with acquired cardiac hypertrophy (SCH) from compensated cardiac hypertrophy (CCH), at autopsy. We aimed to elucidate the proteomic alteration in SCH, which can be a guideline for future postmortem diagnosis. Methods: Cardiac tissues were sampled at autopsy. SCH group consisted of ischemic heart failure, hypertensive heart failure, and aortic stenosis. CCH group included cases of non-cardiac death with cardiac hypertrophy. The control group comprised cases of non-cardiac death without cardiac hypertrophy. All patients were aged > 40 years, and hypertrophic cardiomyopathy was not included in this study. We performed histological examination and shotgun proteomic analysis, followed by quantitative polymerase chain reaction analysis. Results: Significant obesity and myocardial hypertrophy, and mild myocardial fibrosis were comparable in SCH and CCH cases compared to control cases. The proteomic profile of SCH cases was distinguishable from those of CCH and control cases, and many sarcomere proteins were increased in SCH cases. Especially, the protein and mRNA levels of MYH7 and MYL3 were significantly increased in SCH cases. Conclusion: This is the first report of cardiac proteomic analysis in SCH and CCH cases. The stepwise upregulation of sarcomere proteins may increase the risk for SCD in acquired cardiac hypertrophy before cardiac fibrosis progresses significantly. These findings can possibly aid in the postmortem diagnosis of SCH in middle-aged and older individuals. [ABSTRACT FROM AUTHOR]

Aficamten is a novel cardiac myosin inhibitor that has demonstrated its ability to safely lower left ventricular outflow tract (LVOT) gradients and improve heart failure symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM). Based on the REDWOOD-HCM open label extension (OLE) study, participants receiving aficamten had significantly reduced resting and Valsalva LVOT gradient within 2 weeks after initiating treatment, with ongoing improvements over 24 weeks, and recent evidence suggests effects can sustain up to 48 weeks. While beta-blockers, calcium channel blockers, and disopyramide have shown some benefits in managing HCM, they have limited direct impact on the underlying disease process in patients with obstructive HCM. Aficamten achieves its therapeutic effect by reducing hypercontractility and improving diastolic function in obstructive HCM. Mavacamten was the first cardiac myosin inhibitor approved for symptomatic obstructive HCM. However, aficamten has a shorter human half-life (t1/2) and fewer drug–drug interactions, making it a preferable treatment option. This review evaluates the long-term clinical value and safety of aficamten in patients with obstructive HCM based on available data from completed and ongoing clinical trials. Additionally, the molecular basis of sarcomere-targeted therapy in reducing LVOT gradients is explored, and its potential in managing obstructive HCM is discussed. [ABSTRACT FROM AUTHOR]

Patients with chronic kidney disease (CKD) confront with cardiovascular disease (CVD) complications which can be ameliorated with exercise. The purpose of the current study was to determine the effect of resistance training on pathological cardiac hypertrophy and FGF23-Klotho axis-induced adverse cardiovascular outcomes in rat model of CKD. Thirty male Wistar rats (7–8 weeks old) were randomly divided into three groups of the 5/6 nephrectomy (5/6NX) with and without resistance training and control group. The resistance training protocol consisted of 3 sessions per week. The proposed blood factors (Klotho, FGF23, serum phosphorus, parathyroid hormone, serum calcium, and vitamin D) evaluated for three groups at the end of 8th week. After confirming the normal distribution of data through Kolmogorov–Smirnov test, data analysis was performed by one-way ANOVA and Bonferroni post hoc test (P > 0.05). The effect of resistance training was significantly different between 3 groups of study for hypertrophy (P = 0.036) and cardiac function (P = 0.004). There was also a significant difference for blood factors of Klotho (P = 0.000), FGF23 (P = 0.043), serum phosphorus (P = 0.00), and parathyroid (P = 0.00). Serum calcium (P = 0.06) and vitamin D status (P = 0.06) improved but the differences were not significant. Resistance training can prevent progression of pathological cardiac hypertrophy in patients with renal disease. In the process of this improvement, changes in FGF23 and Klotho were significant; however, the vitamin D and calcium have played a less important role. [ABSTRACT FROM AUTHOR]

Coumarin, a plant secondary metabolite, has various pharmacological activities, including antioxidant stress and anti-inflammatory effects. Umbelliferone, a common coumarin compound found in almost all higher plants, has been extensively studied for its pharmacological effects in different disease models and doses with complex action mechanisms. This review aims to summarize these studies and provide useful information to relevant scholars. The pharmacological studies demonstrate that umbelliferone has diverse effects such as anti-diabetes, anti-cancer, anti-infection, anti-rheumatoid arthritis, neuroprotection, and improvement of liver, kidney, and myocardial tissue damage. The action mechanisms of umbelliferone include inhibition of oxidative stress, inflammation, and apoptosis, improvement of insulin resistance, myocardial hypertrophy, and tissue fibrosis, in addition to regulation of blood glucose and lipid metabolism. Among the action mechanisms, the inhibition of oxidative stress and inflammation is the most critical. In short, these pharmacological studies disclose that umbelliferone is expected to treat many diseases, and more research should be conducted. [ABSTRACT FROM AUTHOR]

Mavacamten (Camzyos®), an oral, once-daily cardiac myosin inhibitor, is an important new option for the treatment of patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM). In the USA, mavacamten is the first approved drug for the treatment of adults with symptomatic New York Heart Association (NYHA) class II–III obstructive HCM to improve functional capacity and symptoms. In a pivotal phase 3 trial in this patient population, mavacamten improved exercise capacity, symptom burden, and left ventricular outflow tract obstruction compared with placebo. Mavacamten was generally well tolerated, with the most common adverse events being dizziness and syncope. Longer-term data up to 84 weeks demonstrated that the efficacy of mavacamten was maintained with no new safety concerns. Mavacamten may increase the risk of heart failure due to systolic dysfunction and therefore, individualized dosage and close monitoring is required. Plain Language Summary: Obstructive hypertrophic cardiomyopathy (HCM) is a heart disorder characterized by increased contractility, thickening of the left ventricle wall, and left ventricular outflow tract obstruction. Symptoms of obstructive HCM include chest pain and shortness of breath during physical activity. Mavacamten (Camzyos®) is the first drug specifically approved for obstructive HCM in adults, which reduces contractility by inhibiting cardiac myosin. In a clinical trial, mavacamten improved exercise capacity and symptoms in patients with obstructive HCM and New York Heart Association (NYHA) class II–III symptoms. Mavacamten was generally well tolerated. Data up to 84 weeks from the long-term extension study show that the efficacy and tolerability of mavacamten were sustained. Given that mavacamten may increase the risk of heart failure due to systolic dysfunction, it should be administered at an individualized dosage with close monitoring. Mavacamten is an important new treatment option for patients who experience symptoms due to obstructive HCM. [ABSTRACT FROM AUTHOR]

Objective: C1q/tumour necrosis factor-related protein 12 (CTRP12) is closely related to coronary artery disease and has an outstanding cardioprotective effect. However, whether CTRP12 participates in heart failure (HF) has not been well studied. This work aimed to explore the role and mechanism of CTRP12 in post-myocardial infarction (MI) HF. Methods: Rats were subjected to left anterior descending artery ligation and then raised for six weeks to establish post-MI HF. Recombinant adeno-associated virus-mediated gene transfer was applied to overexpress or silence CTRP12 in rat hearts. RT-qPCR, Immunoblot, Echocardiography, Haematoxylin–eosin (HE) staining, Masson's trichrome staining, TUNEL staining and ELISA were carried out. Results: CTRP12 levels were decreased in the hearts of rats with post-MI HF. The overexpression of CTRP12 improved cardiac function and attenuated cardiac hypertrophy and fibrosis in rats with post-MI HF. CTRP12 silencing exacerbated cardiac dysfunction, hypertrophy and fibrosis in rats with post-MI HF. The cardiac apoptosis, oxidative stress and inflammatory response induced by post-MI HF were weakened by CTRP12 overexpression or aggravated by CTRP12 silencing. CTRP12 inhibited the activation of the transforming growth factor‐β activated kinase 1 (TAK1)-p38 mitogen‐activated protein kinase (MAPK)/c‐Jun N‐terminal kinase (JNK) pathway in the hearts of rats with post-MI HF. Treatment with the TAK1 inhibitor reversed the adverse effects of CTRP12 silencing on post-MI HF. Conclusions: CTRP12 protects against post-MI HF by modulating the TAK1-p38 MAPK/JNK pathway. CTRP12 may be a therapeutic target for the treatment of post-MI HF. [ABSTRACT FROM AUTHOR]

Background: In the neonatal period, cardiac hypertrophy (CH) has been commonly associated with hyperinsulinemic pathologies, and the first case of CH in an extremely preterm infant treated with insulin infusion has recently been reported. To confirm this association, we report a case series of patients who developed CH after insulin therapy. Methods: Infants with gestational age < 30 weeks and birth weight < 1500 g, born from November 2017 to June 2022, were studied if they developed hyperglycemia requiring treatment with insulin and had echocardiographic diagnosis of CH. Results: We studied 10 extremely preterm infants (24.3 ± 1.4 weeks) who developed CH at a mean age of 124 ± 37 h of life, 98 ± 24 h after the initiation of insulin therapy. All surviving patients had resolution of CH at discharge, while three of four (75%) of the deceased patients had persistent CH. Conclusions: Our case series supports the association between the development of CH and insulin therapy in extremely preterm infants and suggests further caution and the need for echocardiographic monitoring when treating these fragile patients with insulin. [ABSTRACT FROM AUTHOR]

Peritoneal dialysis (PD) is associated with increased cardiovascular (CV) risk. Studies of PD-related CV pathology in animal models are lacking despite the clinical importance. Here we introduce the phenotypic evaluation of a rat model of cardiorenal syndrome in response to chronic PD, complemented by a rich transcriptomic dataset detailing chronic PD-induced changes in left ventricle (LV) and kidney tissues. This study aims to determine how PD alters CV parameters and risk factors while identifying pathways for potential therapeutic targets. Sprague Dawley rats underwent Sham or 5/6 nephrectomy (5/6Nx) at 10 weeks of age. Six weeks later an abdominal dialysis catheter was placed in all rats before random assignment to Control or PD (3 daily 1-h exchanges) groups for 8 days. Renal and LV pathology and transcriptomic analysis was performed. The PD regimen reduced circulating levels of BUN in 5/6Nx, indicating dialysis efficacy. PD did not alter blood pressure or cardiovascular function in Sham or 5/6Nx rats, though it attenuated cardiac hypertrophy. Importantly PD increased serum triglycerides in 5/6Nx rats. Furthermore, transcriptomic analysis revealed that PD induced numerous changed transcripts involved with inflammatory pathways, including neutrophil activation and atherosclerosis signaling. We have adapted a uremic rat model of chronic PD. Chronic PD induced transcriptomic changes related to inflammatory signaling that occur independent of 5/6Nx and augmented circulating triglycerides and predicted atherosclerosis signaling in 5/6Nx LV tissues. The changes are indicative of increased CV risk due to PD and highlight several pathways for potential therapeutic targets. [ABSTRACT FROM AUTHOR]

TRIM-containing 44 (TRIM44) is a promoter of multiple cancers. However, its role in cardiac hypertrophy has not been elucidated. This study explored the role of TRIM44 on pressure overload-induced cardiac hypertrophy in mice. Mice were subjected to aortic banding to establish an adverse cardiac hypertrophy model, followed by the administration of AAV9-TRIM44 or AAV9shTRIM44 to overexpress or knock down TRIM44. Echocardiography was used to assess cardiac function. H9c2 cells were cultured and transfected with either Ad-TRIM44 or TRIM44 siRNA to overexpress or silence TRIM44. Cells were also stimulated with angiotensin II to establish a cardiomyocyte hypertrophy model. Results indicated that TRIM44 was downregulated in mice hearts and cardiomyocytes that were treated with aortic banding or angiotensin II. TRIM44 overexpression in mice hearts aggravated cardiac hypertrophy and fibrosis, as well as inhibited cardiac function post-aortic banding. Moreover, mice with TRIM44 overexpression displayed increased ferroptosis post-aortic banding. Mice with TRIM44 knockdown revealed ameliorated cardiac hypertrophy, ferroptosis, and fibrosis, as well as improved cardiac function post-aortic banding. In H9c2 cells transfected with Ad-TRIM44, angiotensin II-induced ferroptosis was enhanced, while cells with silenced TRIM44 reported reduced ferroptosis post-angiotensin II administration. Furthermore, TRIM44 interacted with TLR4, which increased the expression of NOX4 and subsequently augmented ferroptosis-associated protein levels. By using TLR4 knockout mice, the inhibitory role of TRIM44 was reduced post-aortic banding. Taken together, TRIM44 aggravated pressure overload-induced cardiac hypertrophy via increased TLR4/NOX4-associated ferroptosis. Key messages: TRIM44 could aggregate pressure overload-induced cardiac hypertrophy via increasing TLR4-NOX4 associated ferroptosis. Target TRIM44 may become a new therapeutic method for preventing or treating pressure overload-induced cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Pathological cardiac hypertrophy is the main predecessor of heart failure. Its pathology is sophisticated, and its progression is associated with multiple cellular processes. To explore new therapeutic approaches, more precise examination of cardiomyocyte subtypes and involved biological processes is required in response to hypertrophic stimuli. Mitochondria and the endoplasmic reticulum (ER) are two crucial organelles associated with the progression of cardiac hypertrophy and are connected through junctions known as mitochondria-associated endoplasmic reticulum membranes (MAMs). Although MAM genes are altered in cardiac hypertrophy, the importance of MAMs in cardiac hypertrophy and the expression pattern of MAMs in certain cardiac cell types require a comprehensive analysis. In this study, we analyzed the temporal expression of MAM proteins in the process of cardiac hypertrophy and observed that MAM-related proteins preferentially accumulated in cardiomyocytes at the initial stage of cardiac hypertrophy and underwent a gradual decline, which was synchronized with the proportion of two cardiomyocyte subtypes (CM2 and CM3). Meanwhile, these subtypes went through a functional switch during cardiac hypertrophy. Trajectory analysis suggested that there was a differentiation trajectory of cardiomyocyte subtypes from high to low MAM protein expression. Distinct regulon modules across different cardiomyocyte cell types were revealed by transcriptional regulatory network analysis. Furthermore, scWGCNA revealed that MAM-related genes were clustered into a module that correlated with diabetic cardiomyopathy. Altogether, we identified cardiomyocyte subtype transformation and the potential critical transcription factors involved, which may serve as therapeutic targets in combating cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

SMYD1, a striated muscle-specific lysine methyltransferase, was originally shown to play a key role in embryonic cardiac development but more recently we demonstrated that loss of Smyd1 in the murine adult heart leads to cardiac hypertrophy and failure. However, the effects of SMYD1 overexpression in the heart and its molecular function in the cardiomyocyte in response to ischemic stress are unknown. In this study, we show that inducible, cardiomyocyte-specific overexpression of SMYD1a in mice protects the heart from ischemic injury as seen by a > 50% reduction in infarct size and decreased myocyte cell death. We also demonstrate that attenuated pathological remodeling is a result of enhanced mitochondrial respiration efficiency, which is driven by increased mitochondrial cristae formation and stabilization of respiratory chain supercomplexes within the cristae. These morphological changes occur concomitant with increased OPA1 expression, a known driver of cristae morphology and supercomplex formation. Together, these analyses identify OPA1 as a novel downstream target of SMYD1a whereby cardiomyocytes upregulate energy efficiency to dynamically adapt to the energy demands of the cell. In addition, these findings highlight a new epigenetic mechanism by which SMYD1a regulates mitochondrial energetics and functions to protect the heart from ischemic injury. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) frequently complicates hypertrophic cardiomyopathy (HCM), and anticoagulation significantly decreases the risk of stroke in this population. To date, no randomized controlled trials (RCTs) have compared direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs). The present study aimed to systematically compare the two anticoagulation strategies in terms of effectiveness and safety. Method: We performed a systematic literature search and meta-analysis in the PubMed, MEDLINE, and EMBASE databases for studies reporting all-cause mortality, major bleeding, or thromboembolic events (TEs). Since no RCTs were available, we included observational studies only. The overall hazard ratio (HR) and 95% confidence interval (CI) for each analyzed parameter were pooled using a random-effects model. Results: Five observational studies including 6919 patients were eligible for inclusion. Compared with VKAs, DOACs were associated with statistically significant lower rates of all-cause mortality (HR 0.64, 95% CI 0.35–0.54; p < 0.00001), comparable major bleeding events (HR 0.64, 95% CI 0.40–1.03; p = 0.07), and TEs (HR 0.94, 95% CI 0.73–1.22; p = 0.65). Conclusions: Compared with VKAs, a DOAC-based strategy might represent an effective and safe strategy regarding all-cause mortality, major/life-threatening bleeding complications, and TEs in HCM patients with concomitant AF. However, further prospective studies are necessary to reinforce a DOAC-based anticoagulation strategy in this population. [ABSTRACT FROM AUTHOR]

Building a reliable and precise model for disease classification and identifying abnormal sites can provide physicians assistance in their decision-making process. Deep learning based image analysis is a promising technique for enriching the decision making process, and accordingly strengthening patient care. This work presents a convolutional attention mapping deep learning model, Cardio-XAttentionNet, to classify and localize cardiomegaly effectively. We revisit the global average pooling (GAP) system and add a weighting term to develop a light and effective Attention Mapping Mechanism (AMM). The model enables the classification of cardiomegaly from chest X-rays through image-level classification and pixel-level localization only from image-level labels. We leverage some of the advanced ConvNet architectures as a backbone-model of the proposed attention mapping network to build Cardio-XAttentionNet. The proposed model is trained on ChestX-Ray14, which is a publicly accessible chest X-ray dataset. The best single model achieves an overall precision, recall, F-1 measure and area under curve (AUC) scores of 0.87, 0.85, 0.86 and 0.89, respectively, for the classification of the cardiomegaly. The results also demonstrate that the Cardio-XAttentionNet model well captures the cardiomegaly class information at image-level as well as localization at pixel-level on chest x-rays. A comparative analysis between the proposed AMM and existing GAP based models shows that the proposed model achieves a state-of-the-art performance on this dataset for cardiomegaly detection using a single model. [ABSTRACT FROM AUTHOR]

Background: Assessment of fluid status in neonatal dialysis has largely focused on traditional tools including clinical assessment, serial weights, and blood pressure (BP) measurements. However, in infants on kidney replacement therapy, the assessment of fluid overload is problematic due to errors in weight assessment, subtlety of physical exam findings, and inaccuracy of non-invasive BP measurements. Case summary: In this presentation of a neonate with bilateral renal agenesis requiring kidney replacement therapy, the treating team assessed a number of variables in determining the ultrafiltration prescription for dialysis across 2 modalities (hemodialysis and continuous kidney replacement therapy). Complications: Fluid overload, cardiomegaly, and worsened respiratory status occurred when attempting to assess the neonate's fluid status by traditional markers (weights, blood pressures, physical exam findings). B-type natriuretic peptide (BNP) was obtained and was noted to correlate with the degree of fluid overload. Key management points: Compared to traditional tools for assessment of fluid status in pediatric dialysis, BNP assisted the medical team in optimizing the volume status of the subject and determining optimal daily ultrafiltration goals. Due to the rapid release in response to myocardial stretch and the lack of kidney clearance of the peptide, BNP may represent an objective, timely, and reliable index of volume status in the pediatric dialysis patient. [ABSTRACT FROM AUTHOR]

We explored the anti-cardiac hypertrophy mechanism of glycyrrhizic acid from the perspective of calcium regulation under pathological conditions. For this purpose, we used a rat model of myocardial hypertrophy induced by pressure overload. The effect of glycyrrhizic acid on BP was measured non-invasively with a sphygmomanometer and recorded in PC. In rats with modeled cardiac hypertrophy, the effect of GA on expression of type 1 matrix interaction molecules was determined in horizontal tissues and cultured cardiomyocytes of the left ventricle. The laser confocal microscopy and calcium ion probe Fluo-4 AM were used to assess the effect of glycyrrhizic acid on stromal interaction molecule 1 (STIM1)-dependent store-operated calcium entry in cultured cardiomyocytes derived from the hypertrophic myocardium. Glycyrrhizic acid exerted the anti-hypertrophic effect in rats with hypertrophic myocardium by down-regulating STIM1 protein expression and reducing the intensity of STIM1-dependent store-operated calcium entry. [ABSTRACT FROM AUTHOR]

Type 2 Diabetes Mellitus (T2DM) and cardiac hypertrophy (CH) are among the top ten leading cause of deaths, worldwide. T2DM and cardiac hypertrophy are the chronic diseases, have close association and direct life-threatening complications like stroke, myocardial infarction, retinopathy, nephropathy, and limb amputation. In addition to other medical approaches, miRNAs-based strategy is considered most efficient for early detection of chronic diseases and also has potential for the treatment of T2DM and cardiac hypertrophy like it is being used for cancer in clinical trials. MicroRNAs (miRNAs) are single stranded (non-coding) of 20 to 22 nucleotides sequences which bind to their target mRNA upon the complimentary basis, to silence the protein expression at post transcriptional level. Bioinformatic databases are used like online mendelian inheritance in man (OMIM), gene testing registry (GTR), TargetScan and ShinyGO for validation of disease linked genes and sorting the common miRNAs in both diseases, such as miR-30-5p/101-3p.2/190-5p/506-3p/9-5p/128-3p/137/96-5p/7-5p/107/101-3p.1/98-5p/124-3p.2/124-3p.116-5p/15-5p/497-5p/ 424-5p/195-5p/1271-5p, let-7-5p. Aforementioned databases were also used for the miRNAs which have more than one disease linked genes target in each pathological condition. Such miRNAs for cardiac hypertrophy are: miR-19-3p/183-5p.2/153-3p/372-3p/302-3p/520-3p/373-3p/129-5p/144-3p/139-5p and for T2DM are: miR-27-3p/206/1-3p/181-5p. This finding would be helpful for the appropriate selection of miRNAs and to design applicable research project in future. It will require more validation by using the miRNAs expression analysis, mimic, and anti-miRNA approach to check their potential against cardiac hypertrophy and T2DM. [ABSTRACT FROM AUTHOR]

NIMA (never in mitosis, gene A)-related kinase-6 (NEK6), a cell cycle regulatory gene, was found to regulate cardiac hypertrophy. However, its role in diabetes-induced cardiomyopathy has not been fully elucidated. This research was designed to illustrate the effect of NEK6 involved in diabetic cardiomyopathy. Here we used a streptozotocin (STZ)-induced mice diabetic cardiomyopathy model and NEK6 knockout mice to explore the role and mechanism of NEK6 in diabetic-induced cardiomyopathy. NEK6 knockout mice and wild-type littermates were subjected to STZ injection (50 mg/kg/day for 5 days) to induce a diabetic cardiomyopathy model. As a result, 4 months after final STZ injection, DCM mice revealed cardiac hypertrophy, fibrosis, and systolic and diastolic dysfunction. NEK6 deficiency causes deteriorated cardiac hypertrophy, fibrosis, and cardiac dysfunction. Furthermore, we observed inflammation and oxidative stress in the hearts of NEK6 deficiency mice under diabetic cardiomyopathy pathology. Adenovirus was used to upregulate NEK6 in neonatal rat cardiomyocytes, and it was found that NEK6 ameliorated high glucose-induced inflammation and oxidative stress. Our findings revealed that NEK6 increased the phosphorylation of heat shock protein 72 (HSP72) and increased the protein level of PGC-1α and NRF2. Co-IP assay experiment confirmed that NEK6 interacted with HSP72. When HSP72 was silenced, the anti-inflammation and anti-oxidative stress effects of NEK6 were blurred. In summary, NEK6 may protect diabetic-induced cardiomyopathy by interacting with HSP72 and promoting the HSP72/PGC-1α/NRF2 signaling. Key messages: NEK6 knockout deteriorated cardiac dysfunction, cardiac hypertrophy, fibrosis as well as inflammation response, and oxidative stress. NEK6 overexpression attenuated high glucose induced inflammation and oxidative stress. The underlying mechanisms of the protective role of NEK6 in the development of diabetic cardiomyopathy seem to involve the regulation of HSP72-NRF2- PGC-1α pathway. NEK6 may become a new therapeutic target for diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Protein kinase D (PrKD), a novel serine-threonine kinase, belongs to a family of calcium calmodulin kinases that consists of three isoforms: PrKD1, PrKD2, and PrKD3. The PrKD isoforms play a major role in pathologic processes such as cardiac hypertrophy and cancer progression. The charter member of the family, PrKD1, is the most extensively studied isoform. PrKD play a dual role as both a proto-oncogene and a tumor suppressor depending on the cellular context. The duplicity of PrKD can be highlighted in advanced prostate cancer (PCa) where expression of PrKD1 is suppressed whereas the expressions of PrKD2 and PrKD3 are upregulated to aid in cancer progression. As understanding of the PrKD signaling pathways has been better elucidated, interest has been garnered in the development of PrKD inhibitors. The broad-spectrum kinase inhibitor staurosporine acts as a potent PrKD inhibitor and is the most well-known; however, several other novel and more specific PrKD inhibitors have been developed over the last two decades. While there is tremendous potential for PrKD inhibitors to be used in a clinical setting, none has progressed beyond preclinical trials due to a variety of challenges. In this review, we focus on PrKD signaling in PCa and the potential role of PrKD inhibitors therein, and explore the possible clinical outcomes based on known function and expression of PrKD isoforms at different stages of PCa. [ABSTRACT FROM AUTHOR]

In mammalian mitochondria, translation of the AUA codon is supported by 5-formylcytidine (f5C) modification in the mitochondrial methionine tRNA anticodon. The 5-formylation is initiated by NSUN3 methylase. Human NSUN3 mutations are associated with mitochondrial diseases. Here we show that Nsun3 is essential for embryonic development in mice with whole-body Nsun3 knockout embryos dying between E10.5 and E12.5. To determine the functions of NSUN3 in adult tissue, we generated heart-specific Nsun3 knockout (Nsun3HKO) mice. Nsun3HKO heart mitochondria were enlarged and contained fragmented cristae. Nsun3HKO resulted in enhanced heart contraction and age-associated mild heart enlargement. In the Nsun3HKO hearts, mitochondrial mRNAs that encode respiratory complex subunits were not down regulated, but the enzymatic activities of the respiratory complexes decreased, especially in older mice. Our study emphasizes that mitochondrial tRNA anticodon modification is essential for mammalian embryonic development and shows that tissue-specific loss of a single mitochondrial tRNA modification can induce tissue aberration that worsens in later adulthood. A mitochondrial tRNA modification enzyme, NSUN3, is found to be essential for embryonic development in mice, with whole-body knockout causing embryonic lethality and heart-specific Nsun3 knockout leading to heart aberration in older mice. [ABSTRACT FROM AUTHOR]

Fabry disease (FD) is a rare lysosomal storage disorder resulting in myocardial sphingolipid accumulation which is detectable by cardiovascular magnetic resonance as low native T1. However, myocardial T1 contains signal from intramyocardial blood which affects variability and consequently measurement precision and accuracy. Correction of myocardial T1 by blood T1 increases precision. We therefore deployed a multicenter study of FD patients (n = 218) and healthy controls (n = 117) to investigate if blood-correction of myocardial native T1 increases the number of FD patients with low T1, and thus reclassifies FD patients as having cardiac involvement. Cardiac involvement was defined as a native T1 value 2 standard deviations below site-specific means in healthy controls for both corrected and uncorrected measures. Overall low T1 was 135/218 (62%) uncorrected vs. 145/218 (67%) corrected (p = 0.02). With blood-correction, 13/83 previously normal patients were reclassified to low T1. This reclassification appears clinically relevant as 6/13 (46%) of reclassified had focal late gadolinium enhancement or left ventricular hypertrophy as signs of cardiac involvement. Blood-correction of myocardial native T1 increases the proportion of FD subjects with low myocardial T1, with blood-corrected results tracking other markers of cardiac involvement. Blood-correction may potentially offer earlier detection and therapy initiation, but merits further prospective studies. [ABSTRACT FROM AUTHOR]

Pathological remodeling of the extracellular matrix is a hallmark of cardiovascular disease. Abnormal fibrosis causes cardiac dysfunction by reducing ejection fraction and impairing electrical conductance, leading to arrhythmias. Hence, accurate quantification of fibrosis deposition in histological sections is of extreme importance for preclinical and clinical studies. Current automatic tools do not perform well under variant conditions. Moreover, users do not have the option to evaluate data from staining methods of their choice according to their purpose. To overcome these challenges, we underline a novel machine learning-based tool (FibroSoft) and we show its feasibility in a model of cardiac hypertrophy and heart failure in mice. Our results demonstrate that FibroSoft can identify fibrosis in diseased myocardium and the obtained results are user-independent. In addition, the results acquired using our software strongly correlate to those obtained by Western blot analysis of collagen 1 expression. Additionally, we could show that this method can be used for Masson's Trichrome and Picosirius Red stained histological images. The evaluation of our method also indicates that it can be used for any particular histology segmentation and quantification. In conclusion, our approach provides a powerful example of the feasibility of machine learning strategies to enable automatic analysis of histological images. [ABSTRACT FROM AUTHOR]

A Kinase Interacting Protein 1 (AKIP1) is a signalling adaptor that promotes physiological hypertrophy in vitro. The purpose of this study is to determine if AKIP1 promotes physiological cardiomyocyte hypertrophy in vivo. Therefore, adult male mice with cardiomyocyte-specific overexpression of AKIP1 (AKIP1-TG) and wild type (WT) littermates were caged individually for four weeks in the presence or absence of a running wheel. Exercise performance, heart weight to tibia length (HW/TL), MRI, histology, and left ventricular (LV) molecular markers were evaluated. While exercise parameters were comparable between genotypes, exercise-induced cardiac hypertrophy was augmented in AKIP1-TG vs. WT mice as evidenced by an increase in HW/TL by weighing scale and in LV mass on MRI. AKIP1-induced hypertrophy was predominantly determined by an increase in cardiomyocyte length, which was associated with reductions in p90 ribosomal S6 kinase 3 (RSK3), increments of phosphatase 2A catalytic subunit (PP2Ac) and dephosphorylation of serum response factor (SRF). With electron microscopy, we detected clusters of AKIP1 protein in the cardiomyocyte nucleus, which can potentially influence signalosome formation and predispose a switch in transcription upon exercise. Mechanistically, AKIP1 promoted exercise-induced activation of protein kinase B (Akt), downregulation of CCAAT Enhancer Binding Protein Beta (C/EBPβ) and de-repression of Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 4 (CITED4). Concludingly, we identified AKIP1 as a novel regulator of cardiomyocyte elongation and physiological cardiac remodelling with activation of the RSK3-PP2Ac-SRF and Akt-C/EBPβ-CITED4 pathway. These findings suggest that AKIP1 may serve as a nodal point for physiological reprogramming of cardiac remodelling. [ABSTRACT FROM AUTHOR]

The etiology of peripartum cardiomyopathy (PPCM) is unknown. Therefore, we evaluated the etiology of patients clinically diagnosed with PPCM using endomyocardial biopsy. We studied five patients diagnosed with PPCM following endomyocardial biopsy (age, 28–42 years; mean age, 35 years). Biopsied samples were evaluated using microscopy, including immunostaining and electron microscopy. The pathological findings were as follows: myocardial hypertrophy, myocardial fibrosis, and cell infiltration. Two patients were diagnosed with lymphocytic myocarditis, one with eosinophilic myocarditis, one with hypertensive heart disease, and one with a combination of hypertension and myocarditis. Endomyocardial biopsy suggested that the causes of PPCM were varied and related to myocarditis and myocardial overload due to hypertension. [ABSTRACT FROM AUTHOR]

Oxidative stress, caused by the over production of oxidants or inactivity of antioxidants, can modulate the redox state of several target proteins such as tyrosine kinases, mitogen-activated protein kinases and tyrosine phosphatases. c-Src is one such non-receptor tyrosine kinase which activates NADPH oxidases (Noxs) in response to various growth factors and shear stress. Interaction between c-Src and Noxs is influenced by cell type and primary messengers such as angiotensin II, which binds to G-protein coupled receptor and activates the intracellular signaling cascade. c-Src stimulated activation of Noxs results in elevated release of intracellular and extracellular reactive oxygen species (ROS). These ROS species disturb vascular homeostasis and cause cardiac hypertrophy, coronary artery disease, atherosclerosis and hypertension. Interaction between c-Src and ROS in the pathobiology of cardiac fibrosis is hypothesized to be influenced by cell type and stimuli. c-Src and ROS have a bidirectional relationship, thus increased ROS levels due to c-Src mediated activation of Noxs can further activate c-Src by promoting the oxidation and sulfenylation of critical cysteine residues. This review highlights the role of c-Src and ROS in mediating downstream signaling pathways underlying cardiovascular diseases. Furthermore, due to the central role of c-Src in activation of various signaling proteins involved in differentiation, migration, proliferation, and cytoskeletal reorganization of vascular cells, it is presented as therapeutic target for treating cardiovascular diseases except cardiac fibrosis. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are the leading cause of death in the global world. The emergence of single-cell technologies has greatly facilitated the research on CVDs. Currently, those single-cell technologies have been widely applied in atherosclerosis, myocardial infarction, cardiac ischemia–reperfusion injury, arrhythmia, hypertrophy cardiomyopathy, and heart failure, which are extremely helpful in elucidating the underlying mechanisms of CVDs from physiological and pathological perspectives at DNA, RNA, protein, post-transcriptional, post-translational, and metabolite levels. In this review, we would like to briefly introduce the current single-cell technologies, and will focus on the utilization of single-cell genomics in various heart diseases. Single-cell technologies have great potential in exploration of CVDs, and widespread application of single-cell genomics will promote the understanding and therapeutic treatments for CVDs. [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic kidney disease (PKD) is a hereditary kidney disorder which can affect cardiovascular system. Cardiac hypertrophy and cardiomyopathy in PKD have been reported by echocardiography analyses, but histopathology analyses of human PKD hearts have never been examined. The current studies evaluated human heart tissues from five subjects without PKD (non-PKD) and five subjects with PKD. Our histopathology data of human PKD hearts showed an increased extracellular matrix associated with cardiac hypertrophy and fibrosis. Hypertrophy- and fibrosis-associated pathways involving abnormal cardiac structure were next analyzed. We found that human PKD myocardium was infiltrated by inflammatory macrophage M1 and M2; expression of transforming growth factor (TGF-β1) and its receptor were upregulated with overexpression of pSmad3 and β-catenin. Because patients with PKD have an abnormal kidney function that could potentially affect heart structure, we used a heart-specific PKD mouse model to validate that cardiac hypertrophy and fibrosis were independent from polycystic kidney. In summary, our data show that hearts from human PKD were characterized by hypertrophy, interstitial fibrosis, perivascular fibrosis, and conduction system fibrosis with upregulated TGF-β1 and its receptor. We suggest that such structural abnormalities may predispose to systolic and diastolic cardiac dysfunction in the PKD myocardium. [ABSTRACT FROM AUTHOR]

During inflammation the conversion of cholesterol to 25-hydroxycholesterol (25HC) vastly increases in macrophages, resulting in a rise in 25HC concentration in plasma and tissues. The latter can act on liver X receptors (LXRs), which are potent modulators of cardiac hypertrophy and metabolism. However, there is no evidence about the role of 25HC and LXRs in regulation of cardiac contractions. Herein, we have found that acute treatment with 25HC slightly increased the contractility and profoundly inhibited the positive inotropic response to β-adrenoceptor stimulation with isoproterenol in mouse atria. Both these effects were suppressed by a selective LXR antagonist as well as lipid raft disruption by methyl-β-cyclodextrin. Agonists of LXRs exerted the same action as 25HC and the effects of the LXR agonist and 25HC co-application were not cumulative. In addition, 25HC affected the atrial membrane properties, towards an increase in lipid raft stability. Taken together, these data point to the existence of 25HC-dependent regulation of atrial inotropy and to the role of plasmalemmal LXRs and lipid rafts in this fast mechanism of contraction control. [ABSTRACT FROM AUTHOR]

Objective: Cardiac dysfunction and remodeling are serious complications of sepsis and are the main causes of death in sepsis. RCAN1 is a feedback regulator of cardiac hypertrophy. Here, we aim to investigate the role of RCAN1 in septic cardiomyopathy. Methods: Mice were randomly divided into control-WT, control-RCAN1−/−, LPS-induced WT and LPS-induced RCAN1−/− groups, some with Midiv-1 or KN93 treatment. The protein levels of RCAN1, p-ERK1/2, NFAT3, Drp1, p-Drp1, p-CaMKII in mouse hearts or cultured cardiomyocytes were determined by Western blotting. Myocardial function was assessed by echocardiography. Cardiac hypertrophy and fibrosis were detected by H&E and Masson's trichrome staining. Mitochondrial morphology was examined by transmission electron microscope. Serum level of LDH was detected by ELISA. Results: Our data show that RCAN1 was downregulated in septic mouse heart and LPS-induced cardiomyocytes. RCAN1−/− mice showed a severe impairment of cardiac function, and increased myocardial hypertrophy and fibrosis. The protein levels of NFAT3 and p-ERK1/2 were significantly increased in the heart tissues of RCAN1−/− mice. Further, RCAN1 deficiency aggravated sepsis-induced cardiac mitochondrial injury as indicated by increased ROS production, pathological fission and the loss of mitochondrial membrane potential. Inhibition of fission with Mdivi-1 reversed LPS-induced cardiac hypertrophy, fibrosis and dysfunction in RCAN1−/− mice. Moreover, RCAN1 depletion promoted mitochondrial translocation of CaMKII, which enhanced fission and septic hypertrophy, while inhibition of CaMKII with KN93 reduced excessive fission, improved LPS-mediated cardiac remodeling and dysfunction in RCAN1−/− mice. Conclusions: Our finding demonstrated that RCAN1 deficiency aggravated mitochondrial injury and septic cardiomyopathy through activating CaMKII. RCAN1 serves as a novel therapeutic target for treatment of sepsis-related cardiac remodeling and dysfunction. [ABSTRACT FROM AUTHOR]

Alterations of serine/threonine phosphorylation of the cardiac proteome are a hallmark of heart failure. However, the contribution of tyrosine phosphorylation (pTyr) to the pathogenesis of cardiac hypertrophy remains unclear. We use global mapping to discover and quantify site-specific pTyr in two cardiac hypertrophic mouse models, i.e., cardiac overexpression of ErbB2 (TgErbB2) and α myosin heavy chain R403Q (R403Q-αMyHC Tg), compared to control hearts. From this, there are significant phosphoproteomic alterations in TgErbB2 mice in right ventricular cardiomyopathy, hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM) pathways. On the other hand, R403Q-αMyHC Tg mice indicated that the EGFR1 pathway is central for cardiac hypertrophy, along with angiopoietin, ErbB, growth hormone, and chemokine signaling pathways activation. Surprisingly, most myofilament proteins have downregulation of pTyr rather than upregulation. Kinase-substrate enrichment analysis (KSEA) shows a marked downregulation of MAPK pathway activity downstream of k-Ras in TgErbB2 mice and activation of EGFR, focal adhesion, PDGFR, and actin cytoskeleton pathways. In vivo ErbB2 inhibition by AG-825 decreases cardiomyocyte disarray. Serine/threonine and tyrosine phosphoproteome confirm the above-described pathways and the effectiveness of AG-825 Treatment. Thus, altered pTyr may play a regulatory role in cardiac hypertrophic models. Quantitative global phosphotyrosine proteomics of two mouse models of hypertrophic cardiomyopathy reveals that tyrosine kinase inhibitors may be a future therapeutic approach for treating hypertrophic cardiomyopathy. [ABSTRACT FROM AUTHOR]

This retrospective cohort study investigated for association between increased extracellular volume (ECV) and left ventricular hypertrophy (LVH) by cardiac magnetic resonance (CMR) and cardiovascular composite outcomes in obesity. Native T1 was measured at the ventricular septum. ECV was calculated from native and post-contrast T1 and hematocrit. Cardiovascular (CV) composite outcomes included acute myocardial infarction, unstable angina requiring hospitalization, myocardial revascularization (excluding early revascularization), heart failure, and CV death. A total of 456 patients with a mean follow-up of 2.1 ± 0.4 years were enrolled. LGE and LVH was detected in 30.5% and 9.2%. 107 patients (23.5%) had the composite outcomes. Multivariable analysis revealed that LGE, LVH, and high ECV as independent predictors for cardiovascular composite outcomes The event rate in the LVH and high ECV, the LVH alone, the high ECV alone, and the no-LVH with lower ECV group was 57.1%, 38.1%, 32.6%, and 17.7%, respectively. Assessment of incremental prognostic value by comparing global chi-square showed that high ECV had additional prognostic value on top of LGE, and LVH. LVH and high ECV are independent predictors of CV composite outcomes in obesity. This is the first study that demonstrate the prognostic value of ECV in obese population. [ABSTRACT FROM AUTHOR]