Hypertrophied Hearts Research Articles

Hypertrophic and fibrotic human PKD hearts are associated with macrophage infiltration and abnormal TGF-β1 signaling.

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.

Sirtuin 1 aggravates hypertrophic heart failure caused by pressure overload via shifting energy metabolism

Sirtuin1 (SIRT1) is involved in regulating substrate metabolism in the cardiovascular system. Metabolic homeostasis plays a critical role in hypertrophic heart failure. We hypothesize that cardiac SIRT1 can modulate substrate metabolism during pressure overload-induced heart failure. The inducible cardiomyocyte Sirt1 knockout (icSirt1−/−) and its wild type littermates (Sirt1f/f) C57BL/6J mice were subjected to transverse aortic constriction (TAC) surgery to induce pressure overload. The pressure overload induces upregulation of cardiac SIRT1 in Sirt1f/f but not icSirt1−/− mice. The cardiac contractile dysfunctions caused by TAC-induced pressure overload occurred in Sirt1f/f but not in icSirt1−/− mice. Intriguingly, Sirt1f/f heart showed a drastic reduction in systolic contractility and electric signals during post-TAC surgery, whereas icSirt1−/− heart demonstrated significant resistance to pathological stress by TAC-induced pressure overload as evidenced by no significant changes in systolic contractile functions and electric properties. The targeted proteomics showed that the pressure overload triggered downregulation of the SIRT1-associated IDH2 (isocitrate dehydrogenase 2) that resulted in increased oxidative stress in mitochondria. Moreover, metabolic alterations were observed in Sirt1f/f but not in icSirt1−/− heart in response to TAC-induced pressure overload. Thus, SIRT1 interferes with metabolic homeostasis through mitochondrial IDH2 during pressure overload. Inhibition of SIRT1 activity benefits cardiac functions under pressure overload-related pathological conditions.

Abstract 14446: Bcl-x Short Isoform is Essential for Maintaining Multiple-Tissue Homeostasis

Regulated cell death is an essential piece of normal development and maintenance of tissue homeostasis, wherein BCL2 like 1 (BCL2L1) protein is involved in key signaling pathways. Alternative splicing in exon 2 of Bcl2l1 produces Bcl-x short (Bcl-xS) isoform. However, mutations in around 5’ splice site are classified as variants of uncertain significance in humans, and the isoform-specific role of endogenous Bcl-xS remains largely unexplored. Here we show the role of Bcl-xS in vivo by generating the mice with a mutation in 5’ splice site of the Bcl2l1 that inhibits Bcl-xS alternative splicing. Although loss of BCL2L1 leads to embryonic lethal with massive cell death, Bcl-xS knockout (KO) mice were born at a mendelian ratio and showed no overt abnormality until 3 months of age. Thereafter, the KO mice developed cardiac hypertrophy (heart weight/tibia length, 8.59+/-0.308 vs 11.61+/-0.631, p = 0.0005 and 2.13-fold increase in individual cardiomyocyte size, p = 0.0001) with contractile dysfunction (EF, 69.25+/-1.31 vs 56.57+/-3.07, p = 0.0028) and splenomegaly (spleen weight/tibia length, 5.32+/-0.25 vs 7.12+/-0.49, p = 0.0051) at 6 months of age. Despite that overexpression of Bcl-xS induced cell death in cardiomyocytes (2.497-fold compared to LacZ, p < 0.0001), there was unexpectedly no overt difference in the level of apoptosis in the KO heart (TUNEL, 0.033+/-0.003 vs 0.030+/-0.002 %, p = 0.359), but fibrosis was significantly increased in the KO heart (1.602+/-0.095 vs 2.340+/-0.145 %, p = 0.0017). Diabetes was not evident in the KO mice (blood glucose, 169.8+/-10.9 vs 153.3+/-8.46 mg/dl, p = 0.2595). Mechanistically, we found that the Akt/mTOR and JNK/cJun signaling are activated in the KO heart and the JNK/cJun signaling is activated with increased Bax expression in the KO spleen. These results suggest that Bcl-xS may be dispensable for development, but is essential for maintaining homeostasis of multiple organs, especially cardiosplenic network, in a tissue-dependent mechanism.

Abstract 13777: Metabolic Phenotyping in Aortic Stenosis: Insights From a Multi-Parametric Cardiac Magnetic Resonance Study

Introduction: Left ventricular hypertrophy in Aortic stenosis (AS) results from pressure overload and relates to perturbations in cardiac fatty acid metabolism with evidence of steatosis and deranged myocardial energetics in severe AS. There is, however, wide individual heterogeneity in the degree of hypertrophy and progression to myocardial fibrosis and heart failure. Underlying interplay of metabolism and hypertrophy may explain this variability. Purpose We sought to determine if a gradient of myocardial metabolic remodelling exists in AS and its relationship with AS severity, degree of hypertrophy and fibrosis. Methods: 74 asymptomatic AS participants including mild (n=18), moderate (n=38), severe (n=18), and 13 healthy volunteers underwent CMR imaging for cardiac function, myocardial PCr/ATP and triglyceride content (MTG) assessment. Participants were divided into quartile groups based on LV wall thickness (LVWT) and peak aortic valve gradient (AVG) to study relationship between cardiac metabolism and hemodynamic markers of LV structure and function. Results: There was a stepwise deterioration in LV structure and function in both the LVWT and AVG quartile groups (p values significant) with increasing AS severity, as expected. Notably, PCr/ATP was reduced early in mild-moderate AS (Q2 1.43±0.13 vs 1.80±0.14 in Q1 controls, p=0.05) with a progressive decline across groups (Q4 PCr/ATP 1.39±0.14, p=0.02 vs Q1). MTG was elevated in mild-moderate AS (Q2 1.52±0.84 vs 1.25±0.70% in Q1, p = 0.032). Global longitudinal strain was impaired across all AS groups, and was related to the degree of energetic impairment (R 0.219, p 0.03). In addition, PCr/ATP was strongly associated with the presence of myocardial fibrosis (p 0.01). Conclusion A gradient of myocardial energetic deficit and steatosis exists across the spectrum of hypertrophied AS hearts, notably these metabolic changes precede irreversible LV remodelling and subclinical dysfunction.

Abstract 13652: A Randomised Double-Blind Placebo-Controlled Study of Fenofibrate as a Metabolic Modulator to Augment Cardiac Physiology in Moderate-Severe Aortic Stenosis

Background: Pressure overload in aortic stenosis (AS) is associated with reduced cardiac fatty acid oxidation (FAO) and evidence of myocardial steatosis and impaired myocardial energetics. Here, we investigated whether modulating myocardial metabolism to increase FAO with a PPARα agonist, Fenofibrate in moderate-severe AS had effects on cardiac metabolism and physiology. Methods: 67 participants with asymptomatic moderate-severe AS were prospectively randomised (double-blinded) to receive either Fenofibrate 200mg once daily (N= 54) or placebo (N=13) for 6 months (180 ± 7 days duration). Follow-up data is available in 42 patients. Primary endpoint was reduction in myocardial triglyceride content (MTG) measured using proton magnetic resonance spectroscopy (MRS). Secondary endpoints included cardiac PCr/ATP measured by 31P-MRS and LV strain assessed using MR tagging. Results: There was significant reduction in MTG content (-0.40%, CI -0.74 to -0.06, p= 0.022), with a no significant reduction seen in placebo. (-0.46%, CI -1.1 to 0.17, p= 0.13). A significant increase in venous butyrate levels was seen in the fibrate group (+0.09 mmol/l, CI 0.006 to 0.17, p= 0.036) in line with increased fatty acid oxidation. No change in cardiac energetics was seen in either group. No change in cardiac function was seen in either group, global longitudinal strain (-0.07%, p 0.89 Fibrate vs -0.31%, p 0.67 Placebo), circumferential strain ( -0.15 %, p 0.80 Fibrate vs 1.71%, p 0.07 Placebo). Conclusions: Fenofibrate can potentially upregulate fatty acid oxidation in hypertrophied AS hearts reducing myocardial lipid content, but this did not have any measurable beneficial physiological effect in moderate-severe AS.

Abstract 9553: Sirtuin1 Aggravates Hypertrophic Heart Failure Caused by Pressure Overload via Shifting Energy Metabolism

Introduction: Sirtuin1 (SIRT1) serves as a deacetylase to regulate cardiac substrate metabolism during physiological and pathological conditions. The alteration in metabolic homeostasis plays a critical role in hypertrophic heart failure. Hypothesis: Cardiomyocyte SIRT1 modulates substrate metabolism to regulate cardiac remodeling during pressure overload-induced heart failure. Methods: The inducible cardiomyocyte specific Sirt1 knockout (icSirt1 -/- ) and its wild type littermates (Sirt1 f/f ) C57BL/6J mice were subjected to transverse aortic constriction (TAC) surgery to induce pressure overload. The cardiac functions were evaluated with echocardiography and electrocardiography measurements. Results: The pressure overload by TAC induces upregulation of cardiac SIRT1 in Sirt1 f/f but not icSirt1 -/- mice. The cardiac contractile dysfunctions caused by TAC-induced pressure overload occurred in Sirt1 f/f but not in icSirt1 -/- mice. Intriguingly, Sirt1 f/f heart showed a drastic reduction in systolic contractility and electric signals during post-TAC surgery, whereas icSirt1 -/- heart demonstrated significant resistance to the pathological stress by TAC-induced pressure overload as evidenced by no significant changes in systolic contractile functions and electric properties. The Seahorse data revealed that TAC-induced pressure overload causes a decrease in basal respiration and ATP generation, as well as reduced OXPHOS (oxidative phosphorylation) integrity of mitochondria in Sirt1 f/f but not in icSirt1 -/- cardiomyocytes. The targeted proteomics showed that the pressure overload trigged downregulation of the SIRT1-associated IDH2 (isocitrate dehydrogenase 2) that result in an increased oxidative stress in mitochondria. Moreover, a significant alteration in substrate metabolism was observed in Sirt1 f/f but not in icSirt1 -/- heart in response to TAC-induced pressure overload stress. Conclusions: SIRT1 interferes metabolic homeostasis through regulating mitochondrial IDH2 during pressure overload. Inhibition of SIRT1 activity benefits cardiac functions under pressure overload-related pathological conditions. SIRT1 antagonism could be a pharmacological approach for hypertrophic heart failure patients.

Abstract 9399: Elevated MCU Expression by CaMKIIδB Limits Pathological Cardiac Remodeling

Introduction: Calcium (Ca 2+ ) is a key regulator of energy metabolism. Impaired Ca 2+ homeostasis damages mitochondria, causing cardiomyocyte death, pathological hypertrophy, and heart failure. This study investigates the regulation and the role of the mitochondrial Ca 2+ uniporter (MCU) in chronic stress-induced pathological cardiac remodeling. Methods: MCU knockout or transgenic mice were infused with isoproterenol (ISO; 10 mg/kg per day, 4 weeks). Cardiac hypertrophy and remodeling were evaluated by echocardiography and histology. Primary cultured rodent adult cardiomyocytes were treated with ISO (100 nmol/L, 48 hours). Intracellular Ca 2+ handling and cell death pathways were monitored. Adenovirus-mediated gene manipulations were used in vitro. Results: Chronic administration of the β-adrenergic receptor agonist ISO increased the levels of the MCU and the MCU complex in cardiac mitochondria, raising mitochondrial Ca 2+ concentrations, in vivo and in vitro. ISO also upregulated MCU without affecting its regulatory proteins in adult cardiomyocytes. It is interesting that ISO-induced cardiac hypertrophy, fibrosis, contractile dysfunction, and cardiomyocyte death were exacerbated in global MCU knockout mice. Cardiomyocytes from knockout mice or overexpressing a dominant negative MCU exhibited defective intracellular Ca 2+ handling and activation of multiple cell death pathways. Conversely, cardiac-specific overexpression of MCU maintained intracellular Ca 2+ homeostasis and contractility, suppressed cell death, and prevented ISO-induced heart hypertrophy. ISO upregulated MCU expression through activation of Ca 2+ /calmodulin kinase II δB (CaMKIIδB) and promotion of its nuclear translocation via calcineurin-mediated dephosphorylation at serine 332. Nuclear CaMKIIδB phosphorylated CREB (cAMP-response element binding protein), which bound the Mcu promoter to enhance Mcu gene transcription. Conclusions: The β-adrenergic receptor/CaMKIIδB/CREB pathway upregulates Mcu gene expression in the heart. MCU upregulation is a compensatory mechanism that counteracts stress-induced pathological cardiac remodeling by preserving Ca2+ homeostasis and cardiomyocyte viability.

Magnetique: an interactive web application to explore transcriptome signatures of heart failure

BackgroundDespite a recent increase in the number of RNA-seq datasets investigating heart failure (HF), accessibility and usability remain critical issues for medical researchers. We address the need for an intuitive and interactive web application to explore the transcriptional signatures of heart failure with this work.MethodsWe reanalysed the Myocardial Applied Genomics Network RNA-seq dataset, one of the largest publicly available datasets of left ventricular RNA-seq samples from patients with dilated (DCM) or hypertrophic (HCM) cardiomyopathy, as well as unmatched non-failing hearts (NFD) from organ donors and patient characteristics that allowed us to model confounding factors. We analyse differential gene expression, associated pathway signatures and reconstruct signaling networks based on inferred transcription factor activities through integer linear programming. We additionally focus, for the first time, on differential RNA transcript isoform usage (DTU) changes and predict RNA-binding protein (RBP) to target transcript interactions using a Global test approach. We report results for all pairwise comparisons (DCM, HCM, NFD).ResultsFocusing on the DCM versus HCM contrast (DCMvsHCM), we identified 201 differentially expressed genes, some of which can be clearly associated with changes in ERK1 and ERK2 signaling. Interestingly, the signs of the predicted activity for these two kinases have been inferred to be opposite to each other: In the DCMvsHCM contrast, we predict ERK1 to be consistently less activated in DCM while ERK2 was more activated in DCM. In the DCMvsHCM contrast, we identified 149 differently used transcripts. One of the top candidates is the O-linked N-acetylglucosamine (GlcNAc) transferase (OGT), which catalyzes a common post-translational modification known for its role in heart arrhythmias and heart hypertrophy. Moreover, we reconstruct RBP – target interaction networks and showcase the examples of CPEB1, which is differentially expressed in the DCMvsHCM contrast.ConclusionMagnetique (https://shiny.dieterichlab.org/app/magnetique) is the first online application to provide an interactive view of the HF transcriptome at the RNA isoform level and to include transcription factor signaling and RBP:RNA interaction networks. The source code for both the analyses (https://github.com/dieterich-lab/magnetiqueCode2022) and the web application (https://github.com/AnnekathrinSilvia/magnetique) is available to the public. We hope that our application will help users to uncover the molecular basis of heart failure.

Reduced CircSMOC1 Level Promotes Metabolic Reprogramming via PTBP1 (Polypyrimidine Tract-Binding Protein) and miR-329-3p in Pulmonary Arterial Hypertension Rats.

Pulmonary arterial hypertension maintains rapid cell proliferation and vascular remodeling through metabolic reprogramming. Recent studies suggested that circRNAs play important role in pulmonary vascular remodeling and pulmonary arterial smooth muscle cells proliferation. However, the relationship between circRNA, cell proliferation, and metabolic reprogramming in pulmonary arterial hypertension has not been investigated. RNA-seq and qRT-PCR reveal the differential expression profile of circRNA in pulmonary arteries of pulmonary arterial hypertension rat models. Transfection was used to examine the effects of circSMOC1 on pulmonary artery smooth muscle cells, and the roles of circSMOC1 in vivo were investigated by adenoassociated virus. Mass spectrometry, RNA pull-down, RNA immunoprecipitation, and dual-luciferase reporter assay were performed to investigate the signaling pathway of circSMOC1 regulating the metabolic reprogramming. CircSMOC1 was significantly downregulated in pulmonary arteries of pulmonary arterial hypertension rats. CircSMOC1 knockdown promoted proliferation and migration and enhanced aerobic glycolysis of pulmonary artery smooth muscle cells. CircSMOC1 overexpression in vivo alleviates pulmonary vascular remodeling, right ventricular pressure, and right heart hypertrophy. In the nucleus, circSMOC1 directly binds to PTBP1 (polypyrimidine tract-binding protein), competitively inhibits the specific splicing of PKM (pyruvate kinase M) premRNA, resulting in the upregulation of PKM2 (pyruvate kinase M2), the key enzyme of aerobic glycolysis, to enhance glycolysis. In the cytoplasm, circSMOC1 acted as a miR-329-3p sponge, and its reduction in pulmonary arterial hypertension suppressed PDHB (pyruvate dehydrogenase E1 subunit beta) expression, leading to the impairment of mitochondrial oxidative phosphorylation. circSMOC1 is crucially involved in the metabolic reprogramming of pulmonary artery smooth muscle cells through PTBP1 and miR-329-3p to regulate pulmonary vascular remodeling in pulmonary arterial hypertension.

Endothelium-Specific Deficiency of Polycystin-1 Promotes Hypertension and Cardiovascular Disorders.

Autosomal dominant polycystic kidney disease is the most frequent hereditary kidney disease and is generally due to mutations in PKD1 and PKD2, encoding polycystins 1 and 2. In autosomal dominant polycystic kidney disease, hypertension and cardiovascular disorders are highly prevalent, but their mechanisms are partially understood. Since endothelial cells express the polycystin complex, where it plays a central role in the mechanotransduction of blood flow, we generated a murine model with inducible deletion of Pkd1 in endothelial cells (Cdh5-CreERT2;Pkd1fl/fl) to specifically determine the role of endothelial polycystin-1 in autosomal dominant polycystic kidney disease. Endothelial deletion of Pkd1 induced endothelial dysfunction, as demonstrated by impaired flow-mediated dilatation of resistance arteries and impaired relaxation to acetylcholine, increased blood pressure and prevented the normal development of arteriovenous fistula. In experimental chronic kidney disease induced by subtotal nephrectomy, endothelial deletion of Pkd1 further aggravated endothelial dysfunction, vascular remodeling, and heart hypertrophy. Altogether, this study provides the first in vivo demonstration that specific deletion of Pkd1 in endothelial cells promotes endothelial dysfunction and hypertension, impairs arteriovenous fistula development, and potentiates the cardiovascular alterations associated with chronic kidney disease.

Prospects for remodeling the hypertrophic heart with myosin modulators

Hypertrophic cardiomyopathy (HCM) is a complex but relatively common genetic disease that usually arises from pathogenic variants that disrupt sarcomere function and lead to variable structural, hypertrophic, and fibrotic remodeling of the heart which result in substantial adverse clinical outcomes including arrhythmias, heart failure, and sudden cardiac death. HCM has had few effective treatments with the potential to ameliorate disease progression until the recent advent of inhibitory myosin modulators like mavacamten. Preclinical investigations and clinical trials utilizing this treatment targeted to this specific pathophysiological mechanism of sarcomere hypercontractility in HCM have confirmed that myosin modulators can alter disease expression and attenuate hypertrophic remodeling. Here, we summarize the state of hypertrophic remodeling and consider the arguments for and against salutary HCM disease modification using targeted myosin modulators. Further, we consider critical unanswered questions for future investigative and therapeutic avenues in HCM disease modification. We are at the precipice of a new era in understanding and treating HCM, with the potential to target agents toward modifying disease expression and natural history of this most common inherited disease of the heart.

Evidence of Advanced Pulmonary Vascular Remodeling in Obstructive Hypertrophic Cardiomyopathy With Pulmonary Hypertension

Elevated mean pulmonary artery pressure (mPAP) is common in patients with hypertrophic cardiomyopathy (HCM) and heart failure symptoms. However, dynamic left ventricular (LV) outflow tract obstruction may confound interpretation of pulmonary hypertension (PH) pathophysiologic features in HCM when relying on resting invasive hemodynamic data alone. Do structural changes to the lung vasculature clarify PH pathophysiologic features in patients with HCM with progressive heart failure? Clinical data and ultrarare lung autopsy specimens were acquired retrospectively from the National Institutes of Health (1975-1992). Patients were included based on the availability of lung tissue and recorded mPAP. Discarded tissue from rejected lung donors served as control specimens. Histomorphology was performed on pulmonary arterioles and veins. Comparisons were calculated using the Student t test and Mann-Whitney U test; Pearson correlation was used to assess association between morphometric measurements and HCM cardiac and hemodynamic measurements. The HCM cohort (n= 7; mean ± SD age, 43 ± 18 years; 71%men) showed maximum mean ± SD LV wall thickness of 25 ± 2.8mm, mean ± SD outflow tract gradient of 90 ± 30mmHg, median mPAP of 25mmHg (interquartile range [IQR], 6mmHg), median pulmonary artery wedge pressure (PAWP) of 16mmHg (IQR, 4mmHg), and median pulmonary vascular resistance of 1.8 Wood units (WU; IQR, 2.4 WU). Compared with control samples (n= 5), patients with HCM showed greater indexed pulmonary arterial hypertrophy (20.7 ± 7.2%vs49.7 ± 12%; P< .001) and arterial wall fibrosis (11.5 ± 3.4mm vs21.0 ± 4.7mm; P< .0001), which correlated with mPAP (r= 0.84; P= .018), PAWP (r= 0.74; P= .05), and LV outflow tract gradient (r= 0.78; P= .035). Compared with control samples, pulmonary vein thickness was increased by 2.9-fold (P= .008) in the HCM group, which correlated with mPAP (r= 0.81; P= .03) and LV outflow tract gradient (r= 0.83; P= .02). To the best of our knowledge, these data demonstrate for the first time that in patients with obstructive HCM, heart failure is associated with pathogenic pulmonary vascular remodeling even when mPAP is elevated only mildly. These observations clarify PH pathophysiologic features in HCM, with future implications for clinical strategies that mitigate outflow tract obstruction.

Cardiac-specific knockdown of Bhlhe40 attenuates angiotensin II (Ang II)-Induced atrial fibrillation in mice.

Atrial fibrosis and atrial inflammation are associated with the pathogenesis of atrial fibrillation (AF). Basic helix–loop–helix family member E40 (Bhlhe40) is an important transcription factor, which is involved in tumors, inflammation, apoptosis, viral infection, and hypoxia. However, its role and molecular mechanism in AF remain unclear. In this study, a mouse model of AF was induced by Ang II infusion. The atrial diameter was evaluated using echocardiography. Induction and duration of AF were measured by programmed electrical stimulation. Atrial structural remodeling was detected using routine histologic examinations. Our results showed that Bhlhe40 was significantly upregulated in angiotensin II (Ang II)-stimulated atrial cardiomyocytes and atrial tissues and in tissues from patients with AF. Cardiac-specific knockdown of Bhlhe40 in mice by a type 9 recombinant adeno-associated virus (rAAV9)-shBhlhe40 significantly ameliorated Ang II-induced atrial dilatation, atrial fibrosis, and atrial inflammation, as well as the inducibility and duration of AF. Mechanistically, cardiac-specific knockdown of Bhlhe40 attenuated Ang II-induced activation of NF-κB/NLRP3, TGF-1β/Smad2 signals, the increased expression of CX43, and the decreased expression of Kv4.3 in the atria. This is the first study to suggest that Bhlhe40 is a novel regulator of AF progression, and identifying Bhlhe40 may be a new therapeutic target for hypertrophic remodeling and heart failure.

Lagerstroemia speciosa Ameliorated Blood Pressure in LNAME Induced Hypertension in Experimental Rats through NO/cGMP and Oxidative Stress Modulation.

Cardiovascular disease is the primary reason for chronic heart diseases and mortality worldwide. Hypertension (HTN) is the utmost dominant risk factor for the evolution of several diseases. Herbal medicines, traditional medicinal herbs, and their extracts are widely utilized to treat and monitor HTN. Herbal components have been shown to help relax arteries and lower oxidative stress. The current study assesses the probable role of herbal plant extract Lagerstroemia speciosa (LS) in the LNAME induced HTN in rats. LNAME (50 mg/100 mL) in drinkable water was given to rats for five weeks. There was a significant upsurge in LNAME-treated hypertensive rats' blood pressure (BP). On treatment with LS, it ameliorates blood pressure. Further, LS also improved body weight, reduced heart weight, and heart hypertrophy. The NO/cGMP concentration was lowered along with a substantial upsurge in the level of glutathione and a decline in MDA level. The LS extract also reduced the inflammatory cytokine markers in the systemic circulation. In conclusion, thus, the extract of LS treatment can efficiently alleviate the BP, oxidative stress markers, and inflammation and improve NO/cGMP concentration in LNAME induced HTN in rats.

Smooth muscle Acid-sensing ion channel 1a as a therapeutic target to reverse hypoxic pulmonary hypertension.

Acid-sensing ion channel 1a (ASIC1a) is a voltage-independent, non-selective cation channel that conducts both Na+ and Ca2+. Activation of ASIC1a elicits plasma membrane depolarization and stimulates intracellular Ca2+-dependent signaling pathways in multiple cell types, including vascular smooth muscle (SM) and endothelial cells (ECs). Previous studies have shown that increases in pulmonary vascular resistance accompanying chronic hypoxia (CH)-induced pulmonary hypertension requires ASIC1a to elicit enhanced pulmonary vasoconstriction and vascular remodeling. Both SM and EC dysfunction drive these processes; however, the involvement of ASIC1a within these different cell types is unknown. Using the Cre-LoxP system to generate cell-type-specific Asic1a knockout mice, we tested the hypothesis that SM-Asic1a contributes to CH-induced pulmonary hypertension and vascular remodeling, whereas EC-Asic1a opposes the development of CH-induced pulmonary hypertension. The severity of pulmonary hypertension was not altered in mice with specific deletion of EC-Asic1a (TekCre-Asic1a fl/fl). However, similar to global Asic1a knockout (Asic1a −/-) mice, mice with specific deletion of SM-Asic1a (MHCCreER-Asic1a fl/fl) were protected from the development of CH-induced pulmonary hypertension and right heart hypertrophy. Furthermore, pulmonary hypertension was reversed when deletion of SM-Asic1a was initiated in conditional MHCCreER-Asic1a fl/fl mice with established pulmonary hypertension. CH-induced vascular remodeling was also significantly attenuated in pulmonary arteries from MHCCreER-Asic1a fl/fl mice. These findings were additionally supported by decreased CH-induced proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) from Asic1a −/- mice. Together these data demonstrate that SM-, but not EC-Asic1a contributes to CH-induced pulmonary hypertension and vascular remodeling. Furthermore, these studies provide evidence for the therapeutic potential of ASIC1a inhibition to reverse pulmonary hypertension.

Cardioprotective potential of the antioxidant-rich bioactive fraction of Garcinia pedunculata Roxb. ex Buch.-Ham. against isoproterenol-induced myocardial infarction in Wistar rats.

This Study aimed to characterise the phenolic compounds in Garcinia pedunculata extract and assess their potential antioxidant activity as well as its cardioprotective potential in isoproterenol-induced cardiac hypertrophy in an experimental animal model. In vitro antioxidant properties were determined using DPPH, ABTS, FRAP, PMD assays. In vitro lipid peroxidation experiment was also performed with heart tissues. Cardioprotective and cardiotoxicity effects were determined using the cell line studies. The cardioprotective effect of GP was assessed in a rat model of isoproterenol-(ISO-) induced cardiac hypertrophy by subcutaneous administration. Heart weight/tail length ratio and cardiac hypertrophy indicators were reduced after oral administration of GP. Additionally, GP reduced oxidative stress and heart inflammation brought on by ISO. In H9c2 cells, the antihypertrophic and anti-inflammatory effects of the extract of GP were seen in the presence of ISO, which were further supported by the in vivo observations. This study makes a compelling case for the possibility that supplementing with dried GP fruit can prevent heart hypertrophy by reducing oxidative stress and inflammation.

Characterisation of metabolic phenotype in aortic stenosis: insights from a multi-parametric cardiac magnetic resonance study

Abstract Introduction Left ventricular hypertrophy develops in Aortic stenosis (AS) as a result of increased afterload and is related to perturbations in cardiac fatty acid metabolism with evidence of steatosis and impaired myocardial energetics in severe AS. However, there is wide individual heterogeneity when it comes to degree of hypertrophy and progression to myocardial fibrosis and heart failure in those with same degree of stenosis. Underlying interplay of metabolism and hypertrophy may explain this variability. Purpose We sought to determine if a gradient of myocardial energetic impairment and steatosis exists across the spectrum of AS and precedes irreversible structural remodelling and subclinical LV dysfunction. We investigated metabolic remodelling in AS, focusing on its relationship with stenosis severity, degree of hypertrophy and fibrosis. Methods 74 AS participants including mild AS (n=18), asymptomatic moderate AS (n=38), asymptomatic severe AS (n=18), and healthy volunteers (n=13) underwent assessment of cardiac function, energetics (myocardial phosphocreatine to adenosine triphosphate ratio, PCr/ATP) and myocardial triglyceride content (MTG) using cardiovascular magnetic resonance (CMR) imaging and spectroscopy. Participants were divided into quartile groups based on their LV wall thickness (LVWT) and peak aortic valve gradient (AVG) to study relationship between cardiac metabolism and hemodynamic markers of LV structure and function. Results Baseline CMR characteristics (Fig. 1B-C) show a stepwise deterioration in LV structure and function across both the LVWT and AVG quartile groups (p values significant) with high LV mass index and relatively dilated LV as disease severity increases. Cardiac energetics (PCr/ATP]) were reduced in mild-moderate AS, Q2 (1.43±0.13 vs normal controls, Q1 1.80±0.14, p=0.05, Fig.2A) with a progressive decline with increasing AS severity (severe AS, Q4 PCr/ATP 1.39±0.14, p=0.02 vs controls). MTG was elevated in mild-moderate AS, Q2 (1.52±0.84 vs normal, Q1 1.25±0.70%, p=0.032, Fig. 2B). Whilst all AS groups had evidence of subclinical LV dysfunction with impaired strain parameters, impaired systolic longitudinal strain was related to the degree of energetic impairment (R 0.219, p 0.03). In addition, PCr/ATP was strongly associated with the presence of myocardial fibrosis (p 0.01) strengthening the hypothesis that metabolic changes may play a causative role in disease progression (Fig. 2C). Conclusion A gradient of myocardial energetic deficit and steatosis exists across the spectrum of hypertrophied AS hearts, notably we show in our study that these metabolic changes precede irreversible LV remodelling and subclinical dysfunction. These findings may have value for defining distinct metabolic phenotypes and identifying those most at risk of decompensation. This also opens another avenue for precision metabolic therapy in AS with a potential to intervene and delay or prevent decompensation. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Clinical Research Training Fellowship

Crim1 inhibits angiotensin II-induced hypertrophy and preserves Kv4.2 expression in cardiomyocytes.

Objective(s):Angiotensin II (Ang II) plays a key role in the regulation of myocardial hypertrophy via downstream cysteine-rich transmembrane bone morphogenetic protein regulator 1 (Crim1). However, it is still unclear whether Crim1 is involved in ionic channel remodeling. The study aimed to explore the effects of Crim1 on transient outward potassium current (Ito) and Kv4.2 (the main subunit of Ito channel) expression in hypertrophic ventricular cardiomyocytes. Materials and Methods:The ventricular cardiomyocytes were isolated from the neonatal rats. Hypertrophy was induced by Ang II. Crim1 expression was modulated by using adenovirus transfection. The expression of myosin heavy chain beta (β-MHC), Crim1, and Kv4.2 was determined by RT-qPCR and western blot. The cellular surface area was assessed using Image J software. Ito was recorded by the whole-cell patch clamp technique. Results:Ang II-induced hypertrophy in cardiomyocytes was identified by their larger cellular surface area and higher mRNA expression of β-MHC. Ang II significantly decreased the expression of Crim1 and Kv4.2 and reduced Ito current density. However, Crim1 overexpression abolished the Ang II-induced hypertrophy and preserved the expression of Kv4.2 and Ito current density. Conclusion:Crim1 overexpression inhibits Ang II-induced hypertrophy and preserves Ito current density via up-regulating Kv4.2 in ventricular cardiomyocytes from neonatal rats. Crim1 could have a role in the development of ventricular arrhythmia in hypertrophic hearts.

IRX2 activated by jumonji domain-containing protein 2A is crucial for cardiac hypertrophy and dysfunction in response to the hypertrophic stimuli

BackgroundIroquois homeobox 2 (IRX2) is a member of the Iroquois family whose upregulation has been potentially correlated to cardiac hypertrophy. This work studied the function of IRX2 and its related molecules in hypertrophic cardiomyopathy (HCM). MethodsA GEO dataset GSE32453 was analyzed to identify aberrantly expressed genes in HCM. Altered expression of IRX2 was induced in mice by lentivirus injection, followed by angiotensin II (Ang II) treatment to induce HCM. The function of IRX2 knockdown in ventricular dysfunction, heart volume and pathological changes in mice, and in surface area, oxidative stress and apoptosis of isolated cardiomyocytes were examined. Binding relationship between jumonji domain-containing protein 2A (JMJD2A) and IRX2 was predicted by online tools and validated. The interaction between JMJD2A and IRX2 in HCM development was examined by joint interventions. ResultsIRX2 was highly expressed in heart tissues with HCM. IRX2 knockdown prevented mice from Ang II-induced ventricular dysfunction, cardiac hypertrophy, inflammation and fibrosis in mouse heart, and it decreased the levels of cardiac hypertrophy-related markers, oxidative stress response, and apoptosis of Ang II-treated cardiomyocytes. JMJD2A catalyzed demethylation of H3K9me3 near the IRX2 promoter to activate its transcription. JMJD2A knockdown similarly exerted protective functions against cardiac hypertrophy in vivo and in vitro, but the protection was blocked upon further IRX2 upregulation. IRX2 was found to increase the Wnt/β-catenin signaling activation. ConclusionThis work reports that JMJD2A activates IRX2 transcription and the Wnt/β-catenin signaling to induce cardiac hypertrophy and dysfunction in HCM.

IMPROVEMENT OF INCEPTIONV3 MODEL CLASSIFICATION PERFORMANCE USING CHEST X-RAY IMAGES

In this study, we attempted to confirm whether the InceptionV3 model, which shows excellent performance in lung disease classification using chest X-ray images, is suitable for cardiac disease classification. In addition, we proposed a method for improving classification accuracy by improving the structure of the existing InceptionV3 model. The deep learning model used in this study was a modified version of the fully-connected hierarchical structure of InceptionV3. The proposed InceptionV3 model structure was constructed to differentiate between a normal heart and hypertrophic heart. The data used for model training were trained after data augmentation on 1026 chest X-ray images of patients diagnosed with normal heart and cardiac hypertrophy at Kyungpook National University Hospital. The experiment showed a learning classification accuracy of 99.57% and loss of 1.42% for the original InceptionV3 model. The accuracy and loss of the modified InceptionV3 model were 99.81% and 0.92%, respectively. Its classification performance was evaluated based on precision, recall, and F1 score. For a normal heart, precision, recall and F1 score were 78%, 100% and 88%, respectively. For cardiomegaly, classification accuracy, recall and F1 score were 78%, 100% and 88%, respectively. Conversely, the modified model showed 100% precision, 92% recall and 96% F1 score. For cardiomegaly, classification accuracy, recall rate and F1 score were 95, 100 and 97%, respectively. In conclusion, better classification can be achieved if the chest X-ray images for a normal heart and cardiomegaly are classified using the proposed model. Hence, the reliability of the classification performance gradually increases.