Publications by authors named "Bernd van der Loo"

33 Publications

Long-term results of simplified frozen elephant trunk technique in complicated acute type A aortic dissection: A case-control study.

Vascular 2016 Oct 14;24(5):523-30. Epub 2016 Jan 14.

Clinic for Cardiovascular Surgery, Zurich University Hospital, Zurich, Switzerland.

Aim: To describe the long-term experience of a simplified frozen elephant trunk technique (sFETT) used in complicated acute type A aortic dissection (AAAD) treatment.

Methods And Results: Between January 2001 and December 2012, 34 patients (mean age 59.9 ± 11.0 years) with complicated AAAD (DeBakey I) underwent an emergency surgery including sFETT. sFETT consisted in gluing the dissected aortic arch wall layers with gelatine-resorcinol adhesive and video-assisted antegrade open arch aortic stent-graft deployment in the arch or proximal descending aorta. In addition to sFETT, the aortic root was addressed with standard techniques. A 30-day mortality was 14.7% (five patients) due to bleeding (1), multiple organ failure (2), and colon ischemia (2). Postoperative morbidity included neurological (2), renal (1) and cardio-pulmonary complications (4), as well as wound infection (1). Mean follow-up was 74.4 ± 45.0 months. Actual survival rates were 73.5% at 1 year, 70.2% at 5 years, and 58.5% at 13 years of follow-up. Six patients died during long-term follow-up from heart failure (1) and unknown reasons (5). Five patients required reoperation for aortic arch (3) or aorto-iliac (2) progression of aneurysm during the mid- and long-term follow-up. The remaining patients showed favorable evolution of the dissected aorta with false lumen occlusion in most cases and stable aortic diameters.

Conclusions: In AAAD patients, sFETT as used in our series is an easy and safe technique to repair the aortic arch. Long-term results after sFETT showed false lumen occlusion and stable aortic diameter in up to 13 years of follow-up.
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http://dx.doi.org/10.1177/1708538115627728DOI Listing
October 2016

Wall shear stress in the stented superficial femoral artery in peripheral arterial disease.

Atherosclerosis 2014 Mar 4;233(1):76-82. Epub 2014 Jan 4.

Department of Medicine II, Division of Angiology, Medical University of Vienna, Vienna, Austria. Electronic address:

Objective: Local changes in wall shear stress (WSS) contribute to vascular wall thickening and subsequent stenosis. Restenosis after stenting is a major concern, especially in the superficial femoral artery (SFA) of patients with peripheral arterial disease (PAD). Local alterations in WSS after stenting might contribute to restenosis/reocclusion. To test the hypothesis that WSS is impaired along the stented SFA segment, we studied the profile of WSS along the femoro-popliteal axis after stent placement in a cross-sectional design.

Methods: Eighty-seven patients with PAD (89 limbs) were included one day after stenting of the SFA. Flow velocities (peak and mean) and vessel diameter were measured by duplex ultrasound in five predefined segments along the femoro-popliteal axis, at rest and after exercise (30 toe raises); WSS (peak and mean) was calculated from flow velocities, vessel diameter and whole blood viscosity.

Results: WSS progressively declined along the stented segment at rest (peak WSS, p < 0.0001; mean WSS, p < 0.05); after exercise, WSS increased in all segments (all p < 0.001), but, again, progressively declined along the stent (peak WSS, p < 0.0001; mean WSS, p < 0.05). The internal vessel diameter remained unchanged after exercise in the stented and in the non-stented parts of the femoro-popliteal axis (all p > 0.05).

Conclusion: In PAD patients with SFA stenting WSS is impaired along the femoro-popliteal axis. The consequences of this finding in terms of local effects on the vessel wall that might favor restenosis/reocclusion needs further investigation.
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http://dx.doi.org/10.1016/j.atherosclerosis.2013.12.035DOI Listing
March 2014

Autocatalytic nitration of prostaglandin endoperoxide synthase-2 by nitrite inhibits prostanoid formation in rat alveolar macrophages.

Antioxid Redox Signal 2012 Nov 25;17(10):1393-406. Epub 2012 Jun 25.

Department of Biology, University of Konstanz, Konstanz, Germany.

Aims: Prostaglandin endoperoxide H(2) synthase (PGHS) is a well-known target for peroxynitrite-mediated nitration. In several experimental macrophage models, however, the relatively late onset of nitration failed to coincide with the early peak of endogenous peroxynitrite formation. In the present work, we aimed to identify an alternative, peroxynitrite-independent mechanism, responsible for the observed nitration and inactivation of PGHS-2 in an inflammatory cell model.

Results: In primary rat alveolar macrophages stimulated with lipopolysaccharide (LPS), PGHS-2 activity was suppressed after 12 h, although the prostaglandin endoperoxide H(2) synthase (PGHS-2) protein was still present. This coincided with a nitration of the enzyme. Coincubation with a nitric oxide synthase-2 (NOS-2) inhibitor preserved PGHS-2 nitration and at the same time restored thromboxane A(2) (TxA(2)) synthesis in the cells. Formation of reactive oxygen species (ROS) was maximal at 4 h and then returned to baseline levels. Nitrite (NO(2)(-)) production occurred later than ROS generation. This rendered generation of peroxynitrite and the nitration of PGHS-2 unlikely. We found that the nitrating agent was formed from NO(2)(-), independent from superoxide ((•)O(2)(-)). Purified PGHS-2 treated with NO(2)(-) was selectively nitrated on the active site Tyr(371), as identified by mass spectrometry (MS). Exposure to peroxynitrite resulted in the nitration not only of Tyr(371), but also of other tyrosines (Tyr).

Innovation And Conclusion: The data presented here point to an autocatalytic nitration of PGHS-2 by NO(2)(-), catalyzed by the enzyme's endogenous peroxidase activity and indicate a potential involvement of this mechanism in the termination of prostanoid formation under inflammatory conditions.
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http://dx.doi.org/10.1089/ars.2011.4485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437048PMC
November 2012

Impact of social characteristics on the treatment of patients with ischaemic events and patent foramen ovale.

Acta Cardiol 2012 Feb;67(1):41-7

Clinic of Cardiology, University Hospital Zurich, Switzerland.

Objective: Percutaneous closure of a patent foramen ovale (PFO) is a technically simple and safe procedure. PFO is a common finding present in up to one third of the population. Although several conditions such as stroke, migraine, and sleep apnoea have been associated with a PFO, as underlined by observational studies, no causal relationship has been documented so far. As this setting may potentially leave more space for the involved physicians for the choice of treatment, we hypothesized that social characteristics of the patient with a PFO might play a role.

Methods: We retrospectively analysed the data of 153 patients with a cerebrovascular and/or peripheral ischaemic event with the diagnosis of a PFO as documented in echocardiography from 2000 until 2005 at the University Hospital in Zurich, Switzerland.

Results: Forty-four patients (= 23%) underwent catheter-based PFO closure. There was no significant difference with respect to age (<40 years: P = 0.094, ns; 40-59 years: P = 0.923, ns; > or =60 years: P= 0.234, ns), gender (P = 0.356, ns) and insurance status (<40 years: P= 0.15, ns; 40-59 years: P= 0.37, ns; 60 years: P = 0.26, ns) between those who underwent percutaneous PFO closure and those who did not.

Conclusion: We conclude from this single-centre experience that social characteristics of patients only have a marginal impact on the indication of percutaneous closure of a PFO, if at all.
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http://dx.doi.org/10.1080/ac.67.1.2146564DOI Listing
February 2012

Vascular aging: chronic oxidative stress and impairment of redox signaling-consequences for vascular homeostasis and disease.

Ann Med 2013 Feb 1;45(1):17-36. Epub 2012 Mar 1.

Vascular Biology Unit, Whitaker Cardiovascular Institute, Boston University Medical Center, Boston, MA, USA.

Characteristic morphological and molecular alterations such as vessel wall thickening and reduction of nitric oxide occur in the aging vasculature leading to the gradual loss of vascular homeostasis. Consequently, the risk of developing acute and chronic cardiovascular diseases increases with age. Current research of the underlying molecular mechanisms of endothelial function demonstrates a duality of reactive oxygen and nitrogen species in contributing to vascular homeostasis or leading to detrimental effects when formed in excess. Furthermore, changes in function and redox status of vascular smooth muscle cells contribute to age-related vascular remodeling. The age-dependent increase in free radical formation causes deterioration of the nitric oxide signaling cascade, alters and activates prostaglandin metabolism, and promotes novel oxidative posttranslational protein modifications that interfere with vascular and cell signaling pathways. As a result, vascular dysfunction manifests. Compensatory mechanisms are initially activated to cope with age-induced oxidative stress, but become futile, which results in irreversible oxidative modifications of biological macromolecules. These findings support the 'free radical theory of aging' but also show that reactive oxygen and nitrogen species are essential signaling molecules, regulating vascular homeostasis.
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http://dx.doi.org/10.3109/07853890.2011.645498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3717565PMC
February 2013

High-dose atorvastatin treatment in patients with peripheral arterial disease: effects on platelet aggregation, blood rheology and plasma homocysteine.

Clin Hemorheol Microcirc 2011 ;47(4):241-51

Department of Medicine, Clinic of Angiology, University Hospital Zurich, Switzerland.

Background: Statins are used for the treatment of hypercholesterolemia. Although they are well known to have pleiotropic effects, their dose-dependent influence on platelet aggregation, hemorheologic properties and the plasma levels of homocysteine in patients with peripheral arterial disease (PAD) has not been thoroughly investigated so far.

Methods And Results: From a total of 100 patients with PAD 48 patients were randomized to a treatment with atorvastatin 80 mg/d for six months, and 52 patients served as controls who continued their medication including statins in lower doses. At baseline and at six months' follow up we assessed platelet aggregation upon stimulation with ADP, collagen and epinephrine using light transmission aggregometry. Furthermore, we determined major hemorheologic variables as well as the plasma levels of homocysteine, folic acid, and vitamin B6 and B12. No patient had obtained folic acid or B vitamin supplement. Platelet aggregation upon agonist-induced stimulation did not differ between patients under high-dose atorvastatin therapy and controls at baseline and after six months (p > 0.05). All hemorheologic parameters (plasma viscosity, red cell aggregation, whole blood viscosity, hematocrit, platelets, leucocytes) measured at baseline and after six months were not significantly different between both groups, too. After therapy with 80 mg atorvastatin homocysteine levels were significantly elevated as compared with baseline values (p = 0.0007), whereas levels remained unchanged in the control group. Folic acid levels were higher in the patients receiving high-dose atorvastatin as compared with controls both at baseline (p = 0.002) and at six months' follow up (p = 0.034). No significant difference in vitamin B6 and B12 levels both at baseline and after six months could be detected in either group.

Conclusions: Treatment with 80 mg atorvastatin did not affect platelet aggregation and major hemorheologic parameters. The finding of an increase of homocysteine plasma levels in the presence of rather elevated levels of folic acid needs further investigation.
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http://dx.doi.org/10.3233/CH-2011-1386DOI Listing
October 2011

Formation of pseudoaneurysm after aortic valve replacement without previous endocarditis: a case-control study.

J Am Soc Echocardiogr 2010 Jul 26;23(7):741-6. Epub 2010 May 26.

Clinic of Cardiology, University Hospital Zurich, and Institute for Social and Preventive Medicine, University of Zurich, Zurich, Switzerland.

Background: The aim of this study was to identify the predisposing factors for pseudoaneurysm formation after aortic valve replacement without previous endocarditis.

Methods: Echocardiography was used to identify patients. Parameters with influence on the occurrence of pseudoaneurysms were analyzed, and the odds ratio for the influence of the type of valve was estimated. The chi2 goodness-of-fit test was used to analyze whether location or underlying etiology was associated with an accumulated occurrence of a pseudoaneurysm. Fisher's exact test was used to assess a possible relation between the occurrence of a pseudoaneurysm after composite graft implantation and etiology or location.

Results: Patients treated with composite grafts had a 27-fold increased risk for developing pseudoaneurysms (psiMH=27; 95% confidence interval, 1.61-454.19) in comparison with aortic valve replacement only. There was a significant difference for the probability of different etiologies to occur (P=.032), with Stanford type A aortic dissection and aortic regurgitation being the most often occurring pathologies. Significant associations between the use of a composite graft and both the underlying etiology (P=.002) and the location of the pseudoaneurysm (P=.04) was found. Furthermore, patients with composite grafts had larger diameters of the aortic root compared with patients with aortic valve replacement only (P=.03). Neither the diameter of the annulus of the aortic valve (95% confidence interval, 0.89-1.32; P=.41) nor the diameter of the ascending aorta (95% confidence interval, 0.27-1.97; P=.54) had any influence on pseudoaneurysm formation.

Conclusions: The underlying disorder, determining the surgical procedure, influences the risk for the development of pseudoaneurysms in patients without previous endocarditis. The location of most pseudoaneurysms at the level of the aortic root may be a consequence of its larger diameter.
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http://dx.doi.org/10.1016/j.echo.2010.04.013DOI Listing
July 2010

A novel operator-independent algorithm for cardiac output measurements based on three-dimensional transoesophageal colour Doppler echocardiography.

Eur J Echocardiogr 2010 Jun 27;11(5):432-7. Epub 2010 Jan 27.

Surgical Planning Lab, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.

Aims: Cardiac output (CO) measurements from three-dimensional (3D) trans-mitral Doppler echocardiography are prone to error as manual selection of the region of interest (i.e. the site of measurement) is required. We newly developed an automated, user-independent algorithm to select the site of colour Doppler CO measurement. We aimed to validate this new method by benchmarking it against thermodilution, the current gold standard for CO measurements.

Methods And Results: Transoesophageal colour 3D Doppler echocardiographic studies were obtained from 15 patients who also had received a pulmonary catheter for invasive CO measurements. Trans-mitral flow was determined using a novel operator-independent algorithm to automatically select the optimal site of measurement. The operator-independent CO measurements were referenced against thermodilution. A good correlation was found between operator-independent Doppler flow computations and thermodilution with a mean bias of 0.09 L/min, standard deviation of bias 1.3 L/min, and a 26% error (2 SD/mean CO). Mean CO was 4.94 L/min (range 3.10-7.10 L/min).

Conclusion: Our findings demonstrate that CO computation from transoesophageal colour 3D Doppler echo can be automated concerning the site of velocity measurement. Our operator-independent algorithm provides an objective and reproducible alternative to thermodilution.
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http://dx.doi.org/10.1093/ejechocard/jep233DOI Listing
June 2010

Isolated cleft in the posterior mitral valve leaflet: a congenital form of mitral regurgitation.

Clin Cardiol 2009 Oct;32(10):553-60

Clinic for Cardiology, University Hospital, 8091 Zurich, Switzerland.

Background: Isolated congenital cleft of the posterior leaflet of the mitral valve is a rare cause of mitral regurgitation (MR). This study describes the clinical, echocardiographic, and intraoperative findings as well as treatment options.

Methods: Adults with an isolated cleft of the posterior mitral valve leaflet diagnosed by transthoracic echocardiography were evaluated with respect to clinical, echocardiographic, preoperative and intraoperative findings, and different surgical strategies.

Results: The prevalence of isolated cleft of the posterior mitral valve leaflet in all patients examined was 0.11% (n = 22 out of 19 320 evaluated echocardiograms); male gender was predominant (73%). Dyspnea on exertion was present in almost all patients with at least moderate regurgitation. The predominant localization of the cleft was within segment P2 (59%), followed by a cleft between P1/P2 (18%). An isolated cleft in segment P3 or segment P1 occurred twice in each segment (n = 2; 9%) and between P2/P3 once (n = 1; 5%). Regurgitation was severe in 50% (n = 11), moderate in 9% (n = 2), mild in 27% (n = 6), and only trivial in 14% (n = 3) of the patients. Surgical treatment involved reconstruction with ring annuloplasty in 45% (n = 10) and replacement in 4.5% (n = 1). A total of 11 patients (50%) with mostly mild or trivial mitral regurgitation were treated medically only.

Conclusion: Two-dimensional high-resolution cross-sectional echocardiography allows the distinct diagnosis of a clefted posterior leaflet, whereas clinical presentation, electrocardiogram, chest x-ray, and angiography are failing to identify the correct etiology of MR in patients with isolated posterior leaflet cleft mitral valve (IPLCMV). Patients with moderate to severe MR were treated surgically with excellent outcome.
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http://dx.doi.org/10.1002/clc.20608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6653238PMC
October 2009

Signalling processes in endothelial ageing in relation to chronic oxidative stress and their potential therapeutic implications in humans.

Exp Physiol 2009 Mar 7;94(3):305-10. Epub 2008 Nov 7.

Clinic of Cardiology, Cardiovascular Centre, Department of Medicine, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland.

Ageing is an important risk factor for the development of cardiovascular diseases. Vascular ageing is mainly characterized by endothelial dysfunction, an alteration of endothelium-dependent signalling processes and vascular remodelling. The underlying mechanisms comprise increased production of reactive oxygen species (ROS), inactivation of nitric oxide (.NO) and subsequent formation of peroxynitrite (ONOO(-)). Elevated ONOO(-) may exhibit new messenger functions by post-translational oxidative modification of intracellular regulatory proteins. Mitochondria are a major source of age-associated superoxide formation, as electrons are misdirected from the respiratory chain. Manganese superoxide dismutase (MnSOD), a mitochondrial antioxidant enzyme, is an integral part of the nucleoids and may protect mitochondrial DNA from ROS. A model linking .NO, mitochondria, MnSOD and its acetylation/deacetylation by sirtuins (NAD+-dependent class III histone deacetylases) may be the basis for a potentially new powerful therapeutic intervention in the ageing process.
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http://dx.doi.org/10.1113/expphysiol.2008.043315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987961PMC
March 2009

Serological evidence for the association of Bartonella henselae infection with arrhythmogenic right ventricular cardiomyopathy.

Clin Cardiol 2008 Oct;31(10):469-71

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

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of sudden death in young adults. On the basis of histopathological findings its pathogenesis may involve both a genetic origin and an inflammatory process. Bartonella henselae may cause endomyocarditis and was detected in myocardium from a young male who succumbed to sudden cardiac death.

Hypothesis: We hypothesized that chronic infection with Bartonella henselae could contribute to the pathogenesis of ARVC.

Methods: We investigated sera from 49 patients with ARVC for IgG antibodies to Bartonella henselae. In this study, 58 Swiss blood donors tested by the same method served as controls.

Results: Six patients with ARVC (12%) had positive (>1:256) IgG titres in the immunofluorescence test with Bartonella henselae. In contrast, only 1 elevated titre was found in 58 controls (p < or = 0.05). Interestingly, all patients with increased titres had no familial occurrence of ARVC.

Conclusions: Further studies in larger patient cohorts seem justified to investigate a possible causal link between chronic Bartonella henselae and ARVC, in particular its sporadic (nonfamilial) form.
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http://dx.doi.org/10.1002/clc.20269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6653530PMC
October 2008

Endogenous peroxynitrite modulates PGHS-1-dependent thromboxane A2 formation and aggregation in human platelets.

Free Radic Biol Med 2008 Aug 15;45(4):512-20. Epub 2008 May 15.

Vascular Biology Unit, Boston University School of Medicine, Boston, MA, 02118, USA.

Aggregation of activated platelets is considerably mediated by the autocrine action of thromboxane A2 (TxA2) which is formed in a prostaglandin endoperoxide H2 synthase-1 (PGHS-1 or COX-1)-dependent manner. The activity of PGHS-1 can be stimulated by peroxides, an effect termed "peroxide tone", that renders PGHS-1 the key regulatory enzyme in the formation of TxA2. Activated platelets release nitric oxide (*NO) and superoxide (O*2) but their interactions with the prostanoid pathway have been controversially discussed in platelet physiology and pathophysiology. The current study demonstrates that endogenously formed peroxynitrite at nanomolar concentrations, originating from the interaction of *NO and *O2, potently activated PGHS-1, which parallels TxA2 formation and aggregation in human platelets. Inhibition of the endogenous formation of either *NO or O*2 resulted in a concentration-dependent decline of PGHS-1 activity, TxA2 release, and aggregation. The concept of peroxynitrite as modulator of TxA2 formation and aggregation explains the interaction of *NO and O*2 with the PGHS pathway and suggests a mechanism by which antioxidants can regulate PGHS-1-dependent platelet aggregation. This may provide a molecular explanation for the clinically observed hyperreactivity of platelets in high-risk patients and serve as a basis for novel therapeutic interventions.
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http://dx.doi.org/10.1016/j.freeradbiomed.2008.04.042DOI Listing
August 2008

High-dose atorvastatin in peripheral arterial disease (PAD): effect on endothelial function, intima-media-thickness and local progression of PAD. An open randomized controlled pilot trial.

Thromb Haemost 2008 Jan;99(1):182-9

Clinic of Angiology, Department of Medicine, University Hospital Zurich, Switzerland.

Beneficial effects of aggressive lipid-lowering with high-dose atorvastatin (80 mg/day) have been demonstrated in patients with coronary and cerebrovascular disease. The impact of such a therapy in patients with peripheral arterial disease (PAD) is less known so far. Here we studied the effects of high-dose atorvastatin on brachial artery endothelial function, common carotid intima-media thickness (IMT) and local progression of PAD in these patients. One hundred of 500 patients screened with documented PAD were randomly assigned to receive 80 mg of atorvastatin daily for six months or to continue on conventional medical treatment. Ninety-six percent of patients in the control group were on standard statin treatment. High resolution B-mode ultrasonography was used to study brachial artery flow-mediated dilation (FMD), IMT and ankle-brachial index (ABI) at baseline and at six months. FMD and IMT at baseline and at six months were 4.1 (0.06-8.6) versus 5.0 (0.76 vs. 8.1) %, p = 0.96, and 0.76 (0.66-0.82) versus 0.73 (0.63-0.81) mm, p = 0.41, respectively, in the atorvastatin group, and 2.66 (-1.9-6.9) versus 3.65 (0.0-8.6)%, p = 0.02, and 0.78 (0.71-0.90) versus 0.77 (0.70-0.90) mm, p = 0.48, in the control group. ABI at baseline and at six months was not different in either group. LDL cholesterol was reduced from 2.53 (2.21-3.28) to 1.86 (1.38-2.29) mM (p < 0.0001) in the atorvastatin group, whereas levels remained stable in the control group [2.38 (1.94-3.16) vs. 2.33 (1.82-2.84) mM, p = 0.61]. Major adverse cardiovascular events occurred in 2.1% in the atorvastatin group and 1.9% in the control group (p = 0.61). In conclusion, in this pilot trial aggressive lipid-lowering with 80 mg of atorvastatin daily for six months had no effect on brachial artery FMD in patients with PAD. IMT and ABI were also similar in patients with and without high-dose atorvastatin at six months.
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http://dx.doi.org/10.1160/TH07-04-0265DOI Listing
January 2008

Inactivity of nitric oxide synthase gene in the atherosclerotic human carotid artery.

Basic Res Cardiol 2007 Jul 15;102(4):308-17. Epub 2007 Mar 15.

Cardiovascular Research, Physiology Institute University of Zürich, Zürich, Switzerland.

Objective: Nitric oxide (NO) inhibits thrombus formation, vascular contraction, and smooth muscle cell proliferation. We investigated whether NO release is enhanced after endothelial NO synthase (eNOS) gene transfer in atherosclerotic human carotid artery ex vivo.

Methods And Results: Western blotting and immunohistochemistry revealed that transduction enhanced eNOS expression; however, neither nitrite production nor NO release measured by porphyrinic microsensor was altered. In contrast, transduction enhanced NO production in non-atherosclerotic rat aorta and human internal mammary artery. In transduced carotid artery, calcium-dependent eNOS activity was minimal and did not differ from control conditions. Vascular tetrahydrobiopterin concentrations did not differ between the experimental groups. Treatment of transduced carotid artery with FAD, FMN, NADPH, L-arginine, and either sepiapterin or tetrahydrobiopterin did not alter NO release. Superoxide formation was similar in transduced carotid artery and control. Treatment of transduced carotid artery with superoxide dismutase (SOD), PEG-SOD, PEG-catalase did not affect NO release.

Conclusions: eNOS transduction in atherosclerotic human carotid artery results in high expression without any measurable activity of the recombinant protein. The defect in the atherosclerotic vessels is neither caused by cofactor deficiency nor enhanced NO breakdown. Since angioplasty is performed in atherosclerotic arteries,eNOS gene therapy is unlikely to provide clinical benefit.
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http://dx.doi.org/10.1007/s00395-007-0650-7DOI Listing
July 2007

[Venous diseases].

Herz 2007 Feb;32(1):1-2

Departement Innere Medizin, HerzKreislaufZentrum, Universitätsspital Zürich, Rämistrasse 100, 8091 Zürich, Switzerland.

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http://dx.doi.org/10.1007/s00059-007-2970-7DOI Listing
February 2007

Low-molecular-weight heparin for prevention of restenosis after femoropopliteal percutaneous transluminal angioplasty: a randomized controlled trial.

J Vasc Surg 2006 Dec;44(6):1247-53

Clinic of Angiology, Department of Internal Medicine, Zurich, Switzerland.

Background: Restenosis after angioplasty is essentially due to intimal hyperplasia. Low-molecular-weight heparins (LMWHs) have experimentally been shown to have antiproliferative effects in addition to their antithrombotic properties. Their potential in reducing restenosis remains to be established. Therefore, we wanted to test the hypothesis that LMWH plus aspirin is more effective than aspirin alone in reducing the incidence of restenosis/reocclusion in patients undergoing percutaneous transluminal angioplasty (PTA) of femoropopliteal arteries. Further, different effects of LMWH in patients treated for critical limb ischemia (CLI) or claudication only should be investigated.

Methods: After successful PTA, 275 patients with symptomatic peripheral arterial disease (claudication or critical limb ischemia) and femoropopliteal obstructions were randomized to receive either 2500 IU of dalteparin subcutaneously for 3 months plus 100 mg of aspirin daily (n = 137), or 100 mg aspirin daily alone (n = 138). The primary end point was restenosis or reocclusion documented by duplex ultrasonography imaging at 12 months.

Results: Restenosis/reocclusion occurred in 58 patients (44%) in the dalteparin group and in 62 patients (50%) in the control group (P = .30). In a subgroup analysis according to the severity of peripheral arterial disease, we found that in patients treated for claudication, restenosis/reocclusion developed in 43 (43%) in the dalteparin group, and in 35 (41%) in the control group (P = .70); in patients treated for CLI, restenosis/reocclusion was significantly lower in the dalteparin group (15, 45%) than in the control group (27, 72%; P = .01). No major bleeding events occurred in either group.

Conclusions: Treatment with 2500 IU dalteparin subcutaneously given for 3 months after femoropopliteal PTA failed to reduce restenosis/reocclusion at 12 months. However, dalteparin may be beneficial in the subgroup of patients with CLI at 12 months follow-up.
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http://dx.doi.org/10.1016/j.jvs.2006.07.044DOI Listing
December 2006

Age-associated cellular relocation of Sod 1 as a self-defense is a futile mechanism to prevent vascular aging.

Biochem Biophys Res Commun 2006 Jun 19;344(3):972-80. Epub 2006 Apr 19.

Clinic of Cardiology, Cardiovascular Centre, University Hospital Zurich, Switzerland.

Vascular aging is characterized by the presence of chronic oxidative stress. Although cytosolic Sod 1 has a key role in the detoxification of superoxide ((*)O(2)(-)), little is known about its importance in vascular aging. We found that inhibition of Sod 1 had no effect on (*)O2- generation. Furthermore, its expression decreased in an age-dependent manner. Interestingly, Sod 1 loses its membrane-association and is also lost from the caveolae with increasing age. Instead, a relocation of Sod 1 to the mitochondria takes place, presumably in an attempt to maintain mitochondrial integrity and to counter-balance age-associated oxidative stress. Unlike Sod 2, which is constitutively expressed in mitochondria to control (*)O2- radical fluxes, Sod 1 is not inactivated by peroxynitrite and is not nitrated as a function of age. These novel insights into oxidative stress-associated vascular aging and the understanding about how redox-systems are regulated in old age may identify new targets to ameliorate aging as the greatest cardiovascular risk factor.
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http://dx.doi.org/10.1016/j.bbrc.2006.03.224DOI Listing
June 2006

Expression and activity patterns of nitric oxide synthases and antioxidant enzymes reveal a substantial heterogeneity between cardiac and vascular aging in the rat.

Biogerontology 2005 ;6(5):325-34

Division of Cardiology, Cardiovascular Centre, University Hospital Zurich, Rämistrasse 100, CH-8091, Zürich, Switzerland.

We investigated the effects of aging and ischemia-reperfusion (I/R) injury on the expression and activity of nitric oxide (*NO) synthases and superoxide dismutase (SOD) isoforms. To this end we perfused excised hearts from young (6 months old) and old (31-34 months old) rats according to the Langendorff technique. The isolated hearts were, after baseline perfusion for 30 min, either subjected to 20 min of global no-flow ischemia followed by 40 min of reperfusion or were control-perfused (60 min normoxic perfusion). Both MnSOD and Cu,ZnSOD expression remained unchanged with increasing age and remained unaltered by I/R. However, SOD activity decreased from 7.55 +/- 0.1 U/mg protein in young hearts to 5.94 +/- 0.44 in old hearts (P<0.05). Furthermore, I/R led to a further decrease in enzyme activity (to 6.35 +/- 0.41 U/mg protein; P<0.05) in myocardium of young, but not in that of old animals. No changes in myocardial protein-bound 3-nitrotyrosine levels could be detected. Endothelial NOS (eNOS) expression and activity remained unchanged in aged left ventricles, irrespective of I/R injury. This was in steep contrast to peripheral (renal and femoral) arteries obtained from the same animals where a marked age-associated increase of eNOS protein expression could be demonstrated. Inducible NOS expression was undetectable either in the peripheral arteries or in the left ventricle, irrespective of age. In particular when associated with an acute pathology, which is furthermore limited to a certain time frame, changes in the aged myocardium with respect to enzymes crucially involved in maintaining the redox homeostasis, seem to be much less pronounced or even absent compared to the vascular aging process. This may point to heterogeneity in the molecular regulation of the cardiovascular aging process.
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http://dx.doi.org/10.1007/s10522-005-4807-1DOI Listing
September 2006

Decreased wall shear stress in the common carotid artery of patients with peripheral arterial disease or abdominal aortic aneurysm: relation to blood rheology, vascular risk factors, and intima-media thickness.

J Vasc Surg 2006 Jan;43(1):56-63; discussion 63

Division of Angiology, Department of Medicine, University Hospital Zurich, Zurich, Switzerland.

Background: Wall shear stress, a local risk factor of atherosclerosis, is decreased in the common carotid artery of patients with vascular risk factors. We evaluated wall shear stress in the common carotid artery of patients with symptomatic peripheral arterial occlusive disease (PAD) and abdominal aortic aneurysm (AAA). As blood viscosity is a determinant of wall shear stress, we further investigated the impact of rheologic variables on wall shear stress in relation to vascular risk factors and intima-media thickness.

Methods: High-resolution ultrasonography scans were used to study intima-media thickness, internal diameter, and blood velocity in the common carotid artery of 31 patients with PAD, 36 patients with AAA, and 37 controls. Furthermore, major hemorheologic variables and vascular risk factors were evaluated, and wall shear stress was calculated.

Results: Wall shear stress was lower in patients with PAD (median [IQR], dynes/cm(2): 14.4 [10 to 19]) and with AAA (12.1 [9 to 15]) than in healthy controls (20.6 [17 to 24]; P < .0001). Wall shear stress was inversely related to red cell aggregation (P = .01), fibrinogen (P = .003), leucocyte count (P = .001), plasma viscosity (P = .04), and intima-media thickness (P < .0001). Furthermore, wall shear stress was negatively associated with age, smoking, and triglycerides, but positively correlated with high-density lipoprotein cholesterol (all P < .001). When the influence of all these predictors were simultaneously taken into account in a multiple regression model, only age (P < .0001), smoking (P = .005), and triglycerides (P = .003) remained significantly associated with wall shear stress.

Conclusions: This is the first report, to our knowledge, showing that wall shear stress of the common carotid artery is decreased in patients with symptomatic PAD and in patients with AAA. Rheologic variables are less important in predicting wall shear stress than age, triglycerides, and smoking.
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http://dx.doi.org/10.1016/j.jvs.2005.09.030DOI Listing
January 2006

Novel doppler assessment of intracoronary volumetric flow reserve: validation against PET in patients with or without flow-dependent vasodilation.

J Nucl Med 2005 Aug;46(8):1272-7

Nuclear Cardiology, Cardiovascular Center, University Hospital, Zurich, Switzerland.

Unlabelled: Volumetric blood flow (Q) determination requires simultaneous assessment of mean blood flow velocity and vessel cross-sectional area. At present, no method provides both values. Intracoronary Doppler-based assessment of coronary flow velocity reserve (CFVR) relies on average peak velocity (APV). Because this does not account for changes in velocity profile or vessel area usually occurring with flow-dependent vasodilation, results can be misleading. The aim of this clinical study was to validate against the current gold standard (measurement of myocardial perfusion reserve [MPR] by PET) a new, Doppler-based method for calculating coronary Q and coronary flow reserve (CFR).

Methods: Doppler-based intracoronary Q was measured with a proprietary guidewire device in a nonstenotic coronary artery at baseline and during adenosine-induced hyperemic flow (140 mug/kg/min intravenously during 7 min). Three gate positions were assessed, of which 2 were lying within the vessel and 1 was intersecting the vessel. The zeroth (M(0)) and the first (M(1)) Doppler moments of the intersecting gate were used to calculate mean blood flow velocity (M(1)/M(0)) and vessel area (M(0)), and M(0) of the 2 proximal gates was used to correct for scattering and attenuation. CFR was calculated as hyperemic/resting flow with Q and compared with APV-derived CFVR and with the corresponding segmental MPR obtained with (15)O-labeled water and PET.

Results: Q (CFR, 2.60 +/- 1.07) correlated well with PET (MPR, 2.58 +/- 1.11) (r = 0.832, P < 0.005; Bland-Altman limits, -1.42 to 1.09), whereas CFVR did not (r = 0.09, P = not statistically significant; Bland-Altman limits, -3.36 to 2.24). However, in vessels without dilation, there was no difference between CFR, CFVR, and MPR.

Conclusion: This procedure for intracoronary Q measurement using the proprietary Doppler guidewire system, which accounts for both changes in flow profile and changes in vessel area, allows invasive, accurate assessment of CFR even in the presence of flow-dependent vasodilation.
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August 2005

Blood fluidity and outcome after femoropopliteal percutaneous transluminal angioplasty (PTA): role of plasma viscosity and low platelet count in predicting restenosis.

Clin Hemorheol Microcirc 2005 ;32(2):159-68

Division of Angiology, Department of Medicine, University Hospital Zurich, Switzerland.

Rheological abnormalities are well known in patients with peripheral arterial occlusive disease (PAOD). We wanted to determine whether rheological variables are related to restenosis after femoropopliteal percutaneous transluminal angioplasty (PTA). In 114 patients (62 men; median age 70 years) undergoing femoropopliteal PTA for symptomatic peripheral arterial occlusive disease (PAOD) plasma viscosity, red cell aggregation, whole blood viscosity, hematocrit, fibrinogen, platelet count, leukocytes and C-reactive protein were determined the day after the procedure and at 1, 3, and 12 months. The primary endpoint was restenosis >50% documented by duplexsonography up to 12 months. Cox proportional hazards analysis was used to assess the risk of restenosis for postinterventional values of rheological variables. Forty-eight patients (42%) developed restenosis at 12 months. Patients with restenosis had higher baseline plasma viscosity (PV) (medians, 1.71 vs. 1.65 millipascal seconds [mPa.s]; p = 0.04) and lower platelet count (224 vs. 240 x 10(3)/microl; p = 0.03) than patients without restenosis. The hazard ratio (HR; 95% CI) of incident restenosis was 9.2 (1.12-76; p = 0.03) for PV and 0.99 (0.99-1.0; p = 0.07) for PLT. When examining jointly both high PV and low platelet count (PLT), patients with PV > 1.66 mPa.s and PLT < 233 x 10(3)/microl (i.e. variables split at their respective median) had an increased risk of restenosis (log-rank test p = 0.01). Multivariate Cox proportional hazard analysis showed that plasma viscosity (p = 0.02), low platelet count (p = 0.01), lesion length (p = 0.0037) and lack of hypertension (p = 0.01) were associated with restenosis at 12 months. No associations were found between restenosis and the other rheological and inflammatory variables studied. Our data suggest that increased PV and low PLT contribute to restenosis after femoropopliteal PTA.
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July 2005

Texture analysis in digitally-acquired echocardiographic images: the effect of JPEG compression and video storage.

Ultrasound Med Biol 2005 Mar;31(3):361-6

Echocardiography, Division of Cardiology, Cardiovascular Center, University Hospital of Zürich, Zürich, Switzerland.

The analysis of texture in video-stored echocardiographic images is an established method to characterize myocardial pathologies. We investigated whether or not texture parameters calculated from video-stored images and those derived from the joint photographic expert group (JPEG) format compressed data are equivalent to those calculated from uncompressed digital images. Texture parameters were calculated using uncompressed digital data, images stored on videotape, and three forms of compressed digital data (baseline JPEG, JPEG 2000 and lossless JPEG 2000). Video storage heavily affected most texture parameters. Although first-order texture parameters derived from JPEG-compressed images were generally equivalent to those derived from the uncompressed data, several second-order parameters differed significantly. We conclude that texture of video-stored images is not comparable to that of digitally-stored images and that JPEG compression changes important second-order texture parameters. This observation should be taken into account when analyzing texture of modern image data (uncompressed or compressed) and comparing the results with earlier studies utilizing video-stored data.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2004.11.009DOI Listing
March 2005

C-reactive protein and red cell aggregation correlate with late venous function after acute deep venous thrombosis.

J Vasc Surg 2004 Oct;40(4):644-9

Division of Angiology, Department of Medicine, University Hospital Zurich, Switzerland.

Objective: Risk factors leading to development and subsequent progression of chronic venous insufficiency after acute deep venous thrombosis (DVT) are only partially identified. Inflammation and rheologic abnormalities might have a causative role. The purpose of this study was to investigate C-reactive protein (CRP), D -dimer, and blood rheologic parameters in patients after acute DVT in relation to clinical outcome.

Subjects And Methods: Patients with a history of acute proved DVT underwent clinical examination and duplex ultrasound scanning of the veins, and Venous Clinical Severity Score (VCSS) and Venous Segmental Disease Score (VSDS) were calculated. Further, CRP, D -dimer, and several rheologic parameters were determined and related to outcome as assessed with venous scores.

Results: Forty-three patients were examined 28 (median) months after the index event. Patients had higher CRP ( P < .001), D -dimer ( P < .001), red blood cell aggregation ( P < .01), fibrinogen concentration ( P < .01), and leukocyte count ( P < .05) than did healthy control subjects. CRP and red blood cell aggregation were positively correlated with VCSS ( r = 0.42 and P < .01, and r = 0.30 and P < 0.05, respectively). Multivariate regression analysis showed that the relation between CRP and VCSS was independent of other laboratory and rheologic parameters and of age, total thrombus load, duration of compression therapy after the index event, recurrence, recanalization, and presence of comorbid conditions ( P < .05).

Conclusions: CRP is independently related to the severity of venous dysfunction in patients after acute DVT. Chronic inflammation as well as changes in blood rheologic parameters may be causally involved in the development of chronic venous insufficiency occurring in the medium-term and long-term course after acute DVT.
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http://dx.doi.org/10.1016/j.jvs.2004.07.004DOI Listing
October 2004

A novel in vivo procedure for volumetric flow measurements.

Ultrasound Med Biol 2004 May;30(5):633-7

Echocardiography, Division of Cardiology, Cardiovascular Center, University Hospital, Zurich, Switzerland.

We report on a novel procedure for invasive volumetric blood flow measurements using a commercially available Doppler flow wire system, which could, until now, only measure flow velocity. We here describe a method applicable in vivo to generate both velocity and cross-sectional area information from the same pulsed-wave Doppler signal for volumetric flow assessment. We demonstrate its feasibility and validation in vivo in pig coronary arteries. Our Doppler-derived volumetric flow measurements were compared with the respective transit-time flow and showed an excellent correlation (r = 0.969; p < 0.0001). Agreement between transit-time and Doppler-derived flow measurements could be observed for flow conditions ranging from 30 to 180 mL/min. The mean values for the two methods were 71.4 +/- 43.7 mL/min and 71.3 +/- 42.2 mL/min, respectively. We conclude that this technique might possibly be introduced into future clinical practice as an invasive procedure of choice for the assessment of volumetric blood flow.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2004.02.004DOI Listing
May 2004

Plasma homocysteine and restenosis after femoropopliteal angioplasty.

J Endovasc Ther 2004 Jun;11(3):302-9

Department of Medicine, University Hospital Zurich, Switzerland.

Purpose: To assess the relationship between plasma homocysteine levels and restenosis after femoropopliteal percutaneous transluminal angioplasty.

Methods: Over a 10-month period, 128 consecutive, symptomatic patients (72 men; median age 70 years) having successful femoropopliteal angioplasty for atherosclerotic occlusive disease were prospectively enrolled in the study. Plasma homocysteine levels were determined the day before the procedure. The primary endpoint was restenosis >50%, documented by duplex sonography, at up to 12 months' follow-up. Cox proportional hazards analysis was used to determine the risk of restenosis in relation to pretreatment homocysteine levels.

Results: The restenosis rate at 12 months was 46%. Median baseline plasma homocysteine levels were not different in patients with and without restenosis (15.4 versus 16.7 micromol/L, p=0.30). Compared to patients with homocysteine levels /=19.7 micromol/L (upper tertile, n=42) (p=0.38). Multivariate analysis showed that lesion length (p<0.0001) and lack of hypertension (p=0.0013) were associated with restenosis.

Conclusions: Elevated plasma homocysteine levels are not associated with restenosis after femoropopliteal angioplasty. Therefore, plasma homocysteine cannot be considered as an important risk factor influencing the outcome after initially successful angioplasty in femoropopliteal arteries.
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http://dx.doi.org/10.1583/03-1086.1DOI Listing
June 2004

Oxidative stress-associated vascular aging is independent of the protein kinase C/NAD(P)H oxidase pathway.

Arch Gerontol Geriatr 2004 Mar-Apr;38(2):181-90

Department of Biology, University of Konstanz, 78434 Konstanz, Germany.

Aging is an independent risk factor for the development of cardiovascular disease. Vascular aging is mainly characterized by endothelial dysfunction, which, in turn, is primarily attributable to increased superoxide (O(2)(*)(-)) formation with age. To date, the source of this age-associated increased O(2)(*)(-) production remains obscure. We investigated whether like in hyperglycemia or hypertension protein kinase C (PKC)-mediated activation of the NAD(P)H oxidase system is involved. Here we show that both PKC translocation, necessary for its activation, and expression of the cytosolic subunits of the NAD(P)H oxidase, p47(phox) and p67(phox), remain unchanged with age. Therefore, we suggest that oxidative stress-associated vascular aging mechanistically differs from endothelial dysfunction seen in the context of other cardiovascular risk factors, for which the PKC/NAD(P)H oxidase pathway has been shown responsible.
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http://dx.doi.org/10.1016/j.archger.2003.09.006DOI Listing
May 2004

Age-related changes of vitamin A status.

J Cardiovasc Pharmacol 2004 Jan;43(1):26-30

Division of Cardiology, Cardiovascular Centre, University Hospital Zurich, Switzerland.

Ageing is an independent risk factor for the development of cardiovascular disease. The ageing process is known to be associated with increased oxidative stress and an increased risk for cardiovascular and other diseases, such as cancer. To delay this process, therapeutic strategies involving the use of naturally occurring antioxidants, such as vitamin A, have gained considerable interest. Therefore, we wanted to investigate in a model of mammalian ageing whether changes in tissue and plasma levels of vitamin A occur with increasing age. This would constitute a prime rationale for its dietary supplementation. Experiments were performed in three different age groups (4-6 months old, 19 months old, 32-35 months old) of F1 (F344 x BN) healthy male rats that were fed a normal diet without any additional supplementation. Vitamin A and carotenoids in plasma and major organs were measured by reverse-phase high-performance liquid chromatography. In 3-year-old rats, vitamin A levels were found to be decreased in plasma (P < 0.0001) as compared with young and middle-aged animals. However, they were markedly increased in the main storage organ (ie, the liver) (P < 0.01-0.0001), and also in the aortic vessel wall. They were undetectable in the heart, irrespective of age. Increased tissue levels of vitamin A, especially in the vasculature, may be part of an age-associated self-regulatory process of adaptation, possibly as a counter-regulation against oxidative tissue damage. Based upon the assumption that in elderly humans, as in our animal model, a similar demand-regulated mechanism may work independently of additional dietary vitamin A supplementation, one may question the strategy of large clinical interventional trials using vitamin A or its derivatives beyond normal dietary intake.
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http://dx.doi.org/10.1097/00005344-200401000-00005DOI Listing
January 2004

Decreased plasma and tissue levels of vitamin C in a rat model of aging: implications for antioxidative defense.

Biochem Biophys Res Commun 2003 Apr;303(2):483-7

Division of Cardiology, Cardiovascular Centre, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland.

Aging is an independent risk factor for the development of cardiovascular and many other diseases. The aging process is known to be associated with increased oxidative stress, possibly related to an age-inherent loss of antioxidant capacity. Vitamin C is a major naturally occurring antioxidant. Thus, we investigated its role in a rat model of aging. Vitamin C in plasma and tissues as well as malondialdehyde in the heart were measured in young (6 months old) and old (27-30 months old) F1 (F344 x BN) healthy male rats fed a normal diet. In old rats, vitamin C plasma levels were found to be decreased (p<0.02) as compared with young animals. Furthermore, there was a tissue-specific distribution: in the heart, liver, kidney, lungs, and skeletal muscle, vitamin C decreased with age (p<0.005 to p<0.05), while no significant differences could be observed in the aortic wall and in the brain. Organs of the digestive tract rather showed an increase of vitamin C levels with age. Oxidative stress, determined representatively in the heart by measuring malondialdehyde tissue levels, exhibited an age-dependent increase (p<0.05). A distinct pattern of specific tissue distribution of vitamin C suggests a differential age-associated regulation. As vitamin C decreased concomitantly to an increase in cardiac lipid peroxidation, its supplementation may be useful to prevent age-related oxidative stress and tissue aging.
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http://dx.doi.org/10.1016/s0006-291x(03)00360-7DOI Listing
April 2003

Isolated noncompaction of the myocardium.

Circulation 2003 Feb;107(7):e50; author reply e50

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http://dx.doi.org/10.1161/01.cir.0000055539.05437.f6DOI Listing
February 2003
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