Role In Cardiac Remodeling Research Articles

Obesity-mediated regulation of cardiac protein acetylation: parallel analysis of total and acetylated proteins via TMT-tagged mass spectrometry.

Lysine residues undergo diverse and reversible post-translational modifications (PTMs). Lysine acetylation has traditionally been studied in the epigenetic regulation of nucleosomal histones that provides an important mechanism for regulating gene expression. Histone acetylation plays a key role in cardiac remodeling and function. However, recent studies have shown that thousands of proteins can be acetylated at multiple acetylation sites, suggesting the acetylome rivals the kinome as a PTM. Based on this, we examined the impact of obesity on protein lysine acetylation in the left ventricle (LV) of male c57BL/6J mice. We reported that obesity significantly increased heart enlargement and fibrosis. Moreover, immunoblot analysis demonstrated that lysine acetylation was markedly altered with obesity and that this phenomenon was cardiac tissue specific. Mass spectral analysis identified 2515 proteins, of which 65 were significantly impacted by obesity. Ingenuity Pathway Analysis® (IPA) further demonstrated that these proteins were involved in metabolic dysfunction and cardiac remodeling. In addition to total protein, 189 proteins were acetylated, 14 of which were significantly impacted by obesity. IPA identified the Cardiovascular Disease Pathway as significantly regulated by obesity. This network included aconitate hydratase 2 (ACO2), and dihydrolipoyl dehydrogenase (DLD), in which acetylation was significantly increased by obesity. These proteins are known to regulate cardiac function yet, the impact for ACO2 and DLD acetylation remains unclear. Combined, these findings suggest a critical role for cardiac acetylation in obesity-mediated remodeling; this has the potential to elucidate novel targets that regulate cardiac pathology.

Abstract 529: Asporin - Extracellular Matrix Protein Mitigates Pathological Remodeling

The cardiac extracellular matrix is a complex network of proteins and plays a key role in cardiac remodeling after myocardial infarction. One of the extracellular matrix proteins, asporin, is a member of the SLRP family and inhibits TGFβ signaling. However, very little is known about the function and regulation of asporin in cardiac remodeling. Using bioinformatics approach, microarray data analysis from publicly available datasets identified asporin as a top candidate showing an increase in left ventricle tissue with ischemic cardiomyopathy as compared to control donor hearts. To confirm, we detected an increase in asporin expression in paired heart biopsies taken before and after cardiopulmonary bypass surgery by western blot analysis. Our group showed that glucagon like receptor 1 agonist (GLP-1Ra) is beneficial for cardiac remodeling and prevents fibrosis. In a permanent coronary artery ligation model, we found increased extracellular asporin expression after 30 days in border zone and scar area with GLP-1Ra treatment compared to vehicle-treatment. To further elucidate the mechanism of asporin secretion, we used H9c2 cells as well as left ventricle tissue from mice and found that asporin was predominantly present in the heavy membrane enriched fraction (8,000xg pellet from postnuclear supernatant). Sequence analysis of asporin protein using SecretomeP 2.0 server predicted asporin might use the non-conventional form of secretion (secretory autophagy). Differentiation of H9c2 cells is accompanied by autophagy and mitochondrial biogenesis, and we found that the abundance of asporin in total lysate and heavy membrane fraction decreased suggesting it could be released via secretory autophagy. Using recombinant human asporin, we demonstrated that asporin stimulates an increase in LC3 and p62 in parallel to a decrease in COX IV and SMAD2 phosphorylation, indicating mitophagy induction and a decrease in TGFβ signaling. Based on our preliminary data and sequence comparison to a previously reported human peptide, we developed a rodent asporin peptide which is predicted to induce mitophagy while decreasing TGFβ signaling to prevent fibrosis. Studies are ongoing to establish the clinical relevance of asporin in animal models of ischemic injury.

Naringenin inhibits NG‑nitro‑L‑arginine methyl ester‑induced hypertensive left ventricular hypertrophy by decreasing angiotensin‑converting enzyme 1 expression

Naringenin (NGN) is a natural flavonoid that exerts antiinflammatory, antioxidant and cardioprotective effects. The present study investigated the effects of NGN on left ventricular hypertrophy in rats with NG-nitro-L-arginine methyl ester (L-NAME)-induced hypertension, and sought to determine the underlying mechanism of action. The rats received the following by gavage daily for 56 days: L-NAME (50 mg/kg/day) + NGN (100 mg/kg/day), L-NAME (50 mg/kg/day) + saline, or saline + saline. Blood pressure, heart rate and body weight were recorded. Left ventricular hypertrophy was assessed by echocardiography and hematoxylin-eosin staining. Angiotensin II (Ang II) and angiotensin-converting enzyme 1 (ACE1), which serve a pivotal role in cardiac remodeling, were evaluated by ELISA, reverse transcription-quantitative polymerase chain reaction and western blot analysis. NGN had no significant effect on body weight, heart rate or blood pressure. The extent of left ventricular hypertrophy in the L-NAME + NGN group was lower than in the L-NAME + saline group on day 56. NGN decreased Ang II and ACE1 protein levels in myocardial tissues. In conclusion, Ang II and ACE1 expression in cardiac tissue was inhibited by NGN in L-NAME-treated rats, which may contribute to the inhibitory effects of NGN on left ventricular hypertrophy that is induced by pressure overload.

Loss of P53 regresses cardiac remodeling induced by pressure overload partially through inhibiting HIF1α signaling in mice

The tumor suppressor p53 is recognized as the guardian of the genome in cell cycle and cell death. P53 expression increases as cardiac hypertrophy worsens to heart failure, suggesting that p53 may play important role in cardiac remodeling. In the present study, deletion of p53 in the mice heart would ameliorate cardiac hypertrophy induced by pressure overload. The role of p53 on heart was investigated using in vivo models. Cardiac hypertrophy in mice was induced by transverse aortic banding surgery. The extent of cardiac hypertrophy was examined by echocardiography, as well as pathological and molecular analyses of heart tissue. Global knockout of p53 in the mice reduced the hypertrophic response and markedly reduced cardiac apoptosis, and fibrosis. Ejection fraction of heart was also improved in hearts without p53 in response to pressure overload. Protein determination further suggested loss of p53 expression markedly increased Hypoxia-inducible factor 1-alpha (HIF1α) and vascular endothelial growth factor (VEGF) expression. The study indicated p53 deteriorated cardiac functions and cardiac hypertrophy, apoptosis, and fibrosis by partially inhibition of HIF1α and VEGF.

Ischemic HeartFailure Induces Simultaneous Downregulation of Myocardial E3 Ligases

Heart failure (HF), developing after a myocardial infarction (MI), is associated with cardiac remodeling and aerobic exercise training (AET) seems to counteract these effects. The ubiquitin proteasome system (UPS) holds a central role in cardiac remodeling. The present animal study investigated different components of the UPS in the left ventricle both early and late post-MI and the effects of AET on HF-induced UPS changes were analyzed.

Bcl11b, a transcriptional repressor: Its role in cardiac homeostasis and remodeling

Diverse forms of cardiomyopathies result in cardiac compensatory remodeling that may progress to ventricular dilation and heart failure. This remodeling is characterized by an increase in the size of cardiomyocytes associated with elevated rates of RNA synthesis and the activation of foetal cardiac genes. It has been shown that Bcl11b, a transcription factor, interacts with the RNApolymeraseII regulatory complex pTefb and exert an inhibitory action on it. To determine the role of Bcl11b in regulating transcription during cardiac homeostasis and remodeling. We generated Bcl11b cardiac-specific, tamoxifen inducible, KO mice and analyzed the phenotype at the functional, morphological and molecular levels. We also inactivated Bcl11b in isolated cardiac cells using Cre expressing adenoviruses. We observed a compromised contractile function in the Bcl11b KO mice by echocardiography, two and six months post-inactivation, evidenced by a 10% decrease in ejection and shortening fractions. At the morphological level, Sirius red staining showed fibrotic regions in mutants’ heart. At the molecular level, hypertrophy markers such as ANF and BNP were upregulated as well as collagen genes. We also observed an increased phosphorylation of SMAD2, which is part of the TGFβ signaling that promotes fibrosis, in mutant mice. In vitro, Bcl11b KO isolated cardiomyocytes showed a downregulation of cardiac transcription factors GATA4, Mef2c and Nkx2.5, with no variations in collagen genes ( Fig. 1 ). Our results suggest that Bcl11b plays a crucial role in cardiac remodeling and the onset of fibrosis. Future experiments will allow us to decipher how Bcl11b is implicated in the molecular mechanisms that govern the onset of pathological cardiac remodeling. In the long term this study could pave the way for potential pharmacological approaches aiming to control and modulate the extent of cardiac hypertrophy and restore myocardial phenotype and function.

Modulation of cardiac stem cell characteristics by metoprolol in hypertensive heart disease.

Cardiac stem cells (CSCs) play a vital role in cardiac remodeling. Uncontrolled hypertension leads to cardiac hypertrophy, followed by cardiac failure. Pathological remodeling is associated with enhanced oxidative stress. Decreased cardiac stem cell efficiency is speculated in heart diseases. Maintaining a healthy stem cell population is essential for preventing progressive cardiac remodeling. Some anti-hypertensive drugs are cardioprotective. However, the effect of these drugs on CSCs has not been investigated. Metoprolol is a cardioprotective anti-hypertensive agent. To examine whether metoprolol can prevent the deterioration of CSC efficiency, spontaneously hypertensive rats (SHRs) were treated with this drug, and the effects on stem cell function were evaluated. Six-month-old male SHRs were treated with metoprolol (50 mg × kg-1per day) for 2 months. The effectiveness of the treatment at reducing blood pressure and reducing hypertrophy was ensured, and the animals were killed. Cardiac stem cells were isolated from the atrial tissue, and the effect of metoprolol on stem cell migration, proliferation, differentiation, and survival was evaluated by comparing the treated SHRs with untreated SHRs and normotensive Wistar rats. Compared to the Wistar rats, the SHR rats presented with a decrease in stem cell migration and proliferation and an increase in intracellular oxidative stress and senescence. Treating SHRs with metoprolol increased CSC migration and proliferation potential and stemness retention. Cellular senescence and oxidative stress were reduced. The attributes of stem cells from the metoprolol-treated SHRs were comparable to those of the Wistar rats. The restoration of stem cell efficiency is expected to prevent hypertension-induced progressive cardiac remodeling.

MicroRNA-195 Regulates Metabolism in Failing Myocardium Via Alterations in Sirtuin 3 Expression and Mitochondrial Protein Acetylation.

Heart failure leads to mitochondrial dysfunction and metabolic abnormalities of the failing myocardium coupled with an energy-depleted state and cardiac remodeling. The mitochondrial deacetylase sirtuin 3 (SIRT3) plays a pivotal role in the maintenance of mitochondrial function through regulating the mitochondrial acetylome. It is interesting to note that unique cardiac and systemic microRNAs have been shown to play an important role in cardiac remodeling by modulating key signaling elements in the myocardium. Cellular signaling was analyzed in human cardiomyocyte-like AC16 cells, and acetylation levels in rodent models of SIRT3-/-and transgenic microRNA-195 (miR-195) overexpression were compared with wild type. Luciferase assays, Western blotting, immunoprecipitation assays, and echocardiographic analysis were performed. Enzymatic activities of pyruvate dehydrogenase (PDH) and ATP synthase were measured. In failing human myocardium, we observed induction of miR-195 along with decreased expression of the mitochondrial deacetylase SIRT3 that was associated with increased global protein acetylation. We further investigated the role of miR-195 in SIRT3-mediated metabolic processes and its impact on regulating enzymes involved in deacetylation. Proteomic analysis of the total acetylome showed increased overall acetylation, and specific lysine acetylation of 2 central mitochondrial metabolic enzymes, PDH and ATP synthase, as well. miR-195 downregulates SIRT3 expression through direct 3'-untranslated region targeting. Treatments with either sirtuin inhibitor nicotinamide, small interfering RNA-mediated SIRT3 knockdown or miR-195 overexpression enhanced acetylation of PDH complex and ATP synthase. This effect diminished PDH and ATP synthase activity and impaired mitochondrial respiration.SIRT3-/- and miR-195 transgenic mice consistently showed enhanced global protein acetylation, including PDH complex and ATP synthase, associated with decreased enzymatic activity. Altogether, these data suggest that increased levels of miR-195 in failing myocardium regulate a novel pathway that involves direct SIRT3 suppression and enzymatic inhibition via increased acetylation of PDH and ATP synthase that are essential for cardiac energy metabolism.

Down-regulation of miR-133a/b in patients with myocardial infarction correlates with the presence of ventricular fibrillation

MicroRNAs (miRNAs) are important regulators of physiologic and pathologic conditions of the heart. Animal models of heart diseases have shown that miRNAs may contribute to the development of arrhythmias. However, little is known about the expression of muscle- and cardiac-specific miRNAs in patients with myocardial infarction (MI) who have developed ventricular fibrillation (VF).Our study included 47 patients who had died from myocardial infarction (MI), 23 with clinically proven VF and 24 without VF. Autopsy samples of infarcted tissue and remote myocardium were available (n = 94). Heart tissue from 8 healthy trauma victims was included as control. Expression of miR-1, miR-133a/b and miR-208 was analyzed using real-time PCR (qPCR).In patients with MI with VF, we observed down-regulation of miR-133a/b, and this down-regulation was even stronger 2–7 days after MI. miR-208 was up-regulated in remote myocardium irrespective of the presence of VF. Deregulation of miR-1 and miR-208 was not related to the presence of VF.Our results suggest that down-regulation of miR-133a/b might contribute to the development of VF in patients with MI. However, up-regulation of miR-1 and miR-208 in remote myocardium might play a role in cardiac remodeling after MI, at least to certain degree.

Role of miRNAs on the Pathophysiology of Cardiovascular Diseases.

MiRNA (or microRNA) is a subclass of non-coding RNAs that is responsible for post-transcriptional gene regulation. It has approximately 22 nucleotides and regulates gene expression in plants and animals at the post-transcriptional level, by the cleavage of a target mRNA or by suppression of its translation. Although many of the processes and mechanisms have not yet been fully elucidated, there is a strong association between miRNA expression and several diseases. It is known that miRNAs are expressed in the cardiovascular system, but their role in cardiovascular diseases (CVDs) has not been clearly established. In this non-systematic review of the literature, we first present the definition of miRNAs and their action at the cellular level. Afterward, we discuss the role of miRNAs as circulating biomarkers of CVDs, and then their role in cardiac remodeling and atherosclerosis. Despite the complexity and challenges, it is crucial to identify deregulated miRNAs in CVDs, as it allows a better understanding of underlying cellular and molecular mechanisms and helps in the development of more accurate diagnostic and prognostic circulating biomarkers, and new therapeutic strategies for different stages of CVDs.

Biomechanical Properties and Mechanobiology of Cardiac ECM.

The heart is comprised of cardiac cells and extracellular matrix (ECM) which function together to pump blood throughout the body, provide organs with nutrients and oxygen, and removemetabolic wastes. Cardiac ECM provides a scaffold to cardiac cells and contributes to the mechanical properties and function of the cardiac tissue. Recently, more evidence suggests that cardiac ECM plays an active role in cardiac remodeling in response to mechanical loads. To that end, we provide an overview of the structure and function of the heart and the currently available in vivo and ex vivo mechanical measurements of cardiac tissues. We also review the biomechanical properties of cardiac tissues including the myocardium and heart valves, with a discussion on the differences between the right ventricle and left ventricle. Lastly, we go into the mechanical factors involved in cardiac remodeling and review the mechanobiology of cardiac tissues, i.e., the biomechanical responses at the cellular and tissue level, with an emphasis on the impact on the cardiac ECM. The regulation of cardiac ECM on cell function, which is a new and open area of research, is also briefly discussed. Future investigation into the ECM deposition and the interaction of cardiac cells and ECM components for mechanotransduction can assist to understand cardiac remodeling and inspire new therapies for cardiac diseases.

Матриксные металлопротеиназы: значение в ремоделировании сердца у пациентов с дисплазией соединительной ткани

Матриксные металлопротеиназы: значение в ремоделировании сердца у пациентов с дисплазией соединительной ткани

Novel Anti-Inflammatory Agent VCP979 Treatment Improves Cardiac Function in Post-Myocardial Infarction Diabetes Mice

Background: Inflammation is a pivotal pathophysiological response following myocardial infarction (MI) in the setting of diabetes. p38 mitogen-activated protein kinase (p38MAPK) is the convergence point of the inflammation that plays an important role in cardiac remodelling and maladaptive processes post-MI in diabetes.

Inhibition of Apoptosis Signal-Regulating Kinase 1 Attenuates Myocyte Hypertrophy and Fibroblast Collagen Synthesis

Cardiac remodelling is a dynamic process whereby structural and functional changes occur within the heart in response to injury or inflammation. Recent studies have demonstrated reactive oxygen species sensitive MAPK, apoptosis signal-regulating kinase 1 (ASK1) plays a critical role in cardiac remodelling. This study aims to determine the effectiveness of small molecule ASK1 inhibitors on these processes and their therapeutic potential. Neonatal rat cardiac fibroblasts (NCF) were pre-treated with ASK1 inhibitors, G2261818A (G226) and G2358939A (G235), for 2hours before stimulated with 100nM angiotensin II (AngII), 10μM indoxyl sulphate (IS) or 10ng/ml transforming growth factor β1 (TGFβ1) for 48hours. Neonatal rat cardiac myocytes (NCM) were pre-treated with G226 and G235 for 2hours before being stimulated with 100nM AngII for 60hours, 10μM IS, 10ng/ml interleukin 1β (IL-1β) or tumour necrosis factor α (TNFα) for 48hours. 3H-proline and 3H-leucine incorporation was used to assess collagen turnover and hypertrophy, respectively. Pro-fibrotic, pro-hypertrophic and THP-1 inflammatory cytokine gene expressions were determined by RT-PCR. Both G226 and G235 dose-dependently attenuated AngII-, IS-, IL-1β- and TNFα-stimulated NCM hypertrophy and hypertrophic gene expression, IS-, AngII- and TGFβ1-stimulated NCF collagen synthesis and AngII- and TGFβ1-stimulated pro-fibrotic gene expression. Inhibition of ASK1 by G226 and G235 inhibited lipopolysaccharides-stimulated inflammatory cytokine gene expression in THP-1 cells. Selective ASK1 inhibition confers anti-hypertrophic and anti-fibrotic effects in cardiac cells, and anti-inflammation in monocytic cells. ASK1 inhibitors may represent novel therapeutic agents to alleviate cardiac remodelling post cardiac injury where hypertrophy, fibrosis and inflammation play critical roles.

Apoptosis inhibitor of macrophage depletion decreased M1 macrophage accumulation and the incidence of cardiac rupture after myocardial infarction in mice.

BackgroundCardiac rupture is an important cause of death in the acute phase after myocardial infarction (MI). Macrophages play a pivotal role in cardiac remodeling after MI. Apoptosis inhibitor of macrophage (AIM) is secreted specifically by macrophages and contributes to macrophage accumulation in inflamed tissue by maintaining survival and recruiting macrophages. In this study, we evaluated the role of AIM in macrophage accumulation in the infarcted myocardium and cardiac rupture after MI.Methods and resultsWild-type (WT) and AIM‒/‒ mice underwent permanent left coronary artery ligation and were followed-up for 7 days. Macrophage accumulation and phenotypes (M1 pro-inflammatory macrophage or M2 anti-inflammatory macrophage) were evaluated by immunohistological analysis and RT-PCR. Matrix metalloproteinase (MMP) activity levels were measured by gelatin zymography. The survival rate was significantly higher (81.1% vs. 48.2%, P<0.05), and the cardiac rupture rate was significantly lower in AIM‒/‒ mice than in WT mice (10.8% vs. 31.5%, P<0.05). The number of M1 macrophages and the expression levels of M1 markers (iNOS and IL-6) in the infarcted myocardium were significantly lower in AIM‒/‒ mice than in WT mice. In contrast, there was no difference in the number of M2 macrophages and the expression of M2 markers (Arg-1, CD206 and TGF-β1) between the two groups. The ratio of apoptotic macrophages in the total macrophages was significantly higher in AIM‒/‒ mice than in WT mice, although MCP-1 expression did not differ between the two groups. MMP-2 and 9 activity levels in the infarcted myocardium were significantly lower in AIM‒/‒ mice than in WT mice.ConclusionsThese findings suggest that AIM depletion decreases the levels of M1 macrophages, which are a potent source of MMP-2 and 9, in the infarcted myocardium in the acute phase after MI by promoting macrophage apoptosis, and leads to a decrease in the incidence of cardiac rupture and improvements in survival rates.

Increased concentrations of soluble ST2 independently predict cardiac and total mortality but not non-fatal cardiovascular events in stable coronary heart disease patients

Aim: Soluble (s) ST2, a member of the interleukin-1 family, has been suggested to play a role in cardiac remodelling and inflammatory signalling. We assessed the long-term predictive value of sST2 in stable coronary heart disease (CHD) patients, simultaneously controlling for a large number of potential confounders.

Abstract 101: FHL2 -null Mice Showing Less Cardiac Remodeling

The four and a half Lin11, Isl-1 and Mec-3 (LIM) domain protein 2 (FHL2) is a member of the four and a half LIM domain-only (FHL) gene family, and has been shown to play an important role in cardiac remodeling. Here, we tested the hypothesis that isoproterenol-induced myocardial fibrosis in mice lacking FHL2 is related to resistant to myocardial fibrosis. We compared the cardiac phenotypes of FHL2 -null mice. Extra-cellular matrix remodeling and apoptosis are examined to determine the roles of FHL2 on cardiac fibrosis induced by isoproterenol. Compared to wild type littermates, FHL2 -null mice exhibited lower mortality. Masson’s Trichrome and silver stains showed significantly less severe ventricle fibrosis in FHL2-null mice. In addition, FHL2 -null mice exhibited lower levels of TGF-β, collagen I/III, but higher membrane-type matrix metalloproteinase-1 (MT1-MMP/MMP-14) during cardiac remodeling. This study shows that alternations of FHL2 might be implicated in the pathogenesis of cardiac fibrosis and suggests FHL2 as novel targets for cardiac fibrosis therapy. Further studies are required to define the mechanism by which FHL2 modulates cardiac remodeling.

Engineered 3D Cardiac Fibrotic Tissue to Study Fibrotic Remodeling.

Activation of cardiac fibroblasts into myofibroblasts is considered to play an essential role in cardiac remodeling and fibrosis. A limiting factor in studying this process is the spontaneous activation of cardiac fibroblasts when cultured on two-dimensional (2D) culture plates. In this study, a simplified three-dimensional (3D) hydrogel platform of contractile cardiac tissue, stimulated by transforming growth factor-β1 (TGF-β1), is presented to recapitulate a fibrogenic microenvironment. It is hypothesized that the quiescent state of cardiac fibroblasts can be maintained by mimicking the mechanical stiffness of native heart tissue. To test this hypothesis, a 3D cell culture model consisting of cardiomyocytes and cardiac fibroblasts encapsulated within a mechanically engineered gelatin methacryloyl hydrogel, is developed. The study shows that cardiac fibroblasts maintain their quiescent phenotype in mechanically tuned hydrogels. Additionally, treatment with a beta-adrenergic agonist increases beating frequency, demonstrating physiologic-like behavior of the heart constructs. Subsequently, quiescent cardiac fibroblasts within the constructs are activated by the exogenous addition of TGF-β1. The expression of fibrotic protein markers (and the functional changes in mechanical stiffness) in the fibrotic-like tissues are analyzed to validate the model. Overall, this 3D engineered culture model of contractile cardiac tissue enables controlled activation of cardiac fibroblasts, demonstrating the usability of this platform to study fibrotic remodeling.

Increased Plasma Concentrations of Soluble ST2 Independently Predict Mortality but not Cardiovascular Events in Stable Coronary Heart Disease Patients: 13-Year Follow-up of the KAROLA Study.

sST2 (soluble suppression of tumorigenicity 2), a member of the interleukin-1 family, has been suggested to play a role in cardiac remodeling and inflammatory signaling. We assessed the association between sST2 in patients with stable coronary heart disease (CHD) with multiple cardiovascular outcomes and total mortality, simultaneously controlling for a large number of potential confounders. Plasma concentrations of sST2 (ELISA, Critical Diagnostics) were measured at baseline in a cohort of 1081 patients. The Cox-proportional hazards model was used to determine the prognostic value of sST2 on a combined cardiovascular disease (CVD) endpoint, on cardiovascular death, and on total mortality after adjustment for covariates. The median sST2 level was 28.9ng/mL (IQR 23.8, 35.1) (mean age at baseline 58.9years, 84.6% male). sST2 concentration was positively correlated with inflammatory markers and emerging risk factors, e.g., cystatin C, N-terminal probrainnatriuretic peptide (NT-proBNP), high-sensitivity (hs)-Troponin T and I, mid-regional pro-atrial natriuretic peptide (MR-proANP), and growth differentiation factor 15 (GDF-15). Results after short- and long-term (4.5 and 12.3years, respectively) follow-up (FU) displayed no statistically significant association with the combined endpoint of non-fatal and fatal CVD events when the top quartile (Q4) of sST2 concentration was compared to the bottom quartile (Q1). A relationship during long-term FU was seen with CVD mortality even after multivariable adjustments including clinical risk variables (HR 1.65; 95% CI 1.02-2.86), but not in a fully adjusted model whereas, in contrast, it was still highly significant after short-term FU (HR (5.97 (95%CI 1.32-27.06)). In addition, the sST2 concentration was still strongly associated with total mortality in the fully adjusted model including clinical variables and cystatin C based estimated glomerular filtration rate, NT-proBNP, hsCRP and hs-TnI comparing Q4 vs Q1 during long-term FU (HR of 1.48 (95% CI 1.03-2.13)) and short-term FU (HR 3.06 (95% CI 1.29-7.24)). Elevated levels of sST2 concentration in stable CHD patients may independently predict short- and long-term risk for fatal CVD events and total mortality but not non-fatal CVD events.

Association of bone morphogenic protein 4 gene polymorphism and left ventricle hypertrophy in diabetic chronic kidney disease patients: A pilot study

BackgroundThe Bone Morphogenetic Protein 4 (BMP4) is identified to play a significant role in cardiac remodelling; gene polymorphism and its resulting associations with Left Ventricular Hypertrophy (LVH) in diabetic Chronic Kidney Disease (CKD) patients of this protein are yet to be established. AimTo analyse the association between BMP4 gene polymorphism and LVH in diabetic CKD patients. Materials and methodsIsolation of DNA from whole blood samples of 50 patients each; patients diagnosed LVH with diabetic CKD and also from LVH patients without diabetic CKD, diabetic CKD without LVH and also normal patients as control were extracted. The gene of interest (BMP4 gene) purified from various samples digested using zero-cutter restriction endonucleases (Hind III and Bam HI) by employing the Restriction Fragment Length Polymorphism (RFLP) technique. The restriction has been analysed using 1% agarose gel Electrophoresis. ResultsThe gene from patient having LVH without diabetic CKD when digested with Hind III showed fragmentation, more specifically, it presented three/four fragments which were at a comparable distance corresponding with the following size reference markers at 2000bp(few cases), 1500bp, between 700–600bp and the last one near 100bp. This fragmentation pattern was repeated identically for the gene from blood sample of patient having LVH with diabetic CKD which was also digested with Hind III. A similar fragmentation was not visualized for sample from patient having diabetic CKD without LVH when digested with Hind III. But no such fragments were noted for the samples from the same patients when digested with Bam HI. ConclusionBMP4 gene polymorphism has been confirmed in patients having LVH regardless of the presence or absence of diabetic CKD along with it. Focal points•Benchside:Left ventricular (LV) hypertrophy is a strong autonomous predictor of increased cardiovascular morbidity and mortality in clinical and population-based samples. Thus understanding the correlation of LVH with BMP4 gene is necessitated to provide alternate therapeutics strategy at genome level. Eventually, genetic investigations provide high assurance for future prevention, early intervention and treatment of this major public health issue.•Bedside:Determination of BMP4 Polymorphism would raise a new drug development target using single nucleotide polymorphism. They also serve as molecular marker for next generation therapeutics of personalized medicine at genome level.•Community:The patient's therapeutic quality would be high due target specific approach with the understanding of personalized medicine. This can prevent unwanted treatment that can guide way to side-effects in the system.•Governments:Funding bodies should continue to acknowledge the importance that the BMP4 gene plays a role in LVH, which can be a causative agent for many other cardio-disorders. Overtime, this will help in benefiting patients and healthcare institutions.