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Biomedical subjects

Z Mallat

Publications and source records attributed to Z Mallat.

At least 19 recordsLinked to original sources
PubMed2000

Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes.

BACKGROUND: Apoptotic microparticles are responsible for almost all tissue factor activity of the plaque lipid core. We hypothesized that elevated levels of procoagulant microparticles could also circulate in the peripheral blood of patients with recent clinical signs of plaque disruption and thrombosis. METHODS AND RESULTS: We studied 39 patients with coronary heart disease, including 12 patients with stable angina and 27 patients with acute coronary syndromes (ACS), and 12 patients with noncoronary heart disease. We isolated the circulating microparticles by capture with annexin V and determined their procoagulant potential with a prothrombinase assay. The cell origins of microparticles were determined in an additional 22 patients by antigenic capture with specific antibodies. The level of procoagulant microparticles did not differ between stable angina patients and noncoronary patients (10.1+/-1.6 nmol/L phosphatidylserine [PS] equivalent versus 9.9+/-1.6 nmol/L PS equivalent, respectively). However, procoagulant microparticles were significantly elevated in patients with ACS (22.2+/-2.7 nmol/L PS equivalent) compared with other coronary (P<0.01) or noncoronary (P<0.01) patients. Microparticles of endothelial origin were significantly elevated in patients with ACS (P<0.01), which suggests an important role for endothelial injury in inducing the procoagulant potential. CONCLUSIONS: High levels of procoagulant endothelial microparticles are present in the circulating blood of patients with ACS and may contribute to the generation and perpetuation of intracoronary thrombi.

Acute Disease↗
PubMed1999

[Atherosclerotic plaque formation].

Atherosclerotic plaque formation involves 5 steps: 1. low density lipoprotein (LDL) accumulation in the intima; 2. oxidation of LDL; 3. recruitment of monocytes-macrophages; 4. uptake of oxidized LDL by macrophage scavenger receptors, and transformation of macrophages into foam cells; 5. formation of a fibrous cap containing smooth muscle cells, which permits stabilization of the plaque. At each step of this process, inflammatory cytokines are implicated making the atherosclerotic process a chronic inflammatory disease.

Arteriosclerosis↗
PubMed1999

Protective role of interleukin-10 in atherosclerosis.

The potential role of anti-inflammatory cytokines in the modulation of the atherosclerotic process remains unknown. Interleukin (IL)-10 has potent deactivating properties in macrophages and T cells and modulates many cellular processes that may interfere with the development and stability of the atherosclerotic plaque. IL-10 is expressed in human atherosclerosis and is associated with decreased signs of inflammation. In the present study, we show that IL-10-deficient C57BL/6J mice fed an atherogenic diet and raised under specific pathogen-free conditions exhibit a significant 3-fold increase in lipid accumulation compared with wild-type mice. Interestingly, the susceptibility of IL-10-deficient mice to atherosclerosis was exceedingly high (30-fold increase) when the mice were housed under conventional conditions. Atherosclerotic lesions of IL-10-deficient mice showed increased T-cell infiltration, abundant interferon-gamma expression, and decreased collagen content. In vivo, transfer of murine IL-10 achieved 60% reduction in lesion size. These results underscore the critical roles of IL-10 in both atherosclerotic lesion formation and stability. Moreover, IL-10 appears to be crucial as a protective factor against the effect of environmental pathogens on atherosclerosis.

Animals↗
PubMed1999

Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity.

BACKGROUND: The specific role of apoptosis in human atherosclerosis remains unknown. During apoptotic cell death, phosphatidylserine exposure on the cell surface confers a high tissue-factor (TF)-dependent procoagulant activity. METHODS AND RESULTS: In this study, we examined the role of apoptotic cell death in the promotion of plaque thrombogenicity. TF expression and its relation to apoptosis was analyzed in 16 human atherosclerotic plaques by the use of immunohistochemical techniques. The presence of shed membrane apoptotic microparticles was analyzed in extracts from 6 human atherosclerotic plaques and 3 underlying arterial walls. The microparticles were captured by annexin V and their amounts estimated with respect to their phospholipid content by use of a prothrombinase assay. The prothrombogenic potential of the microparticles was further assessed by the measurement of total and microparticle-dependent TF activity in the extracts. The cell origin of the microparticles was determined after capture by specific antibodies. We were able to detect marked TF expression in the plaques in close proximity to apoptotic cells and debris, suggesting a potential interaction between TF and the apoptotic cell surfaces. High levels of shed membrane apoptotic microparticles were detected in extracts from atherosclerotic plaques but not in the underlying arterial walls (29.5+/-3.7 nmol/L phosphatidylserine equivalent versus 1.3+/-0.4 nmol/L, respectively, P<0.02). The microparticles were mainly of monocytic and lymphocytic origin and retained 97+/-2% of total TF activity, indicating a direct causal relationship between shed membrane microparticles and procoagulant activity of plaque extracts. CONCLUSIONS: These results indicate that shed membrane microparticles with procoagulant potential are produced in human atherosclerotic plaques. Apoptosis could be a critical determinant of plaque thrombogenicity after plaque rupture.

Acute Disease↗
PubMed1999

Expression of interleukin-10 in advanced human atherosclerotic plaques: relation to inducible nitric oxide synthase expression and cell death.

Inflammation is a major feature of human atherosclerosis and is central to development and progression of the disease. A variety of proinflammatory cytokines are expressed in the atherosclerotic plaque and may modulate extracellular matrix remodeling, cell proliferation, and cell death. Little is known, however, about the expression and potential role of anti-inflammatory cytokines in human atherosclerosis. Interleukin-10 (IL-10) is a major anti-inflammatory cytokine whose expression and potential effects in advanced human atherosclerotic plaques have not been evaluated. We studied 21 advanced human atherosclerotic plaques. IL-10 expression was analyzed by use of reverse transcription-polymerase chain reaction and immunohistochemical techniques. Inducible nitric oxide synthase expression was assessed by using immunohistochemistry, and cell death was determined by use of the TUNEL method. Reverse transcription-polymerase chain reaction identified IL-10 mRNA in 12 of 17 atherosclerotic plaques. Immunohistochemical staining of serial sections and double staining identified immunoreactive IL-10 mainly in macrophages, as well as in smooth muscle cells. Consistent with its anti-inflammatory properties, high levels of IL-10 expression were associated with significant decrease in inducible nitric oxide synthase expression (P<0.0001) and cell death (P<0. 0001). Hence, IL-10, a potent anti-inflammatory cytokine, is expressed in a substantial number of advanced human atherosclerotic plaques and might contribute to the modulation of the local inflammatory response and protect from excessive cell death in the plaque.

Aorta, Abdominal↗
PubMed1999

The relationship of hydroxyeicosatetraenoic acids and F2-isoprostanes to plaque instability in human carotid atherosclerosis.

Evidence for increased oxidant stress has been reported in human atherosclerosis. However, no information is available about the importance of in situ oxidant stress in relation to plaque stability. This information is relevant because the morbidity and mortality of atherosclerosis are essentially the consequences of acute ischemic syndromes due to unstable plaques. We studied 30 carotid atherosclerotic plaques retrieved by endarterectomy from 18 asymptomatic (stable plaques) and 12 symptomatic patients (unstable plaques). Four normal arteries served as controls. After lipid extraction and ester hydrolysis, quantitation of different indices of oxidant stress were analyzed, including hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatetraenoic acids (EETs), ketoeicosatetraenoic acids (oxo-ETEs), and F2-isoprostanes using online reverse-phase high-performance liquid chromatography tandem mass spectrometry (LC/MS/MS). All measurements were carried out in a strictly double-blind procedure. We found elevated levels of the different compounds in atherosclerotic plaques. Levels of HETEs were 24 times higher than EETs, oxo-ETEs, or F2-isoprostanes. Levels of HETEs, but not those of EETs, oxo-ETEs or F2-isoprostanes, were significantly elevated in plaques retrieved from symptomatic patients compared with those retrieved from asymptomatic patients (1, 738 +/- 274 vs. 1,002 +/- 107 pmol/ micromol lipid phosphorous, respectively; P < 0.01). One monooxygenated arachidonate species, 9-HETE, which cannot be derived from known enzymatic reactions, was the most abundant and significant compound observed in plaques, suggesting that nonenzymatic lipid peroxidation predominates in advanced atherosclerosis and may promote plaque instability.

Arteriosclerosis↗
PubMed1998

Elevated levels of 8-iso-prostaglandin F2alpha in pericardial fluid of patients with heart failure: a potential role for in vivo oxidant stress in ventricular dilatation and progression to heart failure.

BACKGROUND: It has been suggested that oxidant stress may play a role in the pathophysiology of heart failure. However, no definitive information is available because most previous approaches used to measure oxidant stress are nonspecific, inaccurate, and unreliable. METHODS AND RESULTS: To evaluate oxidant stress in the heart, we measured pericardial fluid levels of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a specific and quantitative marker of oxidant stress in vivo, in a series of 51 consecutive patients with ischemic and/or valvular heart disease referred for cardiac surgery. Pericardial levels of 8-iso-PGF2alpha were correlated with the functional severity of heart failure (NYHA classification) and with echocardiographic indices of ventricular dilatation measured by independent physicians. Pericardial levels of 8-iso-PGF2alpha were significantly increased in patients with symptomatic heart failure compared with asymptomatic patients and gradually increased with the functional severity of heart failure (P=.0003). In addition, pericardial levels of 8-iso-PGF2alpha were significantly correlated with left ventricular end-diastolic and end-systolic diameters (P=.008 and .026, respectively). CONCLUSIONS: Pericardial levels of 8-iso-PGF2alpha increase with the functional severity of heart failure and are associated with ventricular dilatation. These data suggest an important role for in vivo oxidant stress on ventricular remodeling and the progression to heart failure.

Adult↗
PubMed1997

Colocalization of CPP-32 with apoptotic cells in human atherosclerotic plaques.

BACKGROUND: Apoptosis that has been reported in human atherosclerosis may contribute to the remodeling of atherosclerotic plaques. The identification of specific markers for apoptosis in these plaques would permit the development of specific therapeutic strategies to limit their progression. Cysteine protease CPP-32 is essential for apoptotic death in mammalian cells and appears to be an attractive candidate. METHODS AND RESULTS: We studied 12 atherosclerotic plaques from 12 patients who underwent carotid endarterectomy. Apoptosis was analyzed by in situ end labeling of fragmented DNA (TUNEL method) and corroborated by the presence of DNA fragmentation in agarose gel electrophoresis. CPP-32 was detected with the use of a specific monoclonal antibody, and its expression was compared with that of interleukin-1beta-converting enzyme (ICE). We showed that CPP-32 was highly expressed in 10 of 12 atherosclerotic plaques and that it colocalized with apoptotic cells. Expression of ICE generally paralleled that of CPP-32, but ICE was also detected in plaques negative for CPP-32 and showing no apoptosis. CONCLUSIONS: CPP-32 is highly expressed within human atherosclerotic plaques and is closely related to apoptosis. This finding suggests that CPP-32 may be the ICE-like enzyme responsible for apoptosis in human atherosclerosis and opens new perspectives for the development of therapeutic strategies to alter the progression of this disease.

Apoptosis↗
PubMed1997

Prediction of head-up tilt test result by analysis of early heart rate variations.

BACKGROUND: Head-up tilt testing is a useful test for investigating vasovagal syncope. The determination of early, accurate, predictive criteria for a negative result would permit a reduction in the duration of the tilt test. METHODS AND RESULTS: Patients with no drug use and no illnesses other than recurrent unexplained syncope were recruited. In an initial study (110 consecutive patients), we aimed to determine a predictive criterion based on heart rate variations during the first minutes of upright tilting that could distinguish between patients with positive and negative tilt tests (patients with an early continual decrease in heart rate or blood pressure were excluded). Then we tested the predictive value of the established criterion in a second independent sample of patients with unexplained syncope (109 consecutive patients). An early sustained increase in heart rate < or = 18 bpm during the first 6 minutes of upright tilting at a 60 degree angle allowed us to predict negative tilt tests with 100% specificity, 100% positive predictive value, and 88.6% sensitivity. This criterion was validated in the second, prospective arm of the study (96.4% specificity, 98.4% positive predictive value, and 87.3% sensitivity), even with subsequent use of isoproterenol in low doses. CONCLUSIONS: In patients with no drug use and no illnesses other than recurrent unexplained syncope, a simple clinical criterion identifies patients who will not develop syncope during a prolonged upright tilt.

Adult↗
PubMed1996

Evidence of apoptosis in arrhythmogenic right ventricular dysplasia.

BACKGROUND: Arrhythmogenic right ventricular dysplasia, a disorder that may lead to severe ventricular arrhythmias and sudden death, is characterized by the progressive replacement of myocardial cells by fat and fibrous tissue. We examined whether the loss of myocardial cells in this disease could result from cell death by apoptosis (programmed cell death). METHODS: Specimens obtained at autopsy from the right ventricular myocardium of eight patients with arrhythmogenic right ventricular dysplasia and four age-matched normal subjects were analyzed. To identify individual cells undergoing apoptosis, we performed in situ end-labeling of fragmented DNA on paraffin sections using biotinylated deoxyuridine triphosphate and the enzyme terminal deoxynucleotidyl transferase. We also examined the level of expression of CPP-32, a cysteine protease required for apoptotic cell death in mammalian cells, using immunohistochemical techniques. RESULTS: Apoptosis was detected in the right ventricular myocardium of six of the eight patients with arrhythmogenic right ventricular dysplasia and was absent in the controls. High levels of expression of CPP-32 were associated with positive in situ end-labeling of fragmented DNA. CONCLUSIONS: These results indicate that apoptotic myocardial cell death occurs in arrhythmogenic right ventricular dysplasia and may contribute to the loss of myocardial cells in this disorder.

Adult↗
PubMed1996

[Right precordial leads and sudden death. Relation with arrhythmogenic right ventricular dysplasia].

Non-coronary ST-segment elevation during right sided chest pain has been described in subjects with episodes of ventricular fibrillation at rest. This syndrome has been attributed to functional phenomena or to structural myocardial changes. A personal case has features belonging to two categories: ST-segment elevation observed before, during and after episodes of arrhythmia was compared to 11 previously recorded ECG recordings. Right ventricular dysplasia was shown by electrocardiography, electrophysiology and echocardiography. In addition, ST-segment elevation is classified in 3 categories: triangular and dome-shaped are the most commonly observed forms during the arrhythmias: the third form with "saddle"-shaped appearances has not been previously described and would seem to be a minor equivalent observed during intercritical periods. This form is found in 30% of clinically documented cases of arrhythmogenic right ventricular dysplasia.

Arrhythmias, Cardiac↗
PubMed1992

Meningoencephalitis due to penicillin-resistant Streptococcus pneumoniae.

The case of a 68-year-old man suffering from pneumococcal meningoencephalitis is reported. Antibacterial susceptibility tests revealed a multiply resistant pneumococcal strain. High doses of cefotaxime were necessary to sterilize the cerebrospinal fluid despite the achievement of a satisfactory level of antibiotic in the cerebrospinal fluid with moderate dosage. In France, as well as in many countries, high doses of third-generation cephalosporins such as cefotaxime or ceftriaxone should be administered for the initial therapy of suspected pneumococcal meningitis.

Aged↗