Cardiac Remodeling In Response Research Articles

Cardiac remodeling in amateur triathletes after 24 weeks of exercise training for a half-Ironman event: a brief report.

Triathletes' physiological adaptations to exercise training can have a different impact on cardiac remodeling based on the extreme exercise preparation. Moreover, cardiac remodeling might be different depending on whether triathletes have trained for many years or if they just decided to be more active. Nevertheless, data are limited in amateur endurance athletes and studies about them are key for their safety. Therefore, we investigated the effects of exercise training for a half-ironman on cardiac remodeling. A total of 24 amateur athletes underwent a 24-week exercise program and were followed by three-dimensional echocardiography to assess its global impact on cardiac remodeling. Subanalyses were performed based on participants past-training experience (low versus high). We found significant group effects on the right and left ventricle, significant time effect on the right ventricle. No significant interaction effects were observed. We observed significant correlations between the right ventricle, clinical and performance characteristics where the peak power output explained 38% of the variance, while the body surface area, weight and power at the second ventilatory threshold explained 34%, 31% and 30%, respectively. Changes in cardiac remodeling in response to an exercise program for a half-ironman are not homogeneous across the ventricles and are influenced by participants' past-training experience. This study strengthens our knowledge of extreme exercise training for a half-ironman to further develop better training programs and medical follow-up in amateur triathletes.

Postnatal Deletion of Bmal1 in Cardiomyocyte Promotes Pressure Overload Induced Cardiac Remodeling in Mice.

BackgroundMice with cardiomyocyte‐specific deletion of Bmal1, a core clock gene, had spontaneous abnormal cardiac metabolism, dilated cardiomyopathy, and shortened lifespan. However, the role of cardiomyocyte Bmal1 in pressure overload induced cardiac remodeling is unknown. Here we aimed to understand the contribution of cardiomyocyte Bmal1 to cardiac remodeling in response to pressure overload induced by transverse aortic constriction or chronic angiotensin Ⅱ (AngⅡ) infusion.Methods and ResultsBy generating a tamoxifen‐inducible cardiomyocyte‐specific Bmal1 knockout mouse line (cKO) and challenging the mice with transverse aortic constriction or AngⅡ, we found that compared to littermate controls, the cKO mice displayed remarkably increased cardiac hypertrophy and augmented fibrosis both after transverse aortic constriction and AngⅡ induction, as assessed by echocardiographic, gravimetric, histologic, and molecular analyses. Mechanistically, RNA‐sequencing analysis of the heart after transverse aortic constriction exposure revealed that the PI3K/AKT signaling pathway was significantly activated in the cKOs. Consistent with the in vivo findings, in vitro study showed that knockdown of Bmal1 in cardiomyocytes significantly promoted phenylephrine‐induced cardiomyocyte hypertrophy and triggered fibroblast‐to‐myofibroblast differentiation, while inhibition of AKT remarkedly reversed the pro‐hypertrophy and pro‐fibrosis effects of Bmal1 knocking down.ConclusionsThese results suggest that postnatal deletion of Bmal1 in cardiomyocytes may promote pressure overload‐induced cardiac remodeling. Moreover, we identified PI3K/AKT signaling pathway as the potential mechanistic ties between Bmal1 and cardiac remodeling.

Angiotensin receptor/Neprilysin inhibitor effects in CRTd non-responders: From epigenetic to clinical beside

ObjectivesWe evaluated whether Angiotensin receptor/Neprilysin inhibitors (ARNI) reduce heart failure (HF) hospitalizations and deaths in cardiac resynchronization therapy with defibrillator (CRTd) non-responders patients at 12 months of follow-up, modulating microRNAs (miRs) implied in adverse cardiac remodeling. Backgroundadverse cardiac remodeling characterized by left ventricle ejection fraction (LVEF) reduction, left ventricular end-systolic volume (LVESv) increase, and the 6-minute walking test (6MWT) reduction are relevant pathological mechanisms in CRTd non-responders and could be linked to changes in miRNAs (miRs), regulating cardiac fibrosis, apoptosis, and hypertrophy. MethodsmiRs levels and clinical outcomes (LVEF, cardiac deaths, and 6MWT) were evaluated at baseline and one year of follow-up in CRTd non-responders divided into ARNI-users and Non-ARNI users. ResultsAt baseline, there were no differences in levels of inflammatory markers, miR-18, miR-145, and miR-181 (p > 0.05) between Non-ARNI users (n 106) and ARNI-users (n 312). At one year of follow-up, ARNI-users vs. Non-ARNI users showed lowest inflammatory markers (p < 0.01) and miR-181 levels (p < 0.01) and higher values of miR-18 (p < 0.01)and miR-145 (p < 0.01). At one year of follow-up, ARNI-users had a higher increase of LVEF (p < 0.01) and 6MWT (p < 0.01) along with a more significant reduction of LVESv (p < 0.01) compared to Non-ARNI users. Cox regression analysis evidenced that ARNI-based therapies increase the probability of anti-remodeling effects of CRTd. Based on symptomatic improvements, echocardiographic and functional classification improvements, 37 (34.9%) patients among ARNI-users became responders, while only twenty (6.4%) patients became responders among Non-ARNi-users. ConclusionsARNI might influence epigenetic mechanisms modulating miRs implicated in the adverse cardiac remodeling responses to CRTd.

Deficiency of Ataxia Telangiectasia‐mutated Kinase (ATM) Preserves Heart Function by Affecting Cardiac Remodeling in Response to Western‐type Diet in Female Mice

BACKGROUNDWestern‐type Diet (WD) and deficiency of ATM protein independently associate with heart disease. Previous work demonstrated that WD in male ATM deficient mice induces accelerated body weight gain and heart dysfunction (Am J Physiol Heart Circ Physiol. 2021;320:H2324‐H2338). Conversely, WD in female ATM deficient mice attenuates weight gain and preserves heart function (unpublished data). Here, we investigated the mechanism by which ATM deficiency preserves heart function in female mice. It is hypothesized that ATM deficiency attenuates adverse myocardial remodeling in female mice, thereby preserving heart function.METHODSFemale wild‐type (WT) and ATM heterozygous knockout (hKO) mice, aged 6 weeks, were fed with normal chow (NC) or WD for 14 weeks. Heart sections were stained with Masson’s trichrome to quantify fibrosis, TUNEL‐stained to quantify apoptosis, and WGA (wheat germ agglutinin)‐stained to quantify myocyte hypertrophy. Data were analyzed using ANOVA followed by Student‐Newman‐Keuls test.RESULTSATM deficiency associated with increased fibrosis, apoptosis (myocytes and non‐myocytes) and hypertrophy in hKO‐NC vs WT‐NC (p&lt;0.05; n=4). WD significantly increased fibrosis in WT‐WD mice, while no increase in fibrosis was observed in hKO‐WD. WD significantly increased apoptosis in both genotypes. However, the increase in apoptosis was significantly lower in hKO‐WD vs WT‐WD (p&lt;0.05; n=4). WD increased hypertrophy in WT group. However, the hypertrophy remained significantly higher in hKO‐WD vs WT‐WD (p&lt;0.05; n=4).CONCLUSIONDecrease in myocardial fibrosis and apoptosis, and increase in myocyte hypertrophy may play a role in preservation of heart function in ATM deficient female mice in response to WD.

Autophagy is Involved in Cardiac Remodeling in Response to Environmental Temperature Change.

Objectives: To study the reversibility of cold-induced cardiac hypertrophy and the role of autophagy in this process. Background: Chronic exposure to cold is known to cause cardiac hypertrophy independent of blood pressure elevation. The reversibility of this process and the molecular mechanisms involved are unknown. Methods: Studies were performed in two-month-old mice exposed to cold (4°C) for 24 h or 10 days. After exposure, the animals were returned to room temperature (21°C) for 24 h or 1 week. Results: We found that chronic cold exposure significantly increased the heart weight/tibia length (HW/TL) ratio, the mean area of cardiomyocytes, and the expression of hypertrophy markers, but significantly decreased the expression of genes involved in fatty acid oxidation. Echocardiographic measurements confirmed hypertrophy development after chronic cold exposure. One week of deacclimation for cold-exposed mice fully reverted the morphological, functional, and gene expression indicators of cardiac hypertrophy. Experiments involving injection of leupeptin at 1 h before sacrifice (to block autophagic flux) indicated that cardiac autophagy was repressed under cold exposure and re-activated during the first 24 h after mice were returned to room temperature. Pharmacological blockage of autophagy for 1 week using chloroquine in mice subjected to deacclimation from cold significantly inhibited the reversion of cardiac hypertrophy. Conclusion: Our data indicate that mice exposed to cold develop a marked cardiac hypertrophy that is reversed after 1 week of deacclimation. We propose that autophagy is a major mechanism underlying the heart remodeling seen in response to cold exposure and its posterior reversion after deacclimation.

CD74 ablation rescues type 2 diabetes mellitus-induced cardiac remodeling and contractile dysfunction through pyroptosis-evoked regulation of ferroptosis

Type 2 diabetes mellitus (T2D) contributes to sustained inflammation and myopathic changes in the heart although the precise interplay between the two remains largely unknown. This study evaluated the impact of deficiency in CD74, the cognate receptor for the regulatory cytokine macrophage migration inhibitory factor (MIF), in T2D-induced cardiac remodeling and functional responses, and cell death domains involved. WT and CD74-/- mice were fed a high fat diet (60% calorie from fat) for 8 weeks prior to injection of streptozotocin (STZ, 35 mg/kg, i.p., 3 consecutive days) and were maintained for another 8 weeks. KEGG analysis for differentially expressed genes (DEGs) reported gene ontology term related to ferroptosis in T2D mouse hearts. T2D patients displayed elevated plasma MIF levels. Murine T2D exerted overt global metabolic derangements, cardiac remodeling, contractile dysfunction, apoptosis, pyroptosis, ferroptosis and mitochondrial dysfunction, ablation of CD74 attenuated T2D-induced cardiac remodeling, contractile dysfunction, various forms of cell death and mitochondrial defects without affecting global metabolic defects. CD74 ablation rescued T2D-evoked NLRP3-Caspase1 activation and oxidative stress but not dampened autophagy. In vitro evidence depicted that high glucose/high fat (HGHF) compromised cardiomyocyte function and promoted lipid peroxidation, the effects were ablated by inhibitors of NLRP3, pyroptosis, and ferroptosis but not by the mitochondrial targeted antioxidant mitoQ. Recombinant MIF mimicked HGHF-induced lipid peroxidation, GSH depletion and ferroptosis, the effects of which were reversed by inhibitors of MIF, NLRP3 and pyroptosis. Taken together, these data suggest that CD74 ablation protects against T2D-induced cardiac remodeling and contractile dysfunction through NLRP3/pyroptosis-mediated regulation of ferroptosis.

Commensal gut microbiota-derived acetate and propionate enhance heart adaptation in response to cardiac pressure overload in mice.

Background: The gut microbiota plays a vital role in maintaining tissue homeostasis and regulating disease pathophysiology; however, the underlying mechanisms remain to be elucidated. We previously showed that mice depleted of gut microbiota with antibiotics (ABX mice) were more prone to cardiac rupture after infarction, suggesting that the gut microbiota impacts cardiac structural remodeling following injury. Here, we aimed to determine whether the gut microbiota is required for adaptive cardiac remodeling in response to pressure overload stress. Methods: Transverse aortic constriction (TAC) surgery was performed and cardiac function was evaluated by echocardiography and catheterization, followed by mechanical tests and extracellular matrix (ECM) studies. Germ-free mice with cecal microbiota transplantation were used for validation. 16S ribosomal DNA sequencing and PICRUSt2 analysis were applied to predict the key metabolic pathways. ABX mice were supplemented with the derived metabolic products and their efficacy was tested. To elucidate the underlying mechanism, we isolated mouse primary cardiac fibroblasts and treated them with the metabolites. Lastly, G-coupled protein receptor 41 (GPR41) and GPR43 double knockdown cardiac fibroblasts were generated and the anti-fibrogenic effect of metabolites was determined. Results: Cardiac hypertrophy and dysfunction were more severe in ABX-TAC mice compared to the controls. Moreover, TAC-induced fibrosis was more profound in ABX hearts, which was accompanied by disrupted ECM structure making the heart tissues mechanically weaker and more brittle. Reconstruction of healthy gut microbiota in germ-free mice successfully restored cardiac function and prevented excessive fibrosis and ECM disarray under stress. Furthermore, functional prediction identified acetate and propionate as critical mediators in the gut microbiota-modulated cardiac mechanics. Supplementation of acetate and propionate improved heart function, attenuated fibrosis, and reversed ECM disarray after TAC. In addition, treating primary cardiac fibroblasts with acetate and propionate attenuated cell contraction, inhibited myofibroblast formation, and reduced collagen formation after TGF-β1 stimulus. Finally, knocking down GPR41 and GPR43 receptors in cardiac fibroblasts blunted the inhibitory effects of acetate and propionate. Conclusions: The gut microbiota is a potential therapeutic target for cardiac ECM remodeling and heart structural integrity. By establishing a healthy gut microbiome or replenishing the derived metabolites, we could improve cardiac health under dysbiosis after pressure-overload stress.

Sterile inflammation through Ca2+/ Calmodulin-dependent protein kinase II signaling is essential for adverse cardiac remodeling

Abstract Introduction and hypothesis Sterile inflammation is associated with cardiac remodeling in response to non-ischemic stress, but how it is initiated in the absence of cell death and how it is propagated are not well elucidated. We tested the hypothesis that activation of CaMKII in cardiomyocytes and macrophages in response to pressure overload initiates inflammatory responses leading to adverse cardiac remodeling. Methods and results Cardiomyocyte specific CaMKIIδ knockout (CKO) mice were subjected to transverse aortic constriction (TAC). CaMKII and NFkB activation were significantly increased in control fl/fl (CTL) but not in CKO hearts. Cardiac mRNA levels for pro-inflammatory cytokines also increased vs sham. These responses were significantly attenuated in the CKO mice. Activated NLRP3 inflammasome was shown by elevated caspase-1 activity in isolated cardiomyocytes of CTL while attenuated in CKO. Macrophage accumulation was attenuated in the CKO and NLRP3 inhibitor MCC950 treated mice. Cardiac fibrosis and subsequent cardiac dysfunction were less impaired in the CKO vs CTL (ejection fraction 43±3% vs 33±5%). Upregulated NLRP3 gene expression, elevated CaMKII and caspase-1 activity were observed in neonatal mouse cardiomyocytes (NMCMs) in response to osmotic stretch. Increased caspase-1 activity was observed in macrophages cultured with media from osmotic-stretched NMCMs and it was attenuated by pretreatment of CaMKII inhibitor KN-93. Coincubation with stretched NMCMs induced inflammatory responses in isolated macrophages from wild-type mice but not in isolated macrophages from KN-93 pretreated mice. Conclusions Activated CaMKIIδ in response to pressure overload triggers inflammatory signals including NLRP3 inflammasome cascade in cardiomyocytes. CaMKII could also contribute amplification of inflammasome signal in macrophages leading fibrosis and consequent cardiac dysfunction. CaMKII in cardiomyocytes and macrophages could be a therapeutic target to prevent progression of non-ischemic heart failure. Funding Acknowledgement Type of funding sources: None.

Renin-angiotensin-aldosterone system genotypes and cardiac remodeling response to essential hypertension

Abstract Background/Introduction Cardiac remodeling represent a response to uncontrolled essential hypertension (EHT). The morphological response is expressed by left ventricular (LV) mass index values and/or relative wall thickness (RWT) &amp;gt;0.42. Functionally response is expressed by isolated alteration of LV diastolic function (E/A&amp;lt;1). Purpose We aimed to establish the association between anatomical and functional adaptation to EHT, with two genetic variants of the renin-angiotensin-aldosterone system (RAAS): M235T-AGT and A3123C-R2 AngII. Methods In 139 hypertensive subjects cohort, we determined the M235T-AGT and A3123C-R2 AngII genotypes, using polymerase chain reaction-restriction fragment length polymorphism methods. The relationship between the studied RAAS gene polymorphisms and morphological and functional cardiac remodeling was assessed by multiple logistic regressions. Results We found that the C/C, A/C genotypes of the A3123C-R2 AngII polymorphism were statistically significantly associated with RWT&amp;lt;0.42 (p=0.033), so hypertensive patients carrying this genotype had a 2.7-fold increased risk to have a non-concentric type of cardiac response. The association was maintained even after adjustment for confounders - age, body mass index (BMI), systolic blood pressure (BP), and diastolic BP (p=0.008). We found statistically significant associations between LV diastolic dysfunction in hypertensive patients cohort carrying the T/T, M/T genotypes (M235T-AGT polymorphism) (p=0.037). Moreover, the association remained statistically significant even after adjustment for age, BMI, systolic BP, and diastolic BP (p=0.039). We could not identify any statistically significant associations between M235T-AGT, A3123C-R2 AngII polymorphisms, and LV mass index. Conclusion(s) Non-concentric type of cardiac response to essential hypertension was associated with A3123C-R2 AngII polymorphism. M235T-AGT polymorphism was found to be statistically significantly associated with alteration of LV diastolic function. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj-Napoca, as part of Doctoral Research Projects (DRP) 2016

Association of Adiponectin, Leptin and Resistin Plasma Concentrations with Echocardiographic Parameters in Patients with Coronary Artery Disease.

The imbalanced network of adipokines may contribute to the development of systemic low-grade inflammation, metabolic diseases and coronary artery disease (CAD). In the last decade, three classic adipokines—adiponectin, leptin and resistin—have been of particular interest in studies of patients with CAD due to their numerous properties in relation to the cardiovascular system. This has directed our attention to the association of adipokines with cardiac structure and function and the development of heart failure (HF), a common end effect of CAD. Thus, the purpose of this study was to analyse the associations of plasma concentrations of adiponectin, leptin and resistin with parameters assessed in the echocardiographic examinations of CAD patients. The presented study enrolled 167 Caucasian patients (133 male; 34 female) with CAD. Anthropometric, echocardiographic and basic biochemical measurements, together with plasma concentrations of adiponectin, leptin and resistin assays, were performed in each patient. Adiponectin concentrations were negatively associated with left ventricular ejection fraction (LVEF) and shortening fraction (LVSF), and positively associated with mitral valve E/A ratio (E/A), left ventricular end-diastolic volume (LVEDV), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter LVESD, and left atrium diameter (LAD). Resistin concentrations were negatively associated with E/A. Leptin concentrations, although correlated with HF severity assessed by the New York Heart Association (NYHA) Functional Classification, were not independently associated with the echocardiographic parameters of cardiac structure or function. In conclusion, adiponectin and resistin, but not leptin, are associated with the echocardiographic parameters of cardiac remodelling and dysfunction. These associations suggest that adiponectin and resistin might be involved in mechanisms of cardiac remodelling or compensative response. We also suggest the possible benefits of adiponectin and resistin level measurements in the monitoring of patients with CAD.

Abstract MP259: The Role Of Sertad4 In Pathological Cardiac Remodeling

Over 6 million Americans suffer from heart failure (HF) while the 5-year mortality rate following first admission for HF is over 40%. Cardiac fibrosis is a clinical hallmark of HF, regardless of the initiating pathology and is thought to contribute to disease progression. Using an epigenomics discovery approach, we uncovered a nuclear protein, Sertad4, as a potential anti-fibrotic target. Our data indicate that Sertad4 is a positive regulator of fibroblast activation. Specifically, cultured cardiac fibroblast experiments demonstrate that Sertad4 targeting with shRNAs blocks fibroblast proliferation and causes cells to arrest in the G2/M phase of the cell cycle. Also, shRNA targeting of Sertad4 dramatically blocked activation of myofibroblast differentiation genes (αSMA/POSTN/COL1A1). Mechanistically, these effects appear to be mediated by Sertad4 regulation of SMAD2 protein stability in the presence of TGF-β1 stimulation as demonstrated by proteasome inhibition experiments. RNA-seq analysis indicate that Sertad4 also regulates the expression of genes involved in ubiquitination and proteasome degradation. Next, we sought to determine the effect of global Sertad4 knockout on post-myocardial infarct (MI) remodeling and cardiac function in mice. After 4 weeks of permanent LAD ligation, echocardiography was performed to measure systolic function. Relative to wild-type (WT) controls, the Sertad4 KO mice showed preserved systolic function as evident by improved ejection fraction (WT 14.4 +/- 3.6 vs. KO 33.9+/-5.9, p=0.035) and fractional shortening (WT 6.5 +/- 1.7 vs. KO 16.4 +/- 3.4, p=0.046). β-gal staining in the Sertad4/LacZ reporter mouse subjected to MI showed robust Sertad4/LacZ expression in the ischemic scar and boarder-zone with almost no expression in control hearts. This data supports the notion that Sertad4 has a key role in cardiac remodeling in response to ischemic injury.

Abstract P231: Aspirin Reverses Placental Gene Expression Changes Associated With Preeclampsia

Aspirin is the only medication recommended for preventing preeclampsia, a hypertensive disorder of pregnancy. However, the mechanism(s) by which aspirin prevents preeclampsia are unknown. To better understand the mechanism by which aspirin prevents preeclampsia, we compared expression of genes involved in signal transduction, cardiac remodeling, ion transport, stress and immune response, apoptosis, sarcomere structure, transcriptional regulation, and cell cycle regulation between placental tissues from 4 different cohorts: preeclamptic women, preeclamptic women who took aspirin during pregnancy, non-preeclamptic women, and non-preeclamptic women who took aspirin (N=3 per cohort). Tissues were obtained from the University of Iowa Maternal Fetal Tissue Bank (IRB# 200910784). When comparing whole thickness samples, 27 genes had a greater than 5-fold change in expression in the tissues of women with preeclampsia compared to those without. For example, CDKN1B whose protein inhibits the cell cycle, is increased in preeclampsia (-3.7ΔΔCt, 13.4-fold increase). However, in women who took aspirin, both those that developed preeclampsia and those who did not, CDKN1B expression was similar to women without preeclampsia who did not take aspirin indicating a decrease in gene expression in response to aspirin. However, aspirin also increases expression of several genes associated with preeclampsia. For example, we identified that RGS2 and PLAC1 in the decidual layer of the placenta were increased in response to aspirin. Decreases in expression of both genes is associated with preeclampsia. However, 19 genes whose expression is increased in preeclampsia compared to controls had no response to aspirin. Identifying specific genes and pathways that serve as targets of aspirin during pregnancy provides valuable insight into the mechanisms by which aspirin reduces the occurrence of preeclampsia and may help to identify who would benefit most from its use. Additionally, it may identify targets for the development of other preeclampsia preventative or therapeutic medications.

Untying the Gordian knot of sex and heart failure therapy

Untying the Gordian knot of sex and heart failure therapy

Adaptive versus maladaptive cardiac remodelling in response to sustained β-adrenergic stimulation in a new 'ISO on/off model'.

On the one hand, sustained β-adrenergic stress is a hallmark of heart failure (HF) and exerts maladaptive cardiac remodelling. On the other hand, acute β-adrenergic stimulation maintains cardiac function under physiological stress. However, it is still incompletely understood to what extent the adaptive component of β-adrenergic signaling contributes to the maintenance of cardiac function during chronic β-adrenergic stress. We developed an experimental catecholamine-based protocol to distinguish adaptive from maladaptive effects. Mice were for 28 days infused with 30 mg/kg body weight/day isoproterenol (ISO) by subcutaneously implanted osmotic minipumps (‘ISO on’). In a second and third group, ISO infusion was stopped after 26 days and the mice were observed for additional two or seven days without further ISO infusion (‘ISO off short’, ‘ISO off long’). In this setup, ‘ISO on’ led to cardiac hypertrophy and slightly improved cardiac contractility. In stark contrast, ‘ISO off’ mice displayed progressive worsening of left ventricular ejection fraction that dropped down below 40%. While fetal and pathological gene expression (increase in Nppa, decrease in Myh6/Myh7 ratios, increase in Xirp2) was not induced in ‘ISO on’, it was activated in ‘ISO off’ mice. After ISO withdrawal, phosphorylation of phospholamban (PLN) at the protein kinase A (PKA) phosphorylation site Ser-16 dropped down to 20% as compared to only 50% at the Ca2+/Calmodulin-dependent kinase II (CaMKII) phosphorylation site Thr-17 in ‘ISO off’ mice. PKA-dependent cardioprotective production of the N-terminal proteolytic product of histone deacetylase 4 (HDAC4-NT) was reduced in ‘ISO off’ as compared to ‘ISO on’. Taken together, these data indicate that chronic ISO infusion induces besides maladaptive remodelling also adaptive PKA signalling to maintain cardiac function. The use of the ‘ISO on/off’ model will further enable the separation of the underlying adaptive from maladaptive components of β-adrenergic signalling and may help to better define and test therapeutic targets downstream of β-adrenergic receptors.

Cardiorenal Systems Modeling: Left Ventricular Hypertrophy and Differential Effects of Antihypertensive Therapies on Hypertrophy Regression.

Cardiac and renal function are inextricably connected through both hemodynamic and neurohormonal mechanisms, and the interaction between these organ systems plays an important role in adaptive and pathophysiologic remodeling of the heart, as well as in the response to renally acting therapies. Insufficient understanding of the integrative function or dysfunction of these physiological systems has led to many examples of unexpected or incompletely understood clinical trial results. Mathematical models of heart and kidney physiology have long been used to better understand the function of these organs, but an integrated model of renal function and cardiac function and cardiac remodeling has not yet been published. Here we describe an integrated cardiorenal model that couples existing cardiac and renal models, and expands them to simulate cardiac remodeling in response to pressure and volume overload, as well as hypertrophy regression in response to angiotensin receptor blockers and beta-blockers. The model is able to reproduce different patterns of hypertrophy in response to pressure and volume overload. We show that increases in myocyte diameter are adaptive in pressure overload not only because it normalizes wall shear stress, as others have shown before, but also because it limits excess volume accumulation and further elevation of cardiac stresses by maintaining cardiac output and renal sodium and water balance. The model also reproduces the clinically observed larger LV mass reduction with angiotensin receptor blockers than with beta blockers. We further provide a mechanistic explanation for this difference by showing that heart rate lowering with beta blockers limits the reduction in peak systolic wall stress (a key signal for myocyte hypertrophy) relative to ARBs.

Cardiac ankyrin repeat protein contributes to dilated cardiomyopathy and heart failure.

Cardiac ankyrin repeat protein (CARP) is a cardiac-specific stress-response protein which exerts diverse effects to modulate cardiac remodeling in response to pathological stimuli. We examined the role of CARP in postnatal cardiac development and function under basal conditions in mice. Transgenic mice that selectively overexpressed CARP in heart (CARP Tg) exhibited dilated cardiac chambers, impaired heart function, and cardiac fibrosis as assessed by echocardiography and histological staining. Furthermore, the mice had a shorter lifespan and reduced survival rate in response to ischemic acute myocardial infarction. Immunofluorescence demonstrated the overexpressed CARP protein was predominantly accumulated in the nuclei of cardiomyocytes. Microarray analysis revealed that the nuclear localization of CARP was associated with the suppression of calcium-handling proteins. In vitro experiments revealed that CARP overexpression resulted in decreased cell contraction and calcium transient. In post-mortem cardiac specimens from patients with dilated cardiomyopathy and end-stage heart failure, CARP was significantly increased. Taken together, our data identified CARP as a crucial contributor in dilated cardiomyopathy and heart failure which was associated with its regulation of calcium-handling proteins.

T helper 17 cell responses induce cardiac hypertrophy and remodeling in essential hypertension.

An increasing body of evidence has shown that type 17 helper T (TH17) cell responses play an important role in the progression of cardiac remodeling stimulated by long‑term pressure overload. We aimed to investigate the relationship between TH17 responses and cardiac remodeling, and the prognostic value of TH17 responses in hypertensive patients. A total of 187 adults with hypertension and 70 healthy controls were enrolled in the present study. TH17 cell frequencies, matrix metallopeptidase 9, procollagen type I, and procollagen type III were studied at baseline. All adults underwent routine echocardiography to assess left ventricular diastolic function (LVDF) at baseline and after 24 months of follow‑up. The percentage of TH17 cells was increased in hypertensive patients, particularly in adults with left ventricular hypertrophy (LVH). Receiver operating characteristic (ROC) analysis revealed that the area under the curve (AUC) of TH17 cells for predicting of LVH was 0.943 (95% CI, 0.914-0.971; P <0.001) and the cutoff value was 2.3%. On logistic regression analysis, the percentage of TH17 cells was an independent predictor of LVH (odds ratio, 1.47; 95% CI, 2.23-2.28; P = 0.005). The percentage of TH17 cells significantly correlated with the levels of fibrotic parameters. According to the cutoff value of TH17 cells, patients with a lower level of TH17 cell differentiation had a better prognosis. The differentiation of TH17 cells reflected the cardiac hypertrophy and remodeling response to hypertension‑induced pressure overload, and it might be a potential inflammatory marker to predict the prognosis of hypertensive patients.

The Role of Tbx20 in Cardiovascular Development and Function

Tbx20 is a member of the Tbx1 subfamily of T-box-containing genes and is known to play a variety of fundamental roles in cardiovascular development and homeostasis as well as cardiac remodeling in response to pathophysiological stresses. Mutations in TBX20 are widely associated with the complex spectrum of congenital heart defects (CHDs) in humans, which includes defects in chamber septation, chamber growth, and valvulogenesis. In addition, genetic variants of TBX20 have been found to be associated with dilated cardiomyopathy and heart arrhythmia. This broad spectrum of cardiac morphogenetic and functional defects is likely due to its broad expression pattern in multiple cardiogenic cell lineages and its critical regulation of transcriptional networks during cardiac development. In this review, we summarize recent findings in our general understanding of the role of Tbx20 in regulating several important aspects of cardiac development and homeostasis and heart function.

Differential expression of exosomal circRNAs and regulatory framework genes in myocardial infarction patients with cardiac remodeling in response to Tongguan Capsules

Differential expression of exosomal circRNAs and regulatory framework genes in myocardial infarction patients with cardiac remodeling in response to Tongguan Capsules

Catecholamine-induced cardiomyopathy: an endocrinologist's perspective.

Although many endocrine diseases can be associated with acquired cardiomyopathy and heart failure, conditions except hypothyroidism, hyperthyroidism, phaeochromocytoma-paraganglioma (PPGL), and primary hyperaldosteronism are rare. PPGL is a rare catecholamine-secreting neuroendocrine tumour arising from the adrenal gland in 80-85% or extra-adrenal chromaffin cells of the autonomic neural ganglia in the remainder. The annual incidence of PPGL is 3-8 cases per million per year in the general population. Catecholamine-induced cardiomyopathy (CICMP) has got a prevalence of 8-11% among patients with PPGL. Hypertension, either sustained or episodic, is present in the vast majority (95%) of PPGL patients. However, among patients with CICMP, hypertension is present only in 65% of cases and the classical triad of paroxysmal headache, sweating, and palpitation is present only in 4%. Based on the cardiac remodelling in response to endogenous catecholamine excess, PPGL patients might present with one of the three CICMPs, including dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), or Takotsubo cardiomyopathy (TCM). Regardless of the subtypes, all CICMPs have many features in common - a dramatic clinical presentation, reversible cardiomyopathy, similar repolarisation electrocardiography changes, mild-moderate cardiac biomarker elevation, and normal coronary arteries on coronary angiography. CICMP should be suspected in patients with non-ischaemic, non-valvular forms of cardiomyopathy, even in those without definite features of catecholamine excess. PPGL associated TCM should be suspected in all acute coronary syndrome (ACS) patients exhibiting pronounced blood pressure variability with no culprit lesions on coronary angiography. This article will provide a review of the various CICMPs, their pathophysiology, clinical features, and the management options.