Publications by authors named "Gabriela M Kuster"

37 Publications

Influence of Antihypertensive Treatment on RAAS Peptides in Newly Diagnosed Hypertensive Patients.

Cells 2021 Mar 3;10(3). Epub 2021 Mar 3.

Hypertension Clinic, Medical Outpatient Department and Hypertension Clinic, ESH Hypertension Centre of Excellence, University Hospital Basel, 4031 Basel, Switzerland.

(1) Background: Recently, influences of antihypertensive treatment on the renin-angiotensin-aldosterone system (RAAS) has gained attention, regarding a possible influence on inflammatory and anti-inflammatory pathways. We aimed to study the effects of newly initiated antihypertensive drugs on angiotensin (Ang) II and Ang (1-7) as representers of two counter-regulatory axes. (2) Methods: In this randomized, open-label trial investigating RAAS peptides after the initiation of perindopril, olmesartan, amlodipine, or hydrochlorothiazide, Ang II and Ang (1-7) equilibrium concentrations were measured at 8 a.m. and 12 a.m. at baseline and after four weeks of treatment. Eighty patients were randomized (1:1:1:1 fashion). (3) Results: Between the four substances, we found significant differences regarding the concentrations of Ang II ( < 0.0005 for 8 a.m., 12 a.m.) and Ang (1-7) ( = 0.019 for 8 a.m., <0.0005 for 12 a.m.) four weeks after treatment start. Ang II was decreased by perindopril ( = 0.002), and increased by olmesartan ( < 0.0005), amlodipine ( = 0.012), and hydrochlorothiazide ( = 0.001). Ang (1-7) was increased by perindopril and olmesartan ( = 0.008/0.002), but not measurably altered by amlodipine and hydrochlorothiazide ( = 0.317/ 0.109). (4) Conclusion: The initiation of all first line antihypertensive treatments causes early and distinct alterations of equilibrium angiotensin levels. Given the additional AT1R blocking action of olmesartan, RAAS peptides shift upon initiation of perindopril and olmesartan appear to work in favor of the anti-inflammatory axis compared to amlodipine and hydrochlorothiazide.
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http://dx.doi.org/10.3390/cells10030534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001814PMC
March 2021

Prevalence and outcome of dysnatremia in patients with COVID-19 compared to controls.

Eur J Endocrinol 2021 Mar;184(3):409-418

Department of Endocrinology, Diabetology and Metabolism, University Hospital Basel, Basel, Switzerland.

Objective: The pandemic of coronavirus disease (COVID-19) has rapidly spread globally and infected millions of people. The prevalence and prognostic impact of dysnatremia in COVID-19 is inconclusive. Therefore, we investigated the prevalence and outcome of dysnatremia in COVID-19.

Design: The prospective, observational, cohort study included consecutive patients with clinical suspicion of COVID-19 triaged to a Swiss Emergency Department between March and July 2020.

Methods: Collected data included clinical, laboratory and disease severity scoring parameters on admission. COVID-19 cases were identified based on a positive nasopharyngeal swab test for SARS-CoV-2, patients with a negative swab test served as controls. The primary analysis was to assess the prognostic impact of dysnatremia on 30-day mortality using a cox proportional hazard model.

Results: 172 (17%) cases with COVID-19 and 849 (83%) controls were included. Patients with COVID-19 showed a higher prevalence of hyponatremia compared to controls (28.1% vs 17.5%, P < 0.001); while comparable for hypernatremia (2.9% vs 2.1%, P = 0.34). In COVID-19 but not in controls, hyponatremia was associated with a higher 30-day mortality (HR: 1.4, 95% CI: 1.10-16.62, P = 0.05). In both groups, hypernatremia on admission was associated with higher 30-day mortality (COVID-19 - HR: 11.5, 95% CI: 5.00-26.43, P < 0.001; controls - HR: 5.3, 95% CI: 1.60-17.64, P = 0.006). In both groups, hyponatremia and hypernatremia were significantly associated with adverse outcome, for example, intensive care unit admission, longer hospitalization and mechanical ventilation.

Conclusion: Our results underline the importance of dysnatremia as predictive marker in COVID-19. Treating physicians should be aware of appropriate treatment measures to be taken for patients with COVID-19 and dysnatremia.
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http://dx.doi.org/10.1530/EJE-20-1374DOI Listing
March 2021

Serum Neurofilament Light Chain Levels in the Intensive Care Unit: Comparison between Severely Ill Patients with and without Coronavirus Disease 2019.

Ann Neurol 2021 03 11;89(3):610-616. Epub 2021 Jan 11.

Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel, University Hospital Basel, University of Basel, Basel, Switzerland.

There is emerging evidence for multifarious neurological manifestations of coronavirus disease 2019 (COVID-19), but little is known regarding whether they reflect structural damage to the nervous system. Serum neurofilament light chain (sNfL) is a specific biomarker of neuronal injury. We measured sNfL concentrations of 29 critically ill COVID-19 patients, 10 critically ill non-COVID-19 patients, and 259 healthy controls. After adjusting for neurological comorbidities and age, sNfL concentrations were higher in patients with COVID-19 versus both comparator groups. Higher sNfL levels were associated with unfavorable short-term outcome, indicating that neuronal injury is common and pronounced in critically ill patients. ANN NEUROL 2021;89:610-616.
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http://dx.doi.org/10.1002/ana.26004DOI Listing
March 2021

A Year in the Life of the EU-CardioRNA COST Action: CA17129 Catalysing Transcriptomics Research in Cardiovascular Disease.

Noncoding RNA 2020 05 18;6(2). Epub 2020 May 18.

Cardiovascular Research Unit, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg.

The EU-CardioRNA Cooperation in Science and Technology (COST) Action is a European-wide consortium established in 2018 with 31 European country members and four associate member countries to build bridges between translational researchers from academia and industry who conduct research on non-coding RNAs, cardiovascular diseases and similar research areas. EU-CardioRNA comprises four core working groups (WG1-4). In the first year since its launch, EU-CardioRNA met biannually to exchange and discuss recent findings in related fields of scientific research, with scientific sessions broadly divided up according to WG. These meetings are also an opportunity to establish interdisciplinary discussion groups, brainstorm ideas and make plans to apply for joint research grants and conduct other scientific activities, including knowledge transfer. Following its launch in Brussels in 2018, three WG meetings have taken place. The first of these in Lisbon, Portugal, the second in Istanbul, Turkey, and the most recent in Maastricht, The Netherlands. Each meeting includes a scientific session from each WG. This meeting report briefly describes the highlights and key take-home messages from each WG session in this first successful year of the EU-CardioRNA COST Action.
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http://dx.doi.org/10.3390/ncrna6020017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345156PMC
May 2020

Renin-angiotensin system and SARS-CoV-2 infection: there is a before and after.

Eur Heart J 2020 06;41(22):2128-2129

Department of Cardiology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.

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http://dx.doi.org/10.1093/eurheartj/ehaa451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314088PMC
June 2020

Switching antihypertensive therapy in times of COVID-19: why we should wait for the evidence.

Eur Heart J 2020 05;41(19):1857

Department of Cardiology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.

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http://dx.doi.org/10.1093/eurheartj/ehaa335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188138PMC
May 2020

Regulatory RNAs in Heart Failure.

Circulation 2020 01 27;141(4):313-328. Epub 2020 Jan 27.

Cardiovascular Research Unit, Luxembourg Institute of Health, Strassen, Luxembourg (C.P.d.C.G., Y.D.).

Cardiovascular disease is an enormous socioeconomic burden worldwide and remains a leading cause of mortality and disability despite significant efforts to improve treatments and personalize healthcare. Heart failure is the main manifestation of cardiovascular disease and has reached epidemic proportions. Heart failure follows a loss of cardiac homeostasis, which relies on a tight regulation of gene expression. This regulation is under the control of multiple types of RNA molecules, some encoding proteins (the so-called messenger RNAs) and others lacking protein-coding potential, named noncoding RNAs. In this review article, we aim to revisit the notion of regulatory RNA, which has been thus far mainly confined to noncoding RNA. Regulatory RNA, which we propose to abbreviate as regRNA, can include both protein-coding RNAs and noncoding RNAs, as long as they contribute, directly or indirectly, to the regulation of gene expression. We will address the regulation and functional role of messenger RNAs, microRNAs, long noncoding RNAs, and circular RNAs (ie, regRNAs) in heart failure. We will debate the utility of regRNAs to diagnose, prognosticate, and treat heart failure, and we will provide directions for future work.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.042474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012349PMC
January 2020

Catalyzing Transcriptomics Research in Cardiovascular Disease: The CardioRNA COST Action CA17129.

Noncoding RNA 2019 03 29;5(2). Epub 2019 Mar 29.

Research Unit of Biomedicine, University of Oulu, 90014 Oulu, Finland.

Cardiovascular disease (CVD) remains the leading cause of death worldwide and, despite continuous advances, better diagnostic and prognostic tools, as well as therapy, are needed. The human transcriptome, which is the set of all RNA produced in a cell, is much more complex than previously thought and the lack of dialogue between researchers and industrials and consensus on guidelines to generate data make it harder to compare and reproduce results. This European Cooperation in Science and Technology (COST) Action aims to accelerate the understanding of transcriptomics in CVD and further the translation of experimental data into usable applications to improve personalized medicine in this field by creating an interdisciplinary network. It aims to provide opportunities for collaboration between stakeholders from complementary backgrounds, allowing the functions of different RNAs and their interactions to be more rapidly deciphered in the cardiovascular context for translation into the clinic, thus fostering personalized medicine and meeting a current public health challenge. Thus, this Action will advance studies on cardiovascular transcriptomics, generate innovative projects, and consolidate the leadership of European research groups in the field.COST (European Cooperation in Science and Technology) is a funding organization for research and innovation networks (www.cost.eu).
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http://dx.doi.org/10.3390/ncrna5020031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630366PMC
March 2019

Chronic heart failure: advances in pharmacological treatment and future perspectives.

Swiss Med Wkly 2019 Mar 24;149:w20036. Epub 2019 Mar 24.

Division of Cardiology, University Hospital Basel, Switzerland / Department of Biomedicine, University Hospital Basel and University of Basel, Switzerland.

Besides noticeable progress in device therapy during the past decade, more recent advances in the management of chronic heart failure have led to exciting new pharmacological options. Among these, the combined angiotensin II receptor/neprilysin inhibitor (ARNI) valsartan/sacubitril has already proven highly effective in heart failure with reduced ejection fraction (HFrEF), and convincing data are available regarding the cardioprotective effects of sodium-glucose-co-transporter 2 (SGLT2) inhibitors. These two treatments have earned a class I and a class II recommendation, respectively, in the European Society of Cardiology guidelines for the diagnosis and treatment of heart failure. Whereas progress with respect to heart failure with preserved ejection fraction (HFpEF) is still slow, both ARNIs and SGLT2 inhibitors hold great promise for this condition as well, and large clinical trials are currently ongoing. In addition, new diagnostic algorithms have recently been developed to improve the diagnostic accuracy for HFpEF, which will ultimately aid the search for effective therapies in future clinical trials. In this review article, these most recent advances in the diagnosis and pharmacological management of HFrEF and HFpEF are highlighted, and set-backs as well as opportunities for future developments (e.g., tafamidis for the treatment of transthyretin amyloid cardiomyopathy) are discussed.
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http://dx.doi.org/10.4414/smw.2019.20036DOI Listing
March 2019

Induction of Endothelial Differentiation in Cardiac Progenitor Cells Under Low Serum Conditions.

J Vis Exp 2019 01 7(143). Epub 2019 Jan 7.

Department of Biomedicine, University Hospital and University of Basel; Division of Cardiology, University Hospital Basel;

Cardiac progenitor cells (CPCs) may have therapeutic potential for cardiac regeneration after injury. In the adult mammalian heart, intrinsic CPCs are extremely scarce, but expanded CPCs could be useful for cell therapy. A prerequisite for their use is their ability to differentiate in a controlled manner into the various cardiac lineages using defined and efficient protocols. In addition, upon in vitro expansion, CPCs isolated from patients or preclinical disease models may offer fruitful research tools for the investigation of disease mechanisms. Current studies use different markers to identify CPCs. However, not all of them are expressed in humans, which limits the translational impact of some preclinical studies. Differentiation protocols that are applicable irrespective of the isolation technique and marker expression will allow for the standardized expansion and priming of CPCs for cell therapy purpose. Here we describe that the priming of CPCs under a low fetal bovine serum (FBS) concentration and low cell density conditions facilitates the endothelial differentiation of CPCs. Using two different subpopulations of mouse and rat CPCs, we show that laminin is a more suitable substrate than fibronectin for this purpose under the following protocol: after culturing for 2 - 3 days in medium including supplements that maintain multipotency and with 3.5% FBS, CPCs are seeded on laminin at <60% confluence and cultured in supplement-free medium with low concentrations of FBS (0.1%) for 20 - 24 hours before differentiation in endothelial differentiation medium. Because CPCs are a heterogeneous population, serum concentrations and incubation times may need to be adjusted depending on the properties of the respective CPC subpopulation. Considering this, the technique can be applied to other types of CPCs as well and provides a useful method to investigate the potential and mechanisms of differentiation and how they are affected by disease when using CPCs isolated from respective disease models.
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http://dx.doi.org/10.3791/58370DOI Listing
January 2019

Polo-Like Kinase 2 is Dynamically Regulated to Coordinate Proliferation and Early Lineage Specification Downstream of Yes-Associated Protein 1 in Cardiac Progenitor Cells.

J Am Heart Assoc 2017 Oct 24;6(10). Epub 2017 Oct 24.

Department of Biomedicine, University Hospital Basel, Basel, Switzerland

Background: Recent studies suggest that adult cardiac progenitor cells (CPCs) can produce new cardiac cells. Such cell formation requires an intricate coordination of progenitor cell proliferation and commitment, but the molecular cues responsible for this regulation in CPCs are ill defined.

Methods And Results: Extracellular matrix components are important instructors of cell fate. Using laminin and fibronectin, we induced two slightly distinct CPC phenotypes differing in proliferation rate and commitment status and analyzed the early transcriptomic response to CPC adhesion (<2 hours). Ninety-four genes were differentially regulated on laminin versus fibronectin, consisting of mostly downregulated genes that were enriched for Yes-associated protein (YAP) conserved signature and TEA domain family member 1 (TEAD1)-related genes. This early gene regulation was preceded by the rapid cytosolic sequestration and degradation of YAP on laminin. Among the most strongly regulated genes was polo-like kinase 2 (). expression depended on YAP stability and was enhanced in CPCs transfected with a nuclear-targeted mutant YAP. Phenotypically, the early downregulation of on laminin was succeeded by lower cell proliferation, enhanced lineage gene expression (24 hours), and facilitated differentiation (3 weeks) compared with fibronectin. Finally, overexpression of Plk2 enhanced CPC proliferation and knockdown of Plk2 induced the expression of lineage genes.

Conclusions: Plk2 acts as coordinator of cell proliferation and early lineage commitment in CPCs. The rapid downregulation of Plk2 on YAP inactivation marks a switch towards enhanced commitment and facilitated differentiation. These findings link early gene regulation to cell fate and provide novel insights into how CPC proliferation and differentiation are orchestrated.
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http://dx.doi.org/10.1161/JAHA.117.005920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721832PMC
October 2017

Noninvasive Contrast-Enhanced Ultrasound Molecular Imaging Detects Myocardial Inflammatory Response in Autoimmune Myocarditis.

Circ Cardiovasc Imaging 2016 08;9(8)

From the Department of Biomedicine (D.C.S., L.X., E.K., E.E., A.O.-E., M.M., G.M.K., B.A.K.), Institute for Pathology University Hospital (K.G.), and Division of Cardiology, University Hospital (G.M.K., B.A.K.), University of Basel, Switzerland.

Background: Cardiac tests for diagnosing myocarditis lack sensitivity or specificity. We hypothesized that contrast-enhanced ultrasound molecular imaging could detect myocardial inflammation and the recruitment of specific cellular subsets of the inflammatory response in murine myocarditis.

Methods And Results: Microbubbles (MB) bearing antibodies targeting lymphocyte CD4 (MBCD4), endothelial P-selectin (MBPSel), or isotype control antibody (MBIso) and MB with a negative electric charge for targeting of leukocytes (MBLc) were prepared. Attachment of MBCD4 was validated in vitro using murine spleen CD4+ T cells. Twenty-eight mice were studied after the induction of autoimmune myocarditis by immunization with α-myosin-peptide; 20 mice served as controls. Contrast-enhanced ultrasound molecular imaging of the heart was performed. Left ventricular function was assessed by conventional and deformation echocardiography, and myocarditis severity graded on histology. Animals were grouped into no myocarditis, moderate myocarditis, and severe myocarditis. In vitro, attachment of MBCD4 to CD4+ T cells was significantly greater than of MBIso. Of the left ventricular ejection fraction or strain and strain rate readouts, only longitudinal strain was significantly different from control animals in severe myocarditis. In contrast, contrast-enhanced ultrasound molecular imaging showed increased signals for all targeted MB versus MBIso both in moderate and severe myocarditis, and MBCD4 signal correlated with CD4+ T-lymphocyte infiltration in the myocardium.

Conclusions: Contrast-enhanced ultrasound molecular imaging can detect endothelial inflammation and leukocyte infiltration in myocarditis in the absence of a detectable decline in left ventricular performance by functional imaging. In particular, imaging of CD4+ T cells involved in autoimmune responses could be helpful in diagnosing myocarditis.
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http://dx.doi.org/10.1161/CIRCIMAGING.116.004720DOI Listing
August 2016

Fortune Favors the Prepared: Safety and Efficacy of Allogeneic Hypoxia Preconditioned Mesenchymal Stromal Cells in Primates.

Circ Res 2016 Mar;118(6):908-10

From the Department of Biomedicine and the Division of Cardiology, University Hospital Basel and University of Basel, Basel, Switzerland (G.M.K.); and Divisions of Genetics and Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (R.L.).

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http://dx.doi.org/10.1161/CIRCRESAHA.116.308410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198302PMC
March 2016

Regenerative therapy for cardiovascular disease.

Transl Res 2014 Apr 11;163(4):307-20. Epub 2013 Dec 11.

Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland; Division of Cardiology, University Hospital Basel, Basel, Switzerland.

Recent insights into myocardial biology uncovered a hereto unknown regenerative capacity of the adult heart. The discovery of dividing cardiomyocytes and the identification and characterization of cardiac stem and progenitor cells with myogenic and angiogenic potential have generated new hopes that cardiac regeneration and repair might become a therapeutic option. During the past decade, multiple candidate cells have been proposed for cardiac regeneration, and their mechanisms of action in the myocardium have been explored. Initial clinical trials have focused on the use of bone marrow-derived cells to promote myocardial regeneration in ischemic heart disease and have yielded very mixed results, with no clear signs of clinically meaningful functional improvement. Although the efficiency of bona fide cardiomyocyte generation is generally low, stem cells delivered into the myocardium act mainly via paracrine mechanisms. More recent studies taking advantage of cardiac committed cells (eg, resident cardiac progenitor cells or primed cardiogenic mesenchymal stem cells) showed promising results in first clinical pilot trials. Also, transplantation of cardiomyogenic cells generated by induced pluripotent stem cells and genetic reprogramming of dividing nonmyocytes into cardiomyocytes may constitute attractive new regenerative approaches in cardiovascular medicine in the future. We discuss advantages and limitations of specific cell types proposed for cell-based therapy in cardiology and give an overview of the first clinical trials using this novel therapeutic approach in patients with cardiovascular disease.
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http://dx.doi.org/10.1016/j.trsl.2013.12.005DOI Listing
April 2014

FLT3 activation improves post-myocardial infarction remodeling involving a cytoprotective effect on cardiomyocytes.

J Am Coll Cardiol 2014 Mar 30;63(10):1011-9. Epub 2013 Oct 30.

Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland; Division of Cardiology, University Hospital Basel, Basel, Switzerland. Electronic address:

Objectives: The goal of this study was to define the role of FMS-like tyrosine kinase 3 (FLT3) in the heart.

Background: FLT3 is a prominent target of receptor tyrosine kinase inhibitors (TKIs) used for anticancer therapy. TKIs can cause cardiomyopathy but understanding of the mechanisms is incomplete, partly because the roles of specific TKI target receptors in the heart are still obscure.

Methods: Myocardial infarction was induced in mice by permanent ligation of the left anterior descending coronary artery followed by intramyocardial injection of FLT3 ligand (FL) or vehicle into the infarct border zone. Cardiac morphology and function were assessed by echocardiography and histological analysis 1 week after infarction. In addition, FLT3 expression and regulation, as well as molecular mechanisms of FLT3 action, were examined in cardiomyocytes in vitro.

Results: The intramyocardial injection of FL into the infarct border zone decreased infarct size and ameliorated post-myocardial infarction remodeling and function in mice. This beneficial effect was associated with reduced apoptosis, including myocytes in the infarct border zone. Cardiomyocytes expressed functional FLT3, and FLT3 messenger ribonucleic acid and protein were up-regulated under oxidative stress, identifying cardiomyocytes as FL target cells. FLT3 activation with FL protected cardiomyocytes from oxidative stress-induced apoptosis via an Akt-dependent mechanism involving Bcl-2 family protein regulation and inhibition of the mitochondrial death pathway.

Conclusions: FLT3 is a cytoprotective system in the heart and a potential therapeutic target in ischemic cardiac injury. The protective mechanisms uncovered here may be further explored in view of potential cardiotoxic effects of FLT3-targeting anticancer therapy, particularly in patients with ischemic heart disease.
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http://dx.doi.org/10.1016/j.jacc.2013.08.1647DOI Listing
March 2014

Cardiovascular management of cancer patients with chemotherapy-associated left ventricular systolic dysfunction in real-world clinical practice.

J Card Fail 2013 Sep;19(9):629-34

Division of Cardiology, University Hospital Basel, Basel, Switzerland.

Background: Chemotherapy-induced left ventricular systolic dysfunction (LVSD) may limit survival in cancer patients and therefore should be treated timely with appropriate heart failure medication. This study aimed to evaluate quality of cardiac care in cancer patients with documented chemotherapy-induced LVSD in real-world clinical practice.

Methods: Using an institutional echo database, we screened 1,520 cancer patients for first documentation of chemotherapy-associated LVSD, defined as left ventricular ejection fraction (LVEF) ≤45%. Hospital charts of all 63 patients meeting inclusion criteria were reviewed regarding patient characteristics and frequency of heart failure medication prescription.

Results: Patients were 61 (interquartile range [IQR], 50-70) years old, mostly symptomatic, and had an average LVEF of 34 ± 8%. Most patients received anthracyclines (73%) and/or alkylating agents (73%) as part of their chemotherapeutic regimen. Median time from cancer diagnosis to first documentation of LVSD was 2.2 (0.7-5.2) years. Fewer than two-thirds of patients received guideline-recommended heart failure medication, and only one-half of patients received cardiology consult. Cardiology consultation was associated with a significantly higher frequency of heart failure medication prescription (100% vs. 52% for angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (P < .0001); 94% vs. 41% for beta-blocker (P < .0001) and better survival (71% vs. 41%; P < .05).

Conclusions: Chemotherapy-associated LVSD is insufficiently treated in cancer patients. Cardiology consultation improves rates of heart failure medication and therefore should be advocated in all patients with chemotherapy-induced LVSD.
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http://dx.doi.org/10.1016/j.cardfail.2013.07.007DOI Listing
September 2013

Hydrogen peroxide-mediated SERCA cysteine 674 oxidation contributes to impaired cardiac myocyte relaxation in senescent mouse heart.

J Am Heart Assoc 2013 Aug 20;2(4):e000184. Epub 2013 Aug 20.

Cardiovascular Medicine Section, Department of Medicine, The Myocardial Biology Unit and Vascular Biology Section, Boston University Medical Center, Boston, MA.

Background: A hallmark of aging of the cardiac myocyte is impaired sarcoplasmic reticulum (SR) calcium uptake and relaxation due to decreased SR calcium ATPase (SERCA) activity. We tested the hypothesis that H2O2-mediated oxidation of SERCA contributes to impaired myocyte relaxation in aging.

Methods And Results: Young (5-month-old) and senescent (21-month-old) FVB wild-type (WT) or transgenic mice with myocyte-specific overexpression of catalase were studied. In senescent mice, myocyte-specific overexpression of catalase (1) prevented oxidative modification of SERCA as evidenced by sulfonation at Cys674, (2) preserved SERCA activity, (3) corrected impaired calcium handling and relaxation in isolated cardiac myocytes, and (4) prevented impaired left ventricular relaxation and diastolic dysfunction. Nitroxyl, which activates SERCA via S-glutathiolation at Cys674, failed to activate SERCA in freshly isolated ventricular myocytes from senescent mice. Finally, in adult rat ventricular myocytes in primary culture, adenoviral overexpression of SERCA in which Cys674 is mutated to serine partially preserved SERCA activity during exposure to H2O2.

Conclusion: Oxidative modification of SERCA at Cys674 contributes to decreased SERCA activity and impaired myocyte relaxation in the senescent heart. Strategies to decrease oxidant levels and/or protect target proteins such as SERCA may be of value to preserve diastolic function in the aging heart.
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http://dx.doi.org/10.1161/JAHA.113.000184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828801PMC
August 2013

Molecular imaging reveals rapid reduction of endothelial activation in early atherosclerosis with apocynin independent of antioxidative properties.

Arterioscler Thromb Vasc Biol 2013 Sep 1;33(9):2187-92. Epub 2013 Aug 1.

Division of Cardiology, Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland.

Objective: Antioxidative drugs continue to be developed for the treatment of atherosclerosis. Apocynin is an nicotinamide adenine dinucleotide phosphate oxidase inhibitor with anti-inflammatory properties. We used contrast-enhanced ultrasound molecular imaging to assess whether short-term apocynin therapy in atherosclerosis reduces vascular oxidative stress and endothelial activation

Approach And Results: Genetically modified mice with early atherosclerosis were studied at baseline and after 7 days of therapy with apocynin (4 mg/kg per day IP) or saline. Contrast-enhanced ultrasound molecular imaging of the aorta was performed with microbubbles targeted to vascular cell adhesion molecule 1 (VCAM-1; MB(V)), to platelet glycoprotein Ibα (MB(Pl)), and control microbubbles (MB(Ctr)). Aortic vascular cell adhesion molecule 1 was measured using Western blot. Aortic reactive oxygen species generation was measured using a lucigenin assay. Hydroethidine oxidation was used to assess aortic superoxide generation. Baseline signal for MBV (1.3 ± 0.3 AU) and MB(Pl )(1.5 ± 0.5 AU) was higher than for MBCtr (0.5 ± 0.2 AU; P<0.01). In saline-treated animals, signal did not significantly change for any microbubble agent, whereas short-term apocynin significantly (P<0.05) reduced vascular cell adhesion molecule 1 and platelet signal (MBV: 0.3 ± 0.1; MBPl: 0.4 ± 0.1; MBCtr: 0.3 ± 0.2 AU; P=0.6 between agents). Apocynin reduced aortic vascular cell adhesion molecule 1 expression by 50% (P<0.05). However, apocynin therapy did not reduce reactive oxygen species content, superoxide generation, or macrophage content.

Conclusions: Short-term treatment with apocynin in atherosclerosis reduces endothelial cell adhesion molecule expression. This change in endothelial phenotype can be detected by molecular imaging before any measurable decrease in macrophage content and is not associated with a detectable change in oxidative burden.
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http://dx.doi.org/10.1161/ATVBAHA.113.301710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888901PMC
September 2013

Noninvasive ultrasound molecular imaging of the effect of statins on endothelial inflammatory phenotype in early atherosclerosis.

PLoS One 2013 15;8(3):e58761. Epub 2013 Mar 15.

Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.

Background/objectives: Inflammatory changes on the endothelium are responsible for leukocyte recruitment to plaques in atherosclerosis. Noninvasive assessment of treatment-effects on endothelial inflammation may be of use for managing medical therapy and developing novel therapies. We hypothesized that molecular imaging of vascular cell adhesion molecule-1 (VCAM-1) with contrast enhanced ultrasound (CEU) could assess treatment effects on endothelial phenotype in early atherosclerosis.

Methods: Mice with atherosclerosis produced by gene deletion of the LDL-receptor and Apobec-1-editing protein were studied. At 12 weeks of age, mice received 8 weeks of regular chow or atorvastatin-enriched chow (10 mg/kg/day). At 20 weeks, CEU molecular imaging for aortic endothelial VCAM-1 expression was performed with VCAM-1-targeted (MB(VCAM)) and control microbubbles (MB(Ctr)). Aortic wall thickness was assessed with high frequency ultrasound. Histology, immunohistology and Western blot were used to assess plaque burden and VCAM-1 expression.

Results: Plaque burden was reduced on histology, and VCAM-1 was reduced on Western blot by atorvastatin, which corresponded to less endothelial expression of VCAM-1 on immunohistology. High frequency ultrasound did not detect differences in aortic wall thickness between groups. In contrast, CEU molecular imaging demonstrated selective signal enhancement for MB(VCAM) in non-treated animals (MB(VCAM) 2±0.3 vs MB(Ctr) 0.7±0.2, p<0.01), but not in statin-treated animals (MB(VCAM) 0.8±0.2 vs MB(Ctr) 1.0±0.2, p = ns; p<0.01 for the effect of statin on MB(VCAM) signal).

Conclusions: Non-invasive CEU molecular imaging detects the effects of anti-inflammatory treatment on endothelial inflammation in early atherosclerosis. This easily accessible, low-cost technique may be useful in assessing treatment effects in preclinical research and in patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058761PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598944PMC
October 2013

NOX2-derived reactive oxygen species are crucial for CD29-induced pro-survival signalling in cardiomyocytes.

Cardiovasc Res 2012 Mar 23;93(3):454-62. Epub 2011 Dec 23.

Myocardial Research, Department of Biomedicine, University and University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland.

Aims: The highly expressed cell adhesion receptor CD29 (β(1)-integrin) is essential for cardiomyocyte growth and survival, and its loss of function causes severe heart disease. However, CD29-induced signalling in cardiomyocytes is ill defined and may involve reactive oxygen species (ROS). A decisive source of cardiac ROS is the abundant NADPH oxidase (NOX) isoform NOX2. Because understanding of NOX-derived ROS in the heart is still poor, we sought to test the role of ROS and NOX in CD29-induced survival signalling in cardiomyocytes.

Methods And Results: In neonatal rat ventricular myocytes, CD29 activation induced intracellular ROS formation (oxidative burst) as assessed by flow cytometry using the redox-sensitive fluorescent dye dichlorodihydrofluorescein diacetate. This burst was inhibited by apocynin and diphenylene iodonium. Further, activation of CD29 enhanced NOX activity (lucigenin-enhanced chemiluminescence) and activated the MEK/ERK and PI3K/Akt survival pathways. CD29 also induced phosphorylation of the inhibitory Ser9 on the pro-apoptotic kinase glycogen synthase kinase-3β in a PI3K/Akt- and MEK-dependent manner, and improved cardiomyocyte viability under conditions of oxidative stress. The ROS scavenger MnTMPyP or adenoviral co-overexpression of the antioxidant enzymes superoxide dismutase and catalase inhibited CD29-induced pro-survival signalling. Further, CD29-induced protective pathways were lost in mouse cardiomyocytes deficient for NOX2 or functional p47(phox), a regulatory subunit of NOX.

Conclusion: p47(phox)-dependent, NOX2-derived ROS are mandatory for CD29-induced pro-survival signalling in cardiomyocytes. These findings go in line with a growing body of evidence suggesting that ROS can be beneficial to the cell and support a crucial role for NOX2-derived ROS in cell survival in the heart.
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http://dx.doi.org/10.1093/cvr/cvr348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282577PMC
March 2012

β1-Integrin is up-regulated via Rac1-dependent reactive oxygen species as part of the hypertrophic cardiomyocyte response.

Free Radic Biol Med 2011 Aug 14;51(3):609-18. Epub 2011 May 14.

Myocardial Research, Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.

β(1)-Integrin mediates cardiomyocyte growth and survival and its proper regulation is essential for the structural and functional integrity of the heart. β(1)-Integrin expression is enhanced in hypertrophy, but the mechanism and significance of its up-regulation are unknown. Because reactive oxygen species (ROS) are important mediators of myocardial remodeling we examined their role in regulated β(1)-integrin expression. Hypertrophy was induced in neonatal cardiomyocytes by endothelin-1 (ET-1), which activated the regulatory NADPH oxidase subunit Rac1, evoked ROS, and enhanced fetal gene expression and cardiomyocyte size. ET-1 also enhanced cell adhesion and FAK phosphorylation and inhibited oxidative stress-induced cardiomyocyte apoptosis. Further, ET-1 increased β(1)-integrin mRNA and protein expression via Rac1-ROS-dependent MEK/ERK and EGF receptor-PI3K/Akt activation as shown by adenoviral dominant-negative Rac1 or overexpression of copper/zinc-superoxide dismutase. The relevance of regulated β(1)-integrin expression was examined in cardiomyocytes, in which targeting siRNA impeded the ET-1-induced β(1)-integrin up-regulation. In these cells, ET-1-induced cell adhesion, FAK phosphorylation, and hypertrophic response were significantly blunted, whereas its antiapoptotic effect was predominantly unchanged, suggesting at least partial dissociation of prohypertrophic and prosurvival signaling elicited by ET-1. In conclusion, β(1)-integrin up-regulation in response to ET-1 is mediated via Rac1-ROS-dependent activation of prohypertrophic pathways and is mandatory for ET-1-induced FAK activation, cell adhesion, and hypertrophic response.
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http://dx.doi.org/10.1016/j.freeradbiomed.2011.05.007DOI Listing
August 2011

Reactive oxygen/nitrogen species and the myocardial cell homeostasis: an ambiguous relationship.

Antioxid Redox Signal 2010 Dec 12;13(12):1899-910. Epub 2010 Oct 12.

Clinic of Cardiology, University Hospital Basel, University of Basel , Basel, Switzerland.

The totality of functional cardiomyocytes and an intact cardiac progenitor cell pool are key players in the myocardial cell homeostasis. Perturbation of either one may compromise the structural and functional integrity of the heart and lead to heart failure. Reactive oxygen/nitrogen species (ROS/RNS) are important regulators of cardiomyocyte viability; more recently, the interrelation between ROS and progenitor cell behavior and fate has moved into the spotlight. Increasing evidence suggests not only that ROS participate in the regulation of cardiac progenitor cell survival but also that they likewise affect their functional properties in terms of self-proliferation and differentiation. The apparent dichotomy of ROS/RNS effects with their adaptive and regulatory character on the one hand and their maladaptive and damaging features on the other pose a great challenge in view of the therapeutic exploitation of their role in the regulation of the myocardial cell homeostasis. In this article, mechanisms and potential significance of ROS/RNS action in the regulation of the myocardial cell homeostasis, in particular with respect to the preservation of viable cardiomyocytes and the maintenance of a functional cardiac progenitor cell pool, will be discussed.
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http://dx.doi.org/10.1089/ars.2010.3464DOI Listing
December 2010

Redox-mediated reciprocal regulation of SERCA and Na+-Ca2+ exchanger contributes to sarcoplasmic reticulum Ca2+ depletion in cardiac myocytes.

Free Radic Biol Med 2010 May 1;48(9):1182-7. Epub 2010 Feb 1.

Cardiovascular Medicine Section, Department of Medicine, and Myocardial and Vascular Biology Units, Boston University Medical Center, Boston, MA 02118, USA.

Myocardial failure is associated with increased oxidative stress and abnormal excitation-contraction coupling characterized by depletion of sarcoplasmic reticulum (SR) Ca(2+) stores and a reduction in Ca(2+)-transient amplitude. Little is known about the mechanisms whereby oxidative stress affects Ca(2+) handling and contractile function; however, reactive thiols may be involved. We used an in vitro cardiomyocyte system to test the hypothesis that short-term oxidative stress induces SR Ca(2+) depletion via redox-mediated regulation of sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA) and the sodium-Ca(2+) exchanger (NCX) and that this is associated with thiol oxidation. Adult rat ventricular myocytes paced at 5 Hz were superfused with H(2)O(2) (100 microM, 15 min). H(2)O(2) caused a progressive decrease in cell shortening followed by diastolic arrest, which was associated with decreases in SR Ca(2+) content, systolic [Ca(2+)](i), and Ca(2+)-transient amplitude, but no change in diastolic [Ca(2+)](i). H(2)O(2) caused reciprocal effects on the activities of SERCA (decreased) and NCX (increased). Pretreatment with the NCX inhibitor KB-R7943 before H(2)O(2) increased diastolic [Ca(2+)](i) and mimicked the effect of SERCA inhibition with thapsigargin. These functional effects were associated with oxidative modification of thiols on both SERCA and NCX. In conclusion, redox-mediated SR Ca(2+) depletion involves reciprocal regulation of SERCA and NCX, possibly via direct oxidative modification of both proteins.
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http://dx.doi.org/10.1016/j.freeradbiomed.2010.01.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847633PMC
May 2010

EMMPRIN mediates beta-adrenergic receptor-stimulated matrix metalloproteinase activity in cardiac myocytes.

J Mol Cell Cardiol 2008 Jan 31;44(1):210-7. Epub 2007 Jul 31.

Myocardial Biology Unit, Boston University School of Medicine, 650 Albany Street, X740, Boston, MA 02118, USA.

Extracellular matrix metalloproteinase inducer (EMMPRIN) expression is increased in myocardium from patients with dilated cardiomyopathy and animal models of heart failure. However, little is known about the regulated expression or functional role of EMMPRIN in the myocardium. In rat cardiac cells, EMMPRIN is expressed on myocytes but not endothelial cells or fibroblasts. Therefore, we tested the hypothesis that EMMPRIN expression regulates matrix metalloproteinase (MMP) activity in rat ventricular myocytes in vitro. In adult rat ventricular myocytes (ARVM), beta-adrenergic receptor (betaAR) stimulation and H(2)O(2) (24 h) each increased EMMPRIN expression as assessed by immunoblotting. Pretreatment with a catalase/superoxide dismutase mimetic or adenoviral-mediated expression of catalase or a dominant-negative c-jun N-terminal kinase-1 (JNK) mutant inhibited the betaAR- and H(2)O(2)-stimulated increases in EMMPRIN expression suggesting that EMMPRIN expression is regulated via a reactive oxygen species-dependent JNK pathway. To determine whether EMMPRIN expression regulates matrix metalloproteinase (MMP) activity, EMMPRIN activity was inhibited by adenoviral expression of an inhibitory mutant of EMMPRIN. Expression of mutant EMMPRIN inhibited the betaAR-stimulated increases in MMP2 expression and zymographic MMP activity. Thus, in cardiac myocytes betaAR stimulation induces the expression of EMMPRIN via the ROS-dependent activation of JNK. The resulting increase in EMMPRIN activity stimulates MMP expression and activity. These findings suggest that in the myocardium the regulated expression of EMMPRIN is a determinant of MMP activity and may thus play a role in myocardial remodeling.
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http://dx.doi.org/10.1016/j.yjmcc.2007.07.054DOI Listing
January 2008

Role of reversible, thioredoxin-sensitive oxidative protein modifications in cardiac myocytes.

Antioxid Redox Signal 2006 Nov-Dec;8(11-12):2153-9

Cardiovascular Medicine Section and the Myocardial Biology Unit, Boston University Medical Center, Boston, Massachusetts 02118, USA.

Reactive oxygen species (ROS) are important mediators of myocardial remodeling. However, the precise molecular mechanisms by which ROS exert their effects are incompletely understood. ROS induce oxidative posttranslational protein modifications that can regulate the function of structural, functional, and signaling proteins. For example, oxidative modification of free reactive thiols (S-thiolation) on the small G protein Ras increases Ras activity and thereby promotes ROS-dependent hypertrophic signaling in cardiac myocytes. By reducing thiols and restoring reversible thiol modifications, thioredoxin and glutaredoxin can act as regulators of ROS-mediated protein function. Understanding the regulation and functional relevance of oxidative protein modifications in myocardial remodeling may lead to new therapeutic strategies.
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http://dx.doi.org/10.1089/ars.2006.8.2153DOI Listing
January 2007

Aldosterone stimulates matrix metalloproteinases and reactive oxygen species in adult rat ventricular cardiomyocytes.

Hypertension 2005 Sep 25;46(3):555-61. Epub 2005 Jul 25.

Whitaker Cardiovascular Institute, Boston University Medical Center, Massachusetts, USA.

Matrix metalloproteinases (MMPs), aldosterone, and reactive oxygen species (ROS) are implicated in myocardial remodeling. Although ROS, cytokines, and neurohormones regulate MMP in cardiac fibroblasts, it is unknown whether aldosterone regulates MMP in cardiomyocytes. Therefore, we tested the hypothesis that aldosterone regulates MMP in cultured adult rat ventricular myocytes (ARVMs). ARVMs were treated with aldosterone for 24 hours, and MMP-2 and MMP-9 activities were measured by zymography. Aldosterone (50 nmol/L) increased MMP-2 (43+/-5%) and MMP-9 (55+/-15%; P<0.001 for both) activities. Pretreatment with spironolactone (100 nmol/L) abolished the aldosterone-induced increase in MMP activities. Aldosterone (50 nmol/L; 30 minutes) increased mitogen/extracellular signal-regulated kinase (MEK) (31+/-3%) and extracellular signal-regulated kinase 1/2 (ERK1/2; 41+/-7%; P<0.001 for both) phosphorylation. U0126 (10 micromol/L), an MEK1/2 inhibitor, abolished the aldosterone-induced increase in MMP activities. Aldosterone increased intracellular ROS as assessed by dichlorofluorescein diacetate (27+/-4%; P<0.05). This increase was inhibited by apocynin, an NADPH oxidase inhibitor. Apocynin likewise inhibited aldosterone-induced ERK1/2 phosphorylation and the increase in MMP activities. Furthermore, the antioxidants MnTMPyP and N-acetylcysteine inhibited the aldosterone-induced increase in ERK1/2 phosphorylation and MMP activities, respectively. Protein kinase C (PKC) is implicated in the nongenomic effects of aldosterone. To test the role of PKC, ARVMs were pretreated with chelerythrine, a PKC inhibitor. Chelerythrine prevented the aldosterone-induced increase in ERK1/2 phosphorylation and MMP activities. Thus, aldosterone induces MMP activity in ARVM via activation of the mineralocorticoid receptor, PKC, and ROS-dependent activation of the MEK/ERK pathway. NADPH oxidase is a likely source of ROS in this system.
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http://dx.doi.org/10.1161/01.HYP.0000176236.55322.18DOI Listing
September 2005

Alpha-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes is mediated via thioredoxin-1-sensitive oxidative modification of thiols on Ras.

Circulation 2005 Mar 21;111(9):1192-8. Epub 2005 Feb 21.

Cardiovascular Medicine Section, Department of Medicine, and the Myocardial and Vascular Biology Units, Boston University Medical Center, Boston, Mass 02118, USA.

Background: Alpha-adrenergic receptor (alphaAR)-stimulated hypertrophy in adult rat ventricular myocytes is mediated by reactive oxygen species-dependent activation of the Ras-Raf-MEK1/2-ERK1/2 signaling pathway. Because Ras is known to have redox-sensitive cysteine residues, we tested the hypothesis that alphaAR-stimulated hypertrophic signaling is mediated via oxidative modification of Ras thiols.

Methods And Results: The effect of alphaAR stimulation on the number of free thiols on Ras was measured with biotinylated iodoacetamide labeling. alphaAR stimulation caused a 48% decrease in biotinylated iodoacetamide-labeled Ras that was reversed by dithiothreitol (10 mmol/L), indicating a decrease in the availability of free thiols on Ras as a result of an oxidative posttranslational modification. This effect was abolished by adenoviral overexpression of thioredoxin-1 (TRX1) and potentiated by the TRX reductase inhibitor azelaic acid. Likewise, alphaAR-stimulated Ras activation was abolished by TRX1 overexpression and potentiated by azelaic acid. TRX1 overexpression inhibited the alphaAR-stimulated phosphorylation of MEK1/2, ERK1/2, and p90RSK and prevented cellular hypertrophy, sarcomere reorganization, and protein synthesis (versus beta-galactosidase). Azelaic acid potentiated alphaAR-stimulated protein synthesis. Although TRX1 can directly reduce thiols, it also can scavenge ROS by increasing peroxidase activity. To examine this possibility, peroxidase activity was increased by transfection with catalase, and intracellular reactive oxygen species were measured with dichlorofluorescein diacetate fluorescence. Although catalase increased peroxidase activity approximately 20-fold, TRX1 had no effect. Likewise, the alphaAR-stimulated increase in dichlorofluorescein diacetate fluorescence was abolished with catalase but retained with TRX1.

Conclusions: AlphaAR-stimulated hypertrophic signaling in adult rat ventricular myocytes is mediated via a TRX1-sensitive posttranslational oxidative modification of thiols on Ras.
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http://dx.doi.org/10.1161/01.CIR.0000157148.59308.F5DOI Listing
March 2005

Mineralocorticoid receptor inhibition ameliorates the transition to myocardial failure and decreases oxidative stress and inflammation in mice with chronic pressure overload.

Circulation 2005 Feb;111(4):420-7

Cardiovascular Medicine Section, Boston University Medical Center, Boston, Mass, USA.

Background: Although aldosterone, acting via mineralocorticoid receptors, causes left ventricular (LV) hypertrophy in experimental models of high-aldosterone hypertension, little is known about the role of aldosterone or mineralocorticoid receptors in mediating adverse remodeling in response to chronic pressure overload.

Methods And Results: We used the mineralocorticoid receptor-selective antagonist eplerenone (EPL) to test the role of mineralocorticoid receptors in mediating the transition from hypertrophy to failure in mice with chronic pressure overload caused by ascending aortic constriction (AAC). One week after AAC, mice were randomized to regular chow or chow containing EPL (200 mg/kg per day) for an additional 7 weeks. EPL had no significant effect on systolic blood pressure after AAC. Eight weeks after AAC, EPL treatment improved survival (94% versus 65%), attenuated the increases in LV end-diastolic (3.4+/-0.1 versus 3.7+/-0.1 mm) and end-systolic (2.0+/-0.1 versus 2.5+/-0.2 mm) dimensions, and ameliorated the decrease in fractional shortening (42+/-2% versus 34+/-4%). EPL also decreased myocardial fibrosis, myocyte apoptosis, and the ratio of matrix metalloproteinase-2/tissue inhibitor of matrix metalloproteinase-2. These beneficial effects of EPL were associated with less myocardial oxidative stress, as assessed by 3-nitrotyrosine staining, reduced expression of the adhesion molecule intercellular adhesion molecule-1, and reduced infiltration by macrophages.

Conclusions: Mineralocorticoid receptors play an important role in mediating the transition from LV hypertrophy to failure with chronic pressure overload. The effects of mineralocorticoid receptor stimulation are associated with alterations in the interstitial matrix and myocyte apoptosis and may be mediated, at least in part, by oxidative stress and inflammation.
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http://dx.doi.org/10.1161/01.CIR.0000153800.09920.40DOI Listing
February 2005

Cost-effectiveness of invasive versus medical management of elderly patients with chronic symptomatic coronary artery disease. Findings of the randomized trial of invasive versus medical therapy in elderly patients with chronic angina (TIME).

Eur Heart J 2004 Dec;25(24):2195-203

Division of Cardiology, University Hospital, CH-4031 Basel, Switzerland.

Aim: To compare benefits and costs of invasive versus medical management in elderly patients with chronic angina.

Methods And Results: In a predefined subgroup of 188 patients of the Trial of Invasive versus Medical therapy in Elderly patients with chronic angina (TIME), one-year benefits were assessed as freedom from major events and improvements in symptoms and quality of live. Costs were determined as one-year costs of resource utilisation. Invasive patients had higher 30-day, but lower months 2-12 hospital and intervention costs than medical patients, resulting in somewhat higher one-year costs for invasive management (p=0.08). However, billing data available for a subgroup of patients showed higher practitioner's charges in the medical patients (adjusted p=0.0015). Incremental costs to prevent one major event by invasive management averaged CHF 10100 (95% CI: -800 to 28300) or 6965, ranging from average CHF 5100 (euro 3515) to CHF 11600 (euro 8000) in a best, compared to a worst, case scenario.

Conclusions: Early increased costs of revascularization in invasive patients were balanced after one year by increased practitioners' charges and symptom-driven late revascularizations in medical patients. Therefore, the invasive strategy with improved clinical effectiveness at only marginally higher costs as medical management was cost-effective. Costs should not be an argument against invasive management of elderly patients with chronic angina.
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http://dx.doi.org/10.1016/j.ehj.2004.09.013DOI Listing
December 2004