Semaglutide ameliorates pressure overload-induced cardiac hypertrophy by improving cardiac mitophagy to suppress the activation of NLRP3 inflammasome.

Pathological cardiac hypertrophy is an important cause of heart failure(HF). Recent studies reveal that glucagon-like peptide-1 receptor (GLP1R) agonists can improve mortality and left ventricular ejection fraction in the patients with type 2 diabetes and HF. The present study aims to investigate whether semaglutide, a long-acting GLP1R agonist, can ameliorate cardiac hypertrophy induced by pressure overload, and explore the potential mechanism. The rats were performed transverse aortic constriction (TAC) to mimic pressure overload model. The rats were divided into four groups including Sham, TAC, TAC + semaglutide, and TAC + semaglutide + HCQ (hydroxychloroquine, an inhibitor of mitophagy). The rats in each experimental group received their respective interventions for 4 weeks. The parameters of left ventricular hypertrophy(LVH) were measured by echocardiography, Hematoxylin-eosin (HE) staining, western-blot and immunohistochemistry (IHC), respectively. The changes of mitophagy were reflected by detecting cytochrome c oxidase subunit II (COXII), LC3II/LC3I, mitochondria, and autophagosomes. Meanwhile, NLRP3, Caspase-1, and interleukin-18 were detected to evaluate the activation of NLRP3 inflammasome in each group. The results suggest that LVH, impaired mitophagy, and activation of NLRP3 inflammasome were present in TAC rats. Semaglutide significantly reduced LVH, improve mitophagy, and down-regulated NLRP3 inflammatory signal pathway in TAC rats. However, the reversed effect of semaglutide on cardiac hypertrophy was abolished by HCQ, which restored the activation of NLRP3 inflammasome suppressed by improved mitophagy. In conclusion, semaglutide ameliorates the cardiac hypertrophy by improving cardiac mitophagy to suppress the activation of NLRP3 inflammasome. Semaglutide may be a novel potential option for intervention of cardiac hypertrophy induced by pressure overload.

Effect of Stanozolol and/or Cannabis Abuse on Hypertrophic Mechanism and Oxidative Stress of Male Albino Rat Cardiac Tissue in Relation to Exercise: A Sport Abuse Practice.

Adolescents commonly co-abuse many drugs including anabolic androgenic steroids either they are athletes or non-athletes. Stanozolol is the major anabolic used in recent years and was reported grouped with cannabis. The current study aimed at evaluating the biochemical and histopathological changes related to the hypertrophic effects of stanozolol and/or cannabis whether in condition of exercise practice or sedentary conditions. Adult male Wistar albino rats received either stanozolol (5 mg/kg, s.c), cannabis (10 mg/kg, i.p.), and a combination of both once daily for two months. Swimming exercise protocol was applied as a training model. Relative heart weight, oxidative stress biomarkers, cardiac tissue fibrotic markers were evaluated. Left ventricular morphometric analysis and collagen quantification was done. The combined treatment exhibited serious detrimental effects on the heart tissues. It increased heart tissue fibrotic markers (Masson's trichrome stain (p < 0.001), cardiac COL3 (p < 0.0001), and VEGF-A (p < 0.05)), lowered heart glutathione levels (p < 0.05) and dramatically elevated oxidative stress (increased malondialdehyde (p < 0.0001) and 8-OHDG (p < 0.0001)). Training was not ameliorating for the observed effects. Misuse of cannabis and stanozolol resulted in more hypertrophic consequences of the heart than either drug alone, which were at least largely assigned to oxidative stress, heart tissue fibrotic indicators, histological alterations, and morphometric changes.

Prevention and treatment of hypertensive left ventricular hypertrophy.

PURPOSE OF REVIEW: Left ventricular (LV) hypertrophy (LVH) is a well recognized target organ adaptation to longstanding uncontrolled hypertension and other cardiovascular risk factors. It is also a strong and independent predictor of many cardiovascular disorders. RECENT FINDINGS: This focused review explores the current concepts in screening, diagnosis, prevention, and treatment of LVH in patients with hypertension. Currently, the primary screening and diagnostic tools for LVH are ECG and 2D echocardiography. Implementing machine learning in the diagnostic modalities can improve sensitivity in the detection of LVH. Lifestyle modifications, blood pressure control with antihypertensive therapy, and management of comorbidities aid in preventing and reversing LV remodeling. SUMMARY: LVH is a common and often silent complication of hypertension. Prevention and reversal of LV remodeling are crucial for cardiovascular risk reduction in patients with hypertension.

Hypericin Alleviates Chronic Kidney Disease-induced Left Ventricular Hypertrophy by Regulation of FGF23-FGFR4 Signaling Pathway.

ABSTRACT: Chronic kidney disease (CKD) is a significant global health threat that imposes a substantial burden on both individuals and societies. CKD frequently correlates with cardiovascular events, particularly left ventricular hypertrophy (LVH), which contributes to the high mortality rate associated with CKD. Fibroblast growth factor 23 (FGF23), a hormone primarily involved in regulating calcium and phosphorus metabolism, has been identified as a major risk factor for LVH in CKD patients. Elevated serum FGF23 levels are known to induce LVH and myocardial fibrosis by activating the fibroblast growth factor receptor 4 (FGFR4) signal pathway. Therefore, targeting FGFR4 and its downstream signaling pathways holds potential as a treatment strategy for cardiac dysfunction in CKD. In our current study, we have discovered that Hypericin, a key component derived from Hypericum perforatum , has the ability to alleviate CKD-related LVH by targeting the FGFR4/phospholipase C gamma 1 (PLCγ1) signaling pathway. Through in vitro experiments using rat cardiac myocyte H9c2 cells, we observed that Hypericin effectively inhibits FGF23-induced hypertrophy and fibrosis by suppressing the FGFR4/PLCγ1/calcineurin/nuclear factor of activated T-cell (NFAT3) signaling pathway. In addition, our in vivo studies using mice on a high-phosphate diet and rat models of 5/6 nephrectomy demonstrated that Hypericin has therapeutic effects against CKD-induced LVH by modulating the FGFR4/PLCγ1/calcineurin/NFAT3 signaling pathway. In conclusion, our research highlights the potential of Hypericin as a candidate for the treatment of CKD-induced cardiomyopathy. By suppressing the FGFR4/PLCγ1 signaling pathway, Hypericin shows promise in attenuating LVH and myocardial fibrosis associated with CKD.

Complexation of the Antihypertensive Drug Olmesartan with Zn: In Vivo Antihypertensive and Cardiac Effects.

This study is based on the premise that the application of chemical synthesis strategies to structurally modify commercial drugs by complexation with biometals is a valid procedure to improve their biological effects. Our purpose is to synthesize a compound with greater efficacy than the original drug, able to enhance its antihypertensive and cardiac pharmacological activity. Herein, the structure of the coordination compound of Zn(II) and the antihypertensive drug olmesartan, [Zn(Olme)(H2O)2] (ZnOlme), is presented. After 8 weeks of treatment in SHR male rats, ZnOlme displayed a better blood pressure-lowering activity compared with olmesartan, with a noticeable effect even in the first weeks of treatment, while ZnCl2 showed similar results than the control. ZnOlme also reduced left ventricle (LV) weight and left ventricle/tibia length ratio (LV/TL), posterior wall thickness (PWT), and intraventricular septum in diastole (IVSd) suggesting its potential to prevent LV hypertrophy. Besides, ZnOlme reduced interstitial fibrosis (contents of collagen types I and III, responsible for giving rigidity and promoting vascular elasticity, respectively). The recovery of heart function was also evidenced by fractional shortening (diastolic left ventricular/systolic left ventricular) diameter determinations. Furthermore, ZnOlme increased the antioxidant capacity and prevented cardiac oxidative stress: it enhanced the reduction of reactive oxygen species generation, exerted a significant decrease in lipid peroxidation and enhanced glutathione contents in heart tissues compared to the control, Zn, and olmesartan treatments. Our results demonstrate that continuous oral administration of ZnOlme causes a better antihypertensive effect and grants enhancement of cardioprotection through antioxidant activity, in combination with hemodynamic improvement.

Beta-blockers in Hypertensive Left Ventricular Hypertrophy and Atrial Fibrillation Prevention.

BACKGROUND: Hypertensive left ventricular hypertrophy (HTN LVH) is a key risk factor for atrial fibrillation (AF). OBJECTIVE: To evaluate the possible role of beta-blockers (BBs) in addition to a renin-angiotensinaldosterone system (RAAS) blocker in AF prevention in patients with HTN LVH. METHODS: We performed a PubMed, Elsevier, SAGE, Oxford, and Google Scholar search with the search items 'beta blocker hypertension left ventricular hypertrophy patient' from 2013-2023. In the end, a 'snowball search', based on the references of relevant papers as well as from papers that cited them was performed. RESULTS: HTN LVH is a risk factor for AF. In turn, AF substantially complicates HTN LVH and contributes to the genesis of heart failure (HF) with preserved ejection fraction (HFpEF). The prognosis of HFpEF is comparable with that of HF with reduced EF (HFrEF), and, regardless of the type, HF is associated with five-year mortality of 50-75%. The antiarrhythmic properties of BBs are wellrecognized, and BBs as a class of drugs are - in general - recommended to decrease the incidence of AF in HTN. CONCLUSION: BBs are recommended (as a class) for AF prevention in several contemporary guidelines for HTN. LVH regression in HTN - used as a single criterion for the choice of antihypertensive medication - does not capture this protective effect. Consequently, it is worth studying how meaningful this antiarrhythmic action (to prevent AF) of BBs is in patients with HTN LVH in addition to a RAAS blocker.

Metabolic surgery in improving arterial health in obese individuals.

PURPOSE: Arterial stiffness has gained recognition as a stand-alone risk factor for cardiovascular disease (CVD). Obesity is intricately linked to elevated arterial stiffness, the development of left ventricular (LV) hypertrophy, and the emergence of diastolic dysfunction, all of which collectively contribute substantially to an unfavorable prognosis. Weight loss has become a standard recommendation for all patients with CVD concurrent with morbid obesity; however, randomized evidence to support this recommendation was limited earlier. The latest scientific studies revealed dynamic changes in aortic stiffness after substantial weight loss by bariatric surgery, also known as metabolic surgery, in patients with obesity. There is also a favorable evolution in LV hypertrophy and a significant impact on arterial hypertension and other promising cardiovascular outcomes in obese people after bariatric surgery. METHODS/RESULTS: We aimed to examine the cardiovascular effects of various metabolic surgeries in morbidly obese individuals, especially their role in improving arterial health, the potential impact on surrogate markers of atherosclerotic vascular disease, and consequently reducing the likelihood of cardiovascular events. CONCLUSION: In conclusion, metabolic surgery is associated with a significant decrease in the occurrence of major adverse cardiovascular events (MACE) and all-cause mortality among obese individuals, alongside remarkable enhancement of arterial health. These findings underscore the critical importance of implementing strategies to combat obesity and reduce adiposity within the general population.

Rationale and design of a randomised trial of trientine in patients with hypertrophic cardiomyopathy.

AIMS: Hypertrophic cardiomyopathy (HCM) is characterised by left ventricular hypertrophy (LVH), myocardial fibrosis, enhanced oxidative stress and energy depletion. Unbound/loosely bound tissue copper II ions are powerful catalysts of oxidative stress and inhibitors of antioxidants. Trientine is a highly selective copper II chelator. In preclinical and clinical studies in diabetes, trientine is associated with reduced LVH and fibrosis, and improved mitochondrial function and energy metabolism. Trientine was associated with improvements in cardiac structure and function in an open-label study in patients with HCM. METHODS: The Efficacy and Mechanism of Trientine in Patients with Hypertrophic Cardiomyopathy (TEMPEST) trial is a multicentre, double-blind, parallel group, 1:1 randomised, placebo-controlled phase II trial designed to evaluate the efficacy and mechanism of action of trientine in patients with HCM. Patients with a diagnosis of HCM according to the European Society of Cardiology Guidelines and in New York Heart Association classes I-III are randomised to trientine or matching placebo for 52 weeks. Primary outcome is change in left ventricular (LV) mass indexed to body surface area, measured using cardiovascular magnetic resonance. Secondary efficacy objectives will determine whether trientine improves exercise capacity, reduces arrhythmia burden, reduces cardiomyocyte injury, improves LV and atrial function, and reduces LV outflow tract gradient. Mechanistic objectives will determine whether the effects are mediated by cellular or extracellular mass regression and improved myocardial energetics. CONCLUSION: TEMPEST will determine the efficacy and mechanism of action of trientine in patients with HCM. TRIAL REGISTRATION NUMBERS: NCT04706429 and ISRCTN57145331.

Eosinophils protect pressure overload- and ß-adrenoreceptor agonist-induced cardiac hypertrophy.

AIMS: Blood eosinophil (EOS) counts and EOS cationic protein (ECP) levels associate positively with major cardiovascular disease (CVD) risk factors and prevalence. This study investigates the role of EOS in cardiac hypertrophy. METHODS AND RESULTS: A retrospective cross-section study of 644 consecutive inpatients with hypertension examined the association between blood EOS counts and cardiac hypertrophy. Pressure overload- and ß-adrenoreceptor agonist isoproterenol-induced cardiac hypertrophy was produced in EOS-deficient ΔdblGATA mice. This study revealed positive correlations between blood EOS counts and left ventricular (LV) mass and mass index in humans. ΔdblGATA mice showed exacerbated cardiac hypertrophy and dysfunction, with increased LV wall thickness, reduced LV internal diameter, and increased myocardial cell size, death, and fibrosis. Repopulation of EOS from wild-type (WT) mice, but not those from IL4-deficient mice ameliorated cardiac hypertrophy and cardiac dysfunctions. In ΔdblGATA and WT mice, administration of ECP mEar1 improved cardiac hypertrophy and function. Mechanistic studies demonstrated that EOS expression of IL4, IL13, and mEar1 was essential to control mouse cardiomyocyte hypertrophy and death and cardiac fibroblast TGF-ß signalling and fibrotic protein synthesis. The use of human cardiac cells yielded the same results. Human ECP, EOS-derived neurotoxin, human EOS, or murine recombinant mEar1 reduced human cardiomyocyte death and hypertrophy and human cardiac fibroblast TGF-ß signalling. CONCLUSION: Although blood EOS counts correlated positively with LV mass or LV mass index in humans, this study established a cardioprotective role for EOS IL4 and cationic proteins in cardiac hypertrophy and tested a therapeutic possibility of ECPs in this human CVD.

Aurintricarboxylic acid protects isoproterenol induced left ventricular hypertrophy by modulating TWEAK signaling.

BACKGROUND: Cardiac hypertrophy is regarded as a compensation mechanism to overcome the increased workload. Aurintricarboxylic acid (ATA) is a derivative of quinomethanes and a selective inhibitor of TWEAK/Fn14 pathway. In this study, we investigated the effect of ATA on isoproterenol (ISO)-induced pathological cardiac hypertrophy. METHODS: Cardiac hypertrophy in H9C2 cells was induced using ISO 20 µM dissolved in PBS. H9C2 cells were treated with ATA (5 µM, 10 µM, 20 µM) followed by ISO stimulation for 24 h. Male SD rats were injected ISO (5 mg/kg/day, s.c) for 21 days and followed by treatment with ATA (10 mg/kg, i.p.) for 14 days. Cardiac functions were assessed. After sacrifice, hearts were subjected to histopathological and western blot analysis. RESULTS: In in-vitro results, upon ATA treatment, ICC results showed significant decrease in TWEAK and ANP expression. In in-vivo results, echocardiography showed significant restoration of cardiac function in ATA treated rats. Histopathological analysis showed a significant decrease in left ventricular wall thickness, cardiomyocytes width and reduced fibrosis in ATA treated rats. Western blotting showed decreased expression of the cardiac hypertrophy maker ANP, inflammatory markers including TWEAK and apoptotic markers after ATA treatment. CONCLUSION: These findings suggested that the TWEAK/Fn14 pathway could be a potential target for therapeutic exploration in ISO induced cardiac hypertrophy. ATA, as an inhibitor of this pathway, exerted significant cardioprotective effect against ISO-induced cardiac hypertrophy in rats.

A Discrepancy: Calcium Channel Blockers Are Effective for the Treatment of Hypertensive Left Ventricular Hypertrophy but Not as Effective for Prevention of Heart Failure.

Arterial hypertension (HTN) is important due to its high prevalence, morbidity, and mortality rates. Calcium channel blockers (CCBs) are the first-line antihypertensive drugs. HTN can lead to heart failure (HF) by causing hypertensive left ventricular hypertrophy (HTN LVH). CCBs are recommended for the treatment of HTN LVH. The aim of this study was to analyze the status of CCBs regarding (1) HTN LVH treatment and (2) capability to prevent HTN-induced HF in the guidelines. For this narrative review, the following databases were searched: Medline, Scopus, Science Direct, Springer, SAGE, Wiley, Oxford Journals, Cambridge, and Google Scholar. CCBs are effective antihypertensive drugs and a very good therapeutic option for HTN LVH as they can cause reverse LVH remodeling. Consequently, we may expect that CCBs would prevent HF. However, evidence suggests that CCBs confer less protection from HF than other first-line antihypertensive drugs. A negative inotropic action of nondihydropyridine CCBs may contribute to suboptimal protection against HF. This discrepancy is clinically relevant because CCBs are in one of the two recommended (single pill) combinations for the initial treatment of HTN. LVH is a strong risk factor for HF in HTN patients. When LVH arises, the risk of HF increases dramatically. CCBs are inferior to renin-angiotensin-aldosterone system blockers but still very effective in bringing about regression of HTN LVH; consequently, CCBs are expected to protect from HF. On the contrary, CCBs protect from HF less effectively than other first-line antihypertensive drugs. This discrepancy needs to be investigated further to improve clinical practice.

mTOR inhibitor improves testosterone-induced myocardial hypertrophy in hypertensive rats.

Compelling evidence has described that the incidence of hypertension and left ventricular hypertrophy (LVH) in postmenopausal women is significantly increased worldwide. Our team's previous research identified that androgen was an underlying factor contributing to increased blood pressure and LVH in postmenopausal women. However, little is known about how androgens affect LVH in postmenopausal hypertensive women. The purpose of this study was to evaluate the role of mammalian rapamycin receptor (mTOR) signaling pathway in myocardial hypertrophy in androgen-induced postmenopausal hypertension and whether mTOR inhibitors can protect the myocardium from androgen-induced interference to prevent and treat cardiac hypertrophy. For that, ovariectomized (OVX) spontaneously hypertensive rats (SHR) aged 12 weeks were used to study the effects of testosterone (T 2.85 mg/kg/weekly i.m.) on blood pressure and myocardial tissue. On the basis of antihypertensive therapy (chlorthalidone 8 mg/kg/day ig), the improvement of blood pressure and myocardial hypertrophy in rats treated with different dose gradients of rapamycin (0.8 mg/kg/day vs 1.5 mg/kg/day vs 2 mg/kg/day i.p.) in OVX + estrogen (E 9.6 mg/kg/day, ig) + testosterone group was further evaluated. After testosterone intervention, the OVX female rats exhibited significant increments in the heart weight/tibial length (TL), area of cardiomyocytes and the mRNA expressions of ANP, ß-myosin heavy chain and matrix metalloproteinase 9 accompanied by a significant reduction in the uterine weight/TL and tissue inhibitor of metalloproteinase 1. mTOR, ribosomal protein S6 kinase (S6K1), 4E-binding protein 1 (4EBP1) and eukaryotic translation initiation factor 4E in myocardial tissue of OVX + estrogen + testosterone group were expressed at higher levels than those of the other four groups. On the other hand, rapamycin abolished the effects of testosterone-induced cardiac hypertrophy, decreased the systolic and diastolic blood pressure of SHR, and inhibited the activation of mTOR/S6K1/4EBP1 signaling pathway in a concentration-dependent manner. Collectively, these data suggest that the mTOR/S6K1/4EBP1 pathway is an important therapeutic target for the prevention of LVH in postmenopausal hypertensive female rats with high testosterone levels. Our findings also support the standpoint that the mTOR inhibitor, rapamycin, can eliminate testosterone-induced cardiomyocyte hypertrophy.

Empagliflozin Disrupts a Tnfrsf12a-Mediated Feed Forward Loop That Promotes Left Ventricular Hypertrophy.

PURPOSE: Although the cardioprotective benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors are now widely appreciated, the mechanisms underlying these benefits remain unresolved. Tumor necrosis factor receptor superfamily member 12a (Tnfrsf12a) is a receptor for tumor necrosis factor superfamily member 12 (Tnfsf12). Tnfrsf12a is highly inducible and plays a key role in the development of cardiac hypertrophy and heart failure. Here we set out to determine if SGLT2 inhibition affects the Tnfsf12/Tnfrsf12a system in the stressed myocardium. METHODS: C57BL/6N mice that had undergone sham or transverse aortic constriction (TAC) surgery were treated with either the SGLT2 inhibitor empagliflozin (400 mg/kg diet; 60-65 mg/kg/day) or standard chow alone and were followed for 8 weeks. Tnfrsf12a expression in mouse hearts was assessed by in situ hybridization, qRT-PCR, and immunoblotting. RESULTS: Left ventricular (LV) mass, end-systolic volume, and end-diastolic volume were all increased in TAC mice and were significantly lower with empagliflozin. Myocyte hypertrophy and interstitial fibrosis in TAC hearts were similarly attenuated with empagliflozin. Tnfrsf12a expression was upregulated in mouse hearts following TAC surgery but not in the hearts of empagliflozin-treated mice. In cultured cardiomyocytes, Tnfrsf12a antagonism attenuated the increase in cardiomyocyte size that was induced by phenylephrine. CONCLUSION: Empagliflozin attenuates LV enlargement in mice with hypertrophic heart failure. This effect may be mediated, at least in part, by a reduction in loading conditions which limits upregulation of the inducible, proinflammatory, and prohypertrophic TNF superfamily receptor, Tnfrsf12a. Disruption of the Tnfsf12/Tnfrsf12a feed forward system may contribute to the cardioprotective benefits of SGLT2 inhibition.

Cardiovascular Effects of Autologous Bone Marrow-Derived Mesenchymal Stromal Cell Therapy With Early Tacrolimus Withdrawal in Renal Transplant Recipients: An Analysis of the Randomized TRITON Study.

Background After renal transplantation, there is a need of immunosuppressive regimens that effectively prevent allograft rejection while minimizing cardiovascular complications. This substudy of the TRITON trial evaluated the cardiovascular effects of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in renal transplant recipients. Methods and Results Renal transplant recipients were randomized to MSC therapy, infused at weeks 6 and 7 after transplantation, with withdrawal at week 8 of tacrolimus or standard tacrolimus dose. Fifty-four patients (MSC group=27; control group=27) underwent transthoracic echocardiography at weeks 4 and 24 after transplantation and were included in this substudy. Changes in clinical and echocardiographic variables were compared. The MSC group showed a benefit in blood pressure control, assessed by a significant interaction between changes in diastolic blood pressure and the treatment group (P=0.005), and a higher proportion of patients achieving the predefined blood pressure target of <140/90 mm Hg compared with the control group (59.3% versus 29.6%, P=0.03). A significant reduction in left ventricular mass index was observed in the MSC group, whereas there were no changes in the control group (P=0.002). The proportion of patients with left ventricular hypertrophy decreased at 24 weeks in the MSC group (33.3% versus 70.4%, P=0.006), whereas no changes were noted in the control group (63.0% versus 48.1%, P=0.29). Additionally, MSC therapy prevented progressive left ventricular diastolic dysfunction, as demonstrated by changes in mitral deceleration time and tricuspid regurgitant jet velocity. Conclusions MSC strategy is associated with improved blood pressure control, regression of left ventricular hypertrophy, and prevention of progressive diastolic dysfunction at 24 weeks after transplantation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03398681.

Antagonizing the CX3CR1 Receptor Markedly Reduces Development of Cardiac Hypertrophy After Transverse Aortic Constriction in Mice.

ABSTRACT: Left-ventricular hypertrophy, characterized by cardiomyocyte hypertrophy, interstitial cell proliferation, and immune cell infiltration, is a high risk factor for heart failure and death. Chemokines interacting with G protein-coupled chemokine receptors probably play a role in left-ventricular hypertrophy development by promoting recruitment of activated leukocytes and modulating left-ventricular remodeling. Using the minimally invasive model of transverse aortic constriction in mice, we demonstrated that a variety of chemokine and chemokine receptor messenger Ribonucleic Acid are overexpressed in the early and late phase of hypertrophy progression. Among the chemokine receptors, Cx3cr1 and Ccr2 were most strongly overexpressed and were significantly upregulated at 3, 7, and 14 days after transverse aortic constriction. Ligands of CX3CR1 (Cx3cl1) and CCR2 (Ccl2, Ccl7, Ccl12) were significantly overexpressed in the left ventricle at the early stages after mechanical pressure overload. Pharmacological inhibition of CX3CR1 signaling using the antagonist AZD8797 led to a significant reduction of hypertrophy, whereas inhibition of CCR2 with the RS504393 antagonist did not show any effect. Furthermore, AZD8797 treatment reduced the expression of the hypertrophic marker genes Nppa and Nppb as well as the profibrotic genes Tgfb1 and Col1a1 at 14 days after transverse aortic constriction. These findings strongly suggest the involvement of the CX3CR1/CX3CL1 pathway in the pathogenesis of left-ventricular hypertrophy.

Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease.

Radiation-induced heart disease (RIHD) is a potential late side-effect of thoracic radiotherapy resulting in left ventricular hypertrophy (LVH) and fibrosis due to a complex pathomechanism leading to heart failure. Angiotensin-II receptor blockers (ARBs), including losartan, are frequently used to control heart failure of various etiologies. Preclinical evidence is lacking on the anti-remodeling effects of ARBs in RIHD, while the results of clinical studies are controversial. We aimed at investigating the effects of losartan in a rat model of RIHD. Male Sprague-Dawley rats were studied in three groups: (1) control, (2) radiotherapy (RT) only, (3) RT treated with losartan (per os 10 mg/kg/day), and were followed for 1, 3, or 15 weeks. At 15 weeks post-irradiation, losartan alleviated the echocardiographic and histological signs of LVH and fibrosis and reduced the overexpression of chymase, connective tissue growth factor, and transforming growth factor-beta in the myocardium measured by qPCR; likewise, the level of the SMAD2/3 protein determined by Western blot decreased. In both RT groups, the pro-survival phospho-AKT/AKT and the phospho-ERK1,2/ERK1,2 ratios were increased at week 15. The antiremodeling effects of losartan seem to be associated with the repression of chymase and several elements of the TGF-ß/SMAD signaling pathway in our RIHD model.

Cost-Effectiveness Analysis of Evolocumab Therapy in Patients at High Risk of Cardiovascular Events in the Context of the Brazilian Unified Health System. / Análise de Custo-Efetividade da Terapia com Evolocumabe em Pacientes com Alto Risco de Eventos Cardiovasculares no Contexto do SUS ­ Brasil.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) and left ventricular hypertrophy (LVH) secondary to systemic hypertension (HTN) may be associated with left atrial (LA) functional abnormalities. OBJECTIVES: We aimed to characterize LA mechanics in HCM and HTN and determine any correlation with the extent of left ventricular (LV) fibrosis measured by cardiac magnetic resonance (CMR) in HCM patients. METHODS: Two-dimensional speckle tracking-derived longitudinal LA function was acquired from apical views in 60 HCM patients, 60 HTN patients, and 34 age-matched controls. HCM patients also underwent CMR, with measurement of late gadolinium enhancement (LGE) extension. Association with LA strain parameters was analyzed. Statistical significance was set at p<0.05. RESULTS: Mean LV ejection fraction was not different between the groups. The E/e' ratio was impaired in the HCM group and preserved in the control group. LA mechanics was significantly reduced in HCM, compared to the HTN group. LA strain rate in reservoir (LASRr) and in contractile (LASRct) phases were the best discriminators of HCM, with an area under the curve (AUC) of 0.8, followed by LA strain in reservoir phase (LASr) (AUC 0.76). LASRr and LASR-ct had high specificity (89% and 91%, respectively) and LASr had sensitivity of 80%. A decrease in 2.79% of LA strain rate in conduit phase (LASRcd) predicted an increase of 1cm in LGE extension (r2=0.42, ß 2.79, p=0.027). CONCLUSIONS: LASRr and LASRct were the best discriminators for LVH secondary to HCM. LASRcd predicted the degree of LV fibrosis assessed by CMR. These findings suggest that LA mechanics is a potential predictor of disease severity in HCM.

FUNDAMENTO: Em associação às estatinas, os inibidores da pró-proteína convertase subtilisina/kexina tipo 9 (PCSK9) demonstraram ser eficazes na redução de eventos cardiovasculares em pacientes de alto risco. OBJETIVO: Analisar a custo-efetividade da implementação de evolocumabe para pacientes com alto risco de eventos cardiovasculares no contexto do Sistema Único de Saúde (SUS) no Brasil. MÉTODOS: Um modelo de Markov foi utilizado, baseando-se em uma amostra ambulatorial de pacientes com doença arterial coronariana. Os desfechos primários analisados foram infarto agudo do miocárdio, acidente vascular cerebral isquêmico (AVCi), revascularização do miocárdio e morte cardiovascular. O resultado foi expresso por meio da razão de custo-efetividade incremental (RCEI), considerando-se uma taxa de desconto de 5% ao ano, e uma análise de sensibilidade foi realizada, tendo em vista a imprecisão de valores. RESULTADOS: Selecionaram-se 61 pacientes com risco cardiovascular estimado em 35% em 10 anos, se em uso de atorvastatina 80mg/dia, e em 22,75%, se adicionado o evolocumabe. O custo global por paciente no período de 10 anos foi de R$ 46.522,44 no grupo em monoterapia com atorvastatina versus R$ 236.141,85 na terapia combinada, com uma efetividade global de 0,54 e 0,73, respectivamente. Isso resultou em uma RCEI R$ 1.011.188,07 (R$ 864.498,95 a R$ 1.296.748,43) por desfecho cardiovascular evitado. CONCLUSÕES: Apesar de não existirem padrões nacionais para custo-efetividade, os dados encontrados sugerem que a estratégia de associação do evolocumabe à terapia com estatina não é, no momento, custo-efetiva.

Análise de Custo-Efetividade da Terapia com Evolocumabe em Pacientes com Alto Risco de Eventos Cardiovasculares no Contexto do SUS - Brasil / Cost-Effectiveness Analysis of Evolocumab Therapy in Patients at High Risk of Cardiovascular Events in the Context of the Brazilian Unified Health System

Resumo Fundamento: Em associação às estatinas, os inibidores da pró-proteína convertase subtilisina/kexina tipo 9 (PCSK9) demonstraram ser eficazes na redução de eventos cardiovasculares em pacientes de alto risco. Objetivo: Analisar a custo-efetividade da implementação de evolocumabe para pacientes com alto risco de eventos cardiovasculares no contexto do Sistema Único de Saúde (SUS) no Brasil. Métodos: Um modelo de Markov foi utilizado, baseando-se em uma amostra ambulatorial de pacientes com doença arterial coronariana. Os desfechos primários analisados foram infarto agudo do miocárdio, acidente vascular cerebral isquêmico (AVCi), revascularização do miocárdio e morte cardiovascular. O resultado foi expresso por meio da razão de custo-efetividade incremental (RCEI), considerando-se uma taxa de desconto de 5% ao ano, e uma análise de sensibilidade foi realizada, tendo em vista a imprecisão de valores. Resultados: Selecionaram-se 61 pacientes com risco cardiovascular estimado em 35% em 10 anos, se em uso de atorvastatina 80mg/dia, e em 22,75%, se adicionado o evolocumabe. O custo global por paciente no período de 10 anos foi de R$ 46.522,44 no grupo em monoterapia com atorvastatina versus R$ 236.141,85 na terapia combinada, com uma efetividade global de 0,54 e 0,73, respectivamente. Isso resultou em uma RCEI R$ 1.011.188,07 (R$ 864.498,95 a R$ 1.296.748,43) por desfecho cardiovascular evitado. Conclusões: Apesar de não existirem padrões nacionais para custo-efetividade, os dados encontrados sugerem que a estratégia de associação do evolocumabe à terapia com estatina não é, no momento, custo-efetiva.

Abstract Background: Hypertrophic cardiomyopathy (HCM) and left ventricular hypertrophy (LVH) secondary to systemic hypertension (HTN) may be associated with left atrial (LA) functional abnormalities. Objectives: We aimed to characterize LA mechanics in HCM and HTN and determine any correlation with the extent of left ventricular (LV) fibrosis measured by cardiac magnetic resonance (CMR) in HCM patients. Methods: Two-dimensional speckle tracking-derived longitudinal LA function was acquired from apical views in 60 HCM patients, 60 HTN patients, and 34 age-matched controls. HCM patients also underwent CMR, with measurement of late gadolinium enhancement (LGE) extension. Association with LA strain parameters was analyzed. Statistical significance was set at p<0.05. Results: Mean LV ejection fraction was not different between the groups. The E/e' ratio was impaired in the HCM group and preserved in the control group. LA mechanics was significantly reduced in HCM, compared to the HTN group. LA strain rate in reservoir (LASRr) and in contractile (LASRct) phases were the best discriminators of HCM, with an area under the curve (AUC) of 0.8, followed by LA strain in reservoir phase (LASr) (AUC 0.76). LASRr and LASR-ct had high specificity (89% and 91%, respectively) and LASr had sensitivity of 80%. A decrease in 2.79% of LA strain rate in conduit phase (LASRcd) predicted an increase of 1cm in LGE extension (r2=0.42, β 2.79, p=0.027). Conclusions: LASRr and LASRct were the best discriminators for LVH secondary to HCM. LASRcd predicted the degree of LV fibrosis assessed by CMR. These findings suggest that LA mechanics is a potential predictor of disease severity in HCM.

Cardioprotective, hypotensive and toxicological studies of Populus ciliata (Wall. ex Royle).

Populus ciliata Wall ex. Royle has folkloric repute to treat various cardiovascular ailments and related disorders. The current study was designed to evaluate the toxic profile, cardioprotective and hypotensive effects of Populus ciliata (Wall. ex Royle). Populus ciliata crude ethanolic extract (Pc. Cr) and its aqueous (Pc. Aq) & organic (Pc. Dcm) fractions were tested on isolated aorta of rat and rabbit having intact and non-intact endothelium respectively. Pc. Cr & Pc. Aq relaxed the contractions induced by PE (1 µM)-induced and K+ (80 mM)-induced on aorta, possibly by mediating endothelium derived relaxing factor (EDRF) in intact endothelium and voltage dependent L-type calcium channels blocking (CCB) mechanism in non-intact endothelium. Pc. Cr showed anti-hypertensive & cardioprotective activity by decreasing force of contraction & heart rate on isolated rabbit paired atria and reduced blood pressure in anesthetized rat. Cardioprotective effect of Pc. Cr was assessed in isoproterenol induced acute myocardial infarction (AMI) and left ventricular hypertrophy (LVH) in Sprague Dawley rats. In LVH, Pc. Cr exerted positive effects by decreasing angiotensin II & renin and increasing cGMP & nitric oxide (NO) with reduced cardiac fibrosis, necrosis and cardiac cell size. In AMI, Pc. Cr responded effectively by decreasing cardiac markers creatinine kinase (CK), creatinine kinase myocardial band (CK-MB) and lactate dehydrogenase (LD) in blood associated with less edema and necrosis. Presence of catechin, vinallic acid, P-coumeric acid and quercitin identified through HPLC support the effectiveness of Pc. Cr in hypertension, AMI and LVH. Pc. Cr showed no significant adverse effects in Sprague Dawley albino rats after acute & sub-acute treatment in histopathological investigation. Extract of Populus ciliata showed vasorelaxant, hypotensive and cardioprotective effect in Sprague Dawley albino rats and white albino rabbit by mediating EDRF and voltage dependent L-type CCB mechanism respectively.

Leptin Attenuates Cardiac Hypertrophy in Patients With Generalized Lipodystrophy.

CONTEXT: Lipodystrophy syndromes are rare disorders of deficient adipose tissue, low leptin, and severe metabolic disease, affecting all adipose depots (generalized lipodystrophy, GLD) or only some (partial lipodystrophy, PLD). Left ventricular (LV) hypertrophy is common (especially in GLD); mechanisms may include hyperglycemia, dyslipidemia, or hyperinsulinemia. OBJECTIVE: Determine effects of recombinant leptin (metreleptin) on cardiac structure and function in lipodystrophy. METHODS: Open-label treatment study of 38 subjects (18 GLD, 20 PLD) at the National Institutes of Health before and after 1 (N = 27), and 3 to 5 years (N = 23) of metreleptin. Outcomes were echocardiograms, blood pressure (BP), triglycerides, A1c, and homeostasis model assessment of insulin resistance. RESULTS: In GLD, metreleptin lowered triglycerides (median [interquartile range] 740 [403-1239], 138 [88-196], 211 [136-558] mg/dL at baseline, 1 year, 3-5 years, P < .0001), A1c (9.5 ±â€…3.0, 6.5 ±â€…1.6, 6.5 ±â€…1.9%, P < .001), and HOMA-IR (34.1 [15.2-43.5], 8.7 [2.4-16.0], 8.9 [2.1-16.4], P < .001). Only HOMA-IR improved in PLD (P < .01). Systolic BP decreased in GLD but not PLD. Metreleptin improved cardiac parameters in patients with GLD, including reduced posterior wall thickness (9.8 ±â€…1.7, 9.1 ±â€…1.3, 8.3 ±â€…1.7 mm, P < .01), and LV mass (140.7 ±â€…45.9, 128.7 ±â€…37.9, 110.9 ±â€…29.1 g, P < .01), and increased septal e' velocity (8.6 ±â€…1.7, 10.0 ±â€…2.1, 10.7 ±â€…2.4 cm/s, P < .01). Changes remained significant after adjustment for BP. In GLD, multivariate models suggested that reduced posterior wall thickness and LV mass index correlated with reduced triglycerides and increased septal e' velocity correlated with reduced A1c. No changes in echocardiographic parameters were seen in PLD. CONCLUSION: Metreleptin attenuated cardiac hypertrophy and improved septal e' velocity in GLD, which may be mediated by reduced lipotoxicity and glucose toxicity. The applicability of these findings to leptin-sufficient populations remains to be determined.