Biomedical subjects

A M Zeiher

Publications and source records attributed to A M Zeiher.

At least 19 recordsLinked to original sources

PubMed2005

[Resuscitation after prehospital cardiovascular arrest].

Initiation of effective cardiopulmonary resuscitation (CPR) at the earliest possible moment is the most important determinant of prognosis for prehospital cardiac arrest. The prognosis is essentially defined by two parameters: survival to hospital admission and survival to discharge. In connection with prehospital cardiac arrest, early defibrillation is particularly important, including the widespread availability of (semi)automatic defibrillators. Further aspects of CPR have recently received increased attention: on the one hand, changed study status regarding the use of antiarrhythmic agents (especially amiodarone), on the other hand, administration of vasopressin during resuscitation, and finally, the efficacy of mild hypothermia following prehospital cardiac arrest. These aspects represent the main subject of the present overview, which also addresses the latest revision of the International Liaison Committee on Resuscitation (ILCOR) guidelines on CPR that resulted in corresponding changes in the European Resuscitation Council (ERC) guidelines.

Amiodarone↗

PubMed2004

Diabetes and cardiovascular risk evaluation and management in primary care: progress and unresolved issues - rationale for a nationwide primary care project in Germany.

This review highlights established and more recently recognized risk factors for coronary heart disease (CHD) relevant for patients seen in primary care, emphasizing the key role of diabetes mellitus type 2. Recent trends in risk factor research as well as current methods of risk stratification, and new systemic markers are discussed. Beyond the need for more forceful public health strategies to improve early recognition and intervention, the necessity of an integrated comprehensive investigation of the overall characteristics of cardiovascular disease, especially in primary care patients as a prerequisite for future concerted actions is pointed out. Based on this, a large-scale epidemiological investigation focusing on CHD and diabetes in the primary care sector is suggested.

Cardiovascular Diseases↗

PubMed2003

Infarct remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infarction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging.

BACKGROUND: Experimental and initial clinical studies suggest that transplantation of circulating blood- (CPC) or bone marrow-derived (BMC) progenitor cells may beneficially affect postinfarction remodeling processes after acute myocardial infarction (AMI). To relate functional characteristics of the infused cells to quantitative measures of outcome at 4-month follow-up, we performed serial contrast-enhanced MRI and assessed the migratory capacity of the transplanted progenitor cells immediately before intracoronary infusion. METHODS AND RESULTS: In 28 patients with reperfused AMI receiving either BMCs or CPCs into the infarct artery 4.7+/-1.7 days after AMI, serial contrast-enhanced MRI performed initially and after 4 months revealed a significant increase in global ejection fraction (from 44+/-10% to 49+/-10%; P=0.003), a decrease in end-systolic volume (from 69+/-26 to 60+/-28 mL; P=0.003), and unchanged end-diastolic volumes (122+/-34 versus 117+/-37 mL; P=NS). Infarct size, measured as late enhancement (LE) volume, decreased significantly, from 46+/-32 to 37+/-28 mL (P<0.05). There was a significant correlation between the reduction in LE volume and global ejection fraction improvement. The migratory capacity of transplanted cells as assessed ex vivo toward a gradient of vascular endothelial growth factor for CPCs and stromal cell derived factor-1 for BMCs was closely correlated with the reduction of LE volume. By multivariate analysis, migratory capacity remained the most important independent predictor of infarct remodeling. CONCLUSIONS: Analysis of serial contrast-enhanced MRI suggests that intracoronary infusion of adult progenitor cells in patients with AMI beneficially affects postinfarction remodeling processes. The migratory capacity of the infused cells is a major determinant of infarct remodeling, disclosing a causal effect of progenitor cell therapy on regeneration enhancement.

Cell Movement↗

PubMed2003

[Coronary stent implantation in elderly patients: acute and long-term results].

UNLABELLED: The number of elderly patients with coronary heart disease is rapidly growing. Morbidity, related with PTCA is increased in elderly patients, presumably because of the more complex adverse baseline characteristics. However, it has not been firmly elucidated whether routine use of coronary stents is associated with a more favourable outcome in this population. Therefore, we investigated the influence of age on acute procedural success, rate of restenosis (quantitative coronary angiography) and major cardiovascular events (death/myocardial infarction [MI]) 6 months after intra-coronary stent implantation in 1306 patients. Patients were categorised into < 65 years (n = 709),65-75 years (n = 443) and >75 years (n= 154). RESULTS: Older patients had a higher amount of multivessel disease (p < 0.001) and a lower left ventricular ejection fraction (p < 0.001). Nevertheless, the rate of acute success and restenosis were comparable between the different age groups. In contrast, older patients had significantly more adverse clinical events during long-term followup. (Death/MI < 65 years 3.0%, 65-75 years 3.9%, > 75 years 7.8%, p = 0.02). However, by multivariate analysis age was no longer an independent predictor of adverse clinical events (p = 0.26), which were predominantly determined by coexisting impaired left ventricular function (p < 0.001). CONCLUSION: After proper judgement of the clinical situation, coronary stent implantation should be considered in selected elderly patients. Thus, advanced age as a solely factor should not be regarded as a contraindication for coronary stent implantation.

Adult↗

PubMed2002

Results of Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial.

BACKGROUND: Restenosis after percutaneous coronary intervention (PCI) is a major problem affecting 15% to 30% of patients after stent placement. No oral agent has shown a beneficial effect on restenosis or on associated major adverse cardiovascular events. In limited trials, the oral agent tranilast has been shown to decrease the frequency of angiographic restenosis after PCI. METHODS AND RESULTS: In this double-blind, randomized, placebo-controlled trial of tranilast (300 and 450 mg BID for 1 or 3 months), 11 484 patients were enrolled. Enrollment and drug were initiated within 4 hours after successful PCI of at least 1 vessel. The primary end point was the first occurrence of death, myocardial infarction, or ischemia-driven target vessel revascularization within 9 months and was 15.8% in the placebo group and 15.5% to 16.1% in the tranilast groups (P=0.77 to 0.81). Myocardial infarction was the only component of major adverse cardiovascular events to show some evidence of a reduction with tranilast (450 mg BID for 3 months): 1.1% versus 1.8% with placebo (P=0.061 for intent-to-treat population). The primary reason for not completing treatment was > or =1 hepatic laboratory test abnormality (11.4% versus 0.2% with placebo, P<0.01). In the angiographic substudy composed of 2018 patients, minimal lumen diameter (MLD) was measured by quantitative coronary angiography. At follow-up, MLD was 1.76+/-0.77 mm in the placebo group, which was not different from MLD in the tranilast groups (1.72 to 1.78+/-0.76 to 80 mm, P=0.49 to 0.89). In a subset of these patients (n=1107), intravascular ultrasound was performed at follow-up. Plaque volume was not different between the placebo and tranilast groups (39.3 versus 37.5 to 46.1 mm(3), respectively; P=0.16 to 0.72). CONCLUSIONS: Tranilast does not improve the quantitative measures of restenosis (angiographic and intravascular ultrasound) or its clinical sequelae.

Administration, Oral↗

PubMed2001

Tumor necrosis factor antagonism with etanercept improves systemic endothelial vasoreactivity in patients with advanced heart failure.

BACKGROUND: Anti-tumor necrosis factor (TNF)-alpha therapy with etanercept, a recombinant TNF receptor that binds to and functionally inactivates TNF-alpha, was shown to improve the functional status of patients with congestive heart failure (CHF). Because administration of TNF-alpha has been shown experimentally to depress endothelium-dependent relaxation, we hypothesized that TNF-alpha antagonism with etanercept might improve the depressed systemic endothelial vasodilator function, which importantly contributes to increased peripheral vascular resistance in patients with advanced CHF. METHODS AND RESULTS: Endothelium-dependent (acetylcholine, ACH; 10 to 50 microgram/min) and endothelium-independent (sodium nitroprusside, SNP; 2 to 8 microgram/min) forearm blood flow (FBF) responses were measured by venous occlusion plethysmography in 13 patients with documented CHF (New York Heart Association class III) before, 6 hours after, and 7 days after subcutaneous injection of a single dose of 25 mg etanercept. Maximum ACH-induced FBF increased significantly from 6.9+/-1.0 to 13.0+/-1.6 mL/min per 100 mL of forearm tissue (P<0.05) 6 hours after administration of etanercept and returned to 7.0+/-1.1 mL/min per 100 mL of forearm tissue after 7 days (P=NS), whereas SNP-induced FBF responses were not significantly affected. In contrast, FBF responses were not altered in control CHF patients, who did not receive etanercept (n=5). Etanercept-induced increases in ACH-mediated FBF were closely correlated with baseline TNF-alpha serum levels (r=0.66; P<0.02). CONCLUSIONS: The administration of etanercept profoundly improves systemic endothelial vasodilator capacity in patients with advanced heart failure, suggesting an important role of inflammatory mediators for impaired endothelial vasoreactivity in CHF. Improvement of systemic endothelial function might importantly contribute to the beneficial effects of etanercept on the functional status of patients with CHF.

Acetylcholine↗

PubMed2001

Vitamin C inhibits endothelial cell apoptosis in congestive heart failure.

BACKGROUND: Proinflammatory cytokines like tumor necrosis factor-alpha and oxidative stress induce apoptotic cell death in endothelial cells (ECs). Systemic inflammation and increased oxidative stress in congestive heart failure (CHF) coincide with enhanced EC apoptosis and the development of endothelial dysfunction. Therefore, we investigated the effects of antioxidative vitamin C therapy on EC apoptosis in CHF patients. METHODS AND RESULTS: Vitamin C dose dependently suppressed the induction of EC apoptosis by tumor necrosis factor-alpha and angiotensin II in vitro as assessed by DNA fragmentation, DAPI nuclear staining, and MTT viability assay. The antiapoptotic effect of vitamin C was associated with reduced cytochrome C release from mitochondria and the inhibition of caspase-9 activity. To assess EC protection by vitamin C in CHF patients, we prospectively randomized CHF patients in a double-blind trial to vitamin C treatment versus placebo. Vitamin C administration to CHF patients markedly reduced plasma levels of circulating apoptotic microparticles to 32+/-8% of baseline levels, whereas placebo had no effect (87+/-14%, P<0.005). In addition, vitamin C administration suppressed the proapoptotic activity on EC of the serum of CHF patients (P<0.001). CONCLUSIONS: Administration of vitamin C to CHF patients suppresses EC apoptosis in vivo, which might contribute to the established functional benefit of vitamin C supplementation on endothelial function.

Administration, Oral↗

PubMed2001

Aging enhances the sensitivity of endothelial cells toward apoptotic stimuli: important role of nitric oxide.

Advanced aging leads to impaired endothelial NO synthesis and enhanced endothelial cell apoptosis; therefore, we investigated the sensitivity of aged endothelial cells toward apoptotic stimuli and determined the role of NO. Human umbilical vein endothelial cells (HUVECs) were cultured until 14th passage. In aged cells, oxLDL and tumor necrosis factor-alpha-induced apoptosis and caspase-3-like activity were significantly enhanced more than 3-fold compared with young cells (passage 3). Because NO contributes to protection against endothelial cell death via S-nitrosylation of caspases, we determined endothelial NO synthase (eNOS) protein expression and the content of S-nitrosylated proteins. Aged HUVECs showed significantly reduced eNOS expression (35+/-10%) and a decrease in the overall S-NO content (33+/-3%), suggesting that eNOS downregulation may be involved in age-dependent increase of apoptosis sensitivity. Indeed, eNOS knockout endothelial cells showed a significantly enhanced apoptosis induction. Exogenous NO donors abolished increased apoptosis and caspase-3-like activity. In contrast, the application of shear stress, which exerts a profound apoptosis inhibitory effect via upregulation of NO synthesis in young cells, failed to inhibit apoptosis in aged cells. Moreover, no upregulation of eNOS protein expression and S-NO content in response to shear stress was detected in aged cells. Overexpression of wild-type eNOS completely restored the antiapoptotic effect of shear stress, whereas only a partial inhibitory effect was detected under steady conditions. Strikingly, transfection of constitutively active phosphomimetic eNOS (S1177D) further abrogated apoptosis in aged HUVECs. Thus, aging of endothelial cells is associated with decreased NO synthesis and concomitantly increased sensitivity of apoptosis, which may contribute to functional impairment of the endothelial monolayer.

Aging↗

PubMed2001

TNFalpha and oxLDL reduce protein S-nitrosylation in endothelial cells.

Nitric oxide (NO) plays an important role in the regulation of the functional integrity of the endothelium. The intracellular reaction of NO with reactive cysteine groups leads to the formation of S-nitrosothiols. To investigate the regulation of S-nitrosothiols in endothelial cells, we first analyzed the composition of the S-nitrosylated molecules in endothelial cells. Gel filtration revealed that more than 95% of the detected S-nitrosothiols had a molecular mass of more than 5000 Da. Moreover, inhibition of de novo synthesis of glutathione using N-butyl-sulfoximine did not diminish the overall cellular S-NO content suggesting that S-nitrosylated glutathione quantitatively plays only a minor role in endothelial cells. Having demonstrated that most of the S-nitrosothiols are proteins, we determined the regulation of the S-nitrosylation by pro-inflammatory and pro-atherogenic factors, such as TNFalpha and mildly oxidized low density lipoprotein (oxLDL). TNFalpha and oxLDL induced denitrosylation of various proteins as assessed by Saville-Griess assay, by immunostaining with an anti-S-nitrosocysteine antibody, and by a Western blot approach. Furthermore, the caspase-3 p17 subunit, which has previously been shown to be S-nitrosylated and thereby inhibited, was denitrosylated by TNFalpha treatment suggesting that S-nitrosylation and denitrosylation are important regulatory mechanisms in endothelial cells contributing to the integrity of the endothelial cell monolayer.

Blotting, Western↗

PubMed2001

Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease.

Recent studies provide increasing evidence that postnatal neovascularization involves bone marrow-derived circulating endothelial progenitor cells (EPCs). The regulation of EPCs in patients with coronary artery disease (CAD) is unclear at present. Therefore, we determined the number and functional activity of EPCs in 45 patients with CAD and 15 healthy volunteers. The numbers of isolated EPCs and circulating CD34/kinase insert domain receptor (KDR)-positive precursor cells were significantly reduced in patients with CAD by approximately 40% and 48%, respectively. To determine the influence of atherosclerotic risk factors, a risk factor score including age, sex, hypertension, diabetes, smoking, positive family history of CAD, and LDL cholesterol levels was used. The number of risk factors was significantly correlated with a reduction of EPC levels (R=-0.394, P=0.002) and CD34-/KDR-positive cells (R=-0.537, P<0.001). Analysis of the individual risk factors demonstrated that smokers had significantly reduced levels of EPCs (P<0.001) and CD34-/KDR-positive cells (P=0.003). Moreover, a positive family history of CAD was associated with reduced CD34-/KDR-positive cells (P=0.011). Most importantly, EPCs isolated from patients with CAD also revealed an impaired migratory response, which was inversely correlated with the number of risk factors (R=-0.484, P=0.002). By multivariate analysis, hypertension was identified as a major independent predictor for impaired EPC migration (P=0.043). The present study demonstrates that patients with CAD revealed reduced levels and functional impairment of EPCs, which correlated with risk factors for CAD. Given the important role of EPCs for neovascularization of ischemic tissue, the decrease of EPC numbers and activity may contribute to impaired vascularization in patients with CAD. The full text of this article is available at http://www.circresaha.org.

AC133 Antigen↗

PubMed2001

Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease.

BACKGROUND: Therapeutic neovascularization may constitute an important strategy to salvage tissue from critical ischemia. Circulating bone marrow-derived endothelial progenitor cells (EPCs) were shown to augment the neovascularization of ischemic tissue. In addition to lipid-lowering activity, hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) reportedly promote the neovascularization of ischemic tissue in normocholesterolemic animals. Methods and Results-Fifteen patients with angiographically documented stable coronary artery disease (CAD) were prospectively treated with 40 mg of atorvastatin per day for 4 weeks. Before and weekly after the initiation of statin therapy, EPCs were isolated from peripheral blood and counted. In addition, the number of hematopoietic precursor cells positive for CD34, CD133, and CD34/kinase insert domain receptor was analyzed. Statin treatment of patients with stable CAD was associated with an approximately 1.5-fold increase in the number of circulating EPCs by 1 week after initiation of treatment; this was followed by sustained increased levels to approximately 3-fold throughout the 4-week study period. Moreover, the number of CD34/kinase insert domain receptor-positive hematopoietic progenitor cells was significantly augmented after 4 weeks of therapy. Atorvastatin treatment increased the further functional activity of EPCs, as assessed by their migratory capacity. CONCLUSION: The results of the present study define a novel mechanism of action of statin treatment in patients with stable CAD: the augmentation of circulating EPCs with enhanced functional activity. Given the well-established role of EPCs of participating in repair after ischemic injury, stimulation of EPCs by statins may contribute to the clinical benefit of statin therapy in patients with CAD.

Adult↗

PubMed2001

Oxidized LDL inhibits vascular endothelial growth factor-induced endothelial cell migration by an inhibitory effect on the Akt/endothelial nitric oxide synthase pathway.

BACKGROUND: Oxidized LDL (oxLDL) inhibits endothelial cell (EC) migration. Stimulating ECs with vascular endothelial growth factor (VEGF) leads to the activation of Akt/protein kinase B, which in turn activates endothelial nitric oxide synthase (eNOS) by phosphorylation on serine 1177. VEGF-induced cell migration is dependent on the generation of nitric oxide (NO). Therefore, we investigated whether oxLDL affects EC migration by an inhibitory effect on the Akt/eNOS pathway. METHODS AND RESULTS: During an in vitro "scratched wound assay," oxLDL dose-dependently inhibited the VEGF-induced migration of human umbilical vein endothelial cells. Western blot analysis revealed that oxLDL dose- and time-dependently led to dephosphorylation and thus deactivation of Akt. Moreover, oxLDL inhibited the VEGF-induced generation of NO, as detected and quantified using a fluorescent NO indicator, 4,5-diaminofluorescein diacetate. Overexpression of a constitutively active Akt construct (Akt T308D/S473D) or a phosphomimetic eNOS construct (eNOS S1177D) almost completely reversed the inhibitory effect of oxLDL on VEGF-induced EC migration and NO generation. CONCLUSIONS: Our data indicate that oxLDL-induced dephosphorylation of Akt, followed by impaired eNOS activation, reduces the intracellular level of NO and thereby inhibits VEGF-induced EC migration.

Amino Acid Substitution↗

PubMed2001

Pro-atherogenic factors induce telomerase inactivation in endothelial cells through an Akt-dependent mechanism.

Advanced aging may contribute to impairment of angiogenesis and development of vascular diseases. Telomerase was shown to delay endothelial cell (EC) senescence. Therefore, we determined the regulation of telomerase activity in EC. Inhibition of phosphoinositol 3-kinase (PI3K) suppressed telomerase activity, whereas inhibitors directed against ERK1/2 or protein kinase C had no effect. Dominant negative Akt significantly reduced telomerase activity. Moreover, pro-atherogenic stimuli such as oxidized low density lipoprotein led to an inactivation of Akt and diminished telomerase activity. Thus, the PI3K/Akt pathway plays an important role in the regulation of telomerase activity. Pro-atherosclerotic factors impair telomerase activity and thereby may promote EC aging.

Aging↗

PubMed2001

Preprocedural C-reactive protein levels and cardiovascular events after coronary stent implantation.

OBJECTIVES: This study assessed the predictive value of preprocedural C-reactive protein (CRP) levels on six-month clinical and angiographic outcome in patients undergoing coronary stent implantation. BACKGROUND: Recent data indicate that low-grade inflammation as detected by elevated CRP serum levels predicts the risk of recurrent coronary events. METHODS: We prospectively investigated the predictive value of preprocedural CRP-levels on restenosis and six-month clinical outcome in 276 patients after coronary stent implantation. The primary combined end point was death due to cardiac causes, myocardial infarction related to the target vessel and repeat intervention of the stented vessel. RESULTS: Grouping patients into tertiles according to preprocedural CRP-levels revealed that, despite identical angiographic and clinical characteristics at baseline and after stent implantation, a primary end point event occurred in 24 (26%) patients of the lowest tertile, in 42 (45.6%) of the middle tertile and in 38 (41.3%) of the highest CRP tertile, p = 0.01. On multivariate analysis, tertiles of CRP levels were independently associated with a higher risk of adverse coronary events (relative risk = 2.0 [1.1 to 3.5], tertile I vs. II and III, p = 0.01) in addition to the minimal lumen diameter after stent (p = 0.04). In addition, restenosis rates were significantly higher in the two upper tertiles compared with CRP levels in the lowest tertile (45.5% vs. 38.3% vs. 18.5%, respectively, p = 0.002). CONCLUSIONS: Low-grade inflammation as evidenced by elevated preprocedural serum CRP-levels is an independent predictor of adverse outcome after coronary stent implantation, suggesting that a systemically detectable inflammatory activity is associated with proliferative responses within successfully implanted stents.

Aged↗

PubMed2001

[Psychocardiology today].

DEFINITION: The term "cardiopsychology" contains the scientific knowledge with regard to psychosocial factors of the emergence, the course, the rehabilitation and the illness processing (coping) of cardiac diseases. STUDIES: Probably there is no psychosocial topic with so many presumably methodically high standing (namely representative prospective and controlled) long-term studies and so many reviews or metaanalyses as we have for cardiac diseases, particularly the coronary heart disease. The knowledge on cardiopsychology is extensive, incoherent and contradictory and in so far incalculable. A group of 38 international scientists came together 1998 and founded the "Status and Consensus Conference Cardiopsychology". The objective of the project is to systematize and evaluate the scientific knowledge about psychosocial factors affecting the etiology, development, rehabilitation of and coping with coronary heart diseases worldwide. The systematic reviews on the above mentioned subjects are intensively discussed and evaluated by all scientists involved in the status conferences. The reviews are finally published only after several revisions leading to a concurring consensus. This working process guarantees an extraordinary high standard of all resulting reviews. Thus the Public Health can be provided with a systematic knowledge basis. The reviews resulting from the status conferences are published as a special series in the publishing house Verlag für Akademische Schriften in Frankfurt, Germany. Besides all essentials are opened for the public and can be visited in the Internet: http://www.psychokardiologie.de. PSYCHOSOCIAL KNOWLEDGE: The essay on hand gives a short historical summary of this field of research and then discusses the psychosocial research to the risk factor model. After this the type A model, the sociological research results and the researches to the illness behavior are discussed. Predictive factors of the disease and effects of psychological interventions were presented. CONCLUSION FOR THE PRACTICE: The following variables are worked out as meaningful in the practice: social inequality and chronic emotional stress at the workplace, vital exhaustion, anxiety and depression, negative emotions, familial and social support, coping mechanisms and psychological interventions.

Anxiety↗

PubMed2001

Apoptosis in the vascular wall and atherosclerosis.

Apoptosis, programmed cell death, has emerged as a key element in the complex pathophysiology underlying the development as well as the progression of atherosclerosis. A number of recent reports provided evidence for both in vivo and in vitro occurrence of apoptotic cell death of vascular cells, namely endothelial cells, macrophages, and vascular smooth muscle cells. In addition, functional studies in disease models underscore the relevance of these findings for the understanding of processes which lead to lesion development, plaque rupture, and thrombus formation. Pathomechanistic in vitro investigations provided an increasingly detailed picture of the involved intracellular signaling pathways that regulate onset and execution of apoptosis. These insights offer the potential of therapeutic interventions targeted to interfere with the molecular processes involving apoptotic cell death in the vascular wall.

Animals↗

PubMed2001

Statin therapy, inflammation and recurrent coronary events in patients following coronary stent implantation.

OBJECTIVES: We sought to investigate whether statin therapy affects the association between preprocedural C-reactive protein (CRP) levels and the risk for recurrent coronary events in patients undergoing coronary stent implantation. BACKGROUND: Low-grade inflammation as detected by elevated CRP levels predicts the risk of recurrent coronary events. The effect of inflammation on coronary risk may be attenuated by statin therapy. METHODS: We investigated a potential interrelation among statin therapy, serum evidence of inflammation, and the risk for recurrent coronary events in 388 consecutive patients undergoing coronary stent implantation. Patients were grouped according to the median CRP level (0.6 mg/dl) and to the presence of statin therapy. RESULTS: A primary combined end point event occurred significantly more frequently in patients with elevated CRP levels without statin therapy (RR [relative risk] 2.37, 95% CI [confidence interval] [1.3 to 4.2]). Importantly, in the presence of statin therapy, the RR for recurrent events was significantly reduced in the patients with elevated CRP levels (RR 1.27 [0.7 to 2.1]) to about the same degree as in patients with CRP levels below 0.6 mg/dl and who did not receive statin therapy (RR 1.1 [0.8 to 1.3]). CONCLUSIONS: Statin therapy significantly attenuates the increased risk for major adverse cardiac events in patients with elevated CRP levels undergoing coronary stent implantation, suggesting that statin therapy interferes with the detrimental effects of inflammation on accelerated atherosclerotic disease progression following coronary stenting.

Aged↗

PubMed2001

Inhibition of caspase-3 improves contractile recovery of stunned myocardium, independent of apoptosis-inhibitory effects.

OBJECTIVES: The aim of this study was to investigate whether the caspase-3 inhibitor Ac-DEVD-CHO functionally improves stunned myocardium. BACKGROUND: Degradation of troponin I contributes to the pathogenesis of myocardial stunning, whereas the role of apoptosis is unknown. Caspase-3 is an essential apoptotic protease that is specifically inhibited by Ac-DEVD-CHO. METHODS: Isolated working hearts of rats were exposed to 30 min of low-flow ischemia, followed by 30 min of reperfusion. Ac-DEVD-CHO (0.1 to 1 micromol/l) was added 15 min before ischemia/reperfusion or 5 min before reperfusion. Cardiac output, external heart power, left ventricular (LV) developing pressure and contractility (dp/dt(max)) were measured. Apoptosis was assessed by TUNEL staining and internucleosomal deoxyribonucleic acid fragmentation. Caspase-3 processing and troponin I cleavage were determined by immunoblotting. Caspase-3 activity was measured using a fluorogenic substrate. RESULTS: The addition of Ac-DEVD-CHO before ischemia/reperfusion or before reperfusion dose-dependently and significantly (p < 0.05) improved post-ischemic recovery of cardiac output, external heart power, LV developing pressure and dp/dt(max), compared with the vehicle (0.01% dimethyl sulfoxide). Ac-DEVD-CHO was similarly effective when given before reperfusion. Ac-DEVD-CHO blocked ischemia/reperfusion-induced caspase-3 activation, but cardiomyocyte apoptosis was unaffected. Troponin I cleavage was not inhibited by Ac-DEVD-CHO. CONCLUSIONS: Caspase-3 is activated in stunned myocardium. Inhibition of caspase-3 by Ac-DEVD-CHO significantly improves post-ischemic contractile recovery of stunned myocardium, even when given after the onset of ischemia. The mechanism(s) of protection by Ac-DEVD-CHO appear to be independent of apoptosis. Inhibition of caspase-3 is a novel therapeutic strategy to improve functional recovery of stunned myocardium.

Animals↗