Modulation of nitric oxide affects myocardial perfusion-contraction matching in anaesthetized dogs with recurrent no-flow ischaemia.

Myocardial perfusion and contraction are closely coupled; however, the effect of recurrent no-flow ischaemia on perfusion-contraction matching remains to be established. In the present studies, we examined the influence of modulating nitric oxide availability on perfusion-contraction matching after recurrent no-flow ischaemia in acute open-chest, anaesthetized dogs. The following three groups were studied: (1) saline; (2) L-NAME (10 mg kg(-1) I.V.); and (3) enalaprilat (1.5 mg kg(-1) I.V.). Regional myocardial blood flow was measured with microspheres and contractile function with piezoelectric crystals to determine systolic wall thickening. Dogs underwent four cycles of 5 min acute ischaemia and 5 min coronary reperfusion; area at risk was similar for all groups. In all dogs, ischaemic zone contractile function was depressed after recurrent no-flow ischaemia despite increased myocardial blood flow during reperfusion; contractile function was further depressed during L-NAME and was partly restored with enalaprilat. Within the ischaemic region, blood flow in subendocardial and subepicardial layers increased significantly compared with baseline during each reperfusion period independently of treatment. Our findings suggest that reduced NO availability can significantly impair myocardial perfusion-contraction matching, which is partly restored by administration of an NO donor.

Enhancement of non-coronary collateral blood flow from the internal thoracic arteries: the theoretical and practical basis of an alternative method of myocardial blood supply.

Non-coronary collateral blood flow arrives to the heart from mediastinal, bronchial, and pericardial channels. These enter the heart through the pericardial reflections surrounding the pulmonary and systemic veins, as well as from the vasa vasorum of the aorta and the pulmonary artery leading to and from the myocardium. Before the advent of cardiopulmonary bypass surgery, surgical bilateral ligature of the internal thoracic arteries (ITAs) was performed in patients with ischemic heart disease to increase the perfusion pressure within the channels leading to the heart. Nowadays, the occurrence of natural collaterals between coronary and extracardiac arteries including the ITAs, the potential hemodynamic effects of ITA ligation, the potential of ITAs for developing important collateral branches, and the current availability of angiogenic growth factors could pave the way for the development of a new field in cardiovascular research aimed at developing an alternative strategy of myocardial blood supply by means of the surgical and biological enhancement of non-coronary collateral circulation.

Autocrine motility factor receptor is a marker for a distinct membranous tubular organelle.

Autocrine motility factor (AMF) is secreted by tumor cells and is capable of stimulating the motility of the secreting cells. In addition to being expressed on the cell surface, its receptor, AMF-R, is found within a Triton X-100 extractable intracellular tubular compartment. AMF-R tubules can be distinguished by double immunofluorescence microscopy from endosomes labeled with the transferrin receptor, lysosomes labeled with LAMP-2, and the Golgi apparatus labeled with beta-COP. AMF-R can also be separated from a LAMP-2 containing lysosomal fraction by differential centrifugation of MDCK cells and is found within a 100,000 g membrane pellet. By electron microscopic immunocytochemistry, AMF-R is localized predominantly to smooth vesicular and tubular membranous organelles as well as to a lesser extent to the plasma membrane and rough endoplasmic reticulum. AMF-R tubules have a variable diameter of 50-250 nm and can acquire an elaborate branched morphology. By immunofluorescence microscopy, AMF-R tubules are clearly distinguished from the calnexin labeled rough endoplasmic reticulum and AMF-R tubule expression is stable to extended cycloheximide treatment. The AMF-R tubule is therefore not a biosynthetic subcompartment of the endoplasmic reticulum. The tubular morphology of the AMF-R tubule is modulated by both the actin and microtubule cytoskeletons. In a similar fashion to that described previously for the tubular lysosome and endoplasmic reticulum, the linear extension and peripheral cellular orientation of the AMF-R tubule are dependent on the integrity of the microtubule cytoskeleton. The AMF-R tubule may thus form part of a family of microtubule-associated tubular organelles.

Characterization of the I4399M variant of apolipoprotein(a): implications for altered prothrombotic properties of lipoprotein(a).

Essentials Elevated lipoproteinp(a) is an independent and causal risk factor for atherothrombotic diseases. rs3798220 (Ile/Met substitution in apo(a) protease-like domain) is associated with disease risk. Recombinant I4399M apo(a) altered clot structure to accelerate coagulation/delay fibrinolysis. Evidence was found for increased solvent exposure and oxidation of Met residue. SUMMARY: Background Lipoprotein(a) (Lp[a]) is a causal risk factor for a variety of cardiovascular diseases. Apolipoprotein(a) (apo[a]), the distinguishing component of Lp(a), is homologous with plasminogen, suggesting that Lp(a) can interfere with the normal fibrinolytic functions of plasminogen. This has implications for the persistence of fibrin clots in the vasculature and hence for atherothrombotic diseases. A single-nucleotide polymorphism (SNP) (rs3798220) in the gene encoding apo(a) has been reported that results in an Ile→Met substitution in the protease-like domain (I4399M variant). In population studies, the I4399M variant has been correlated with elevated plasma Lp(a) levels and higher coronary heart disease risk, and carriers of the SNP had increased cardiovascular benefit from aspirin therapy. In vitro studies suggested an antifibrinolytic role for Lp(a) containing this variant. Objectives We performed a series of experiments to assess the effect of the Ile→Met substitution on fibrin clot formation and lysis, and on the architecture of the clots. Results We found that the Met variant decreased coagulation time and increased fibrin clot lysis time as compared with wild-type apo(a). Furthermore, we observed that the presence of the Met variant significantly increased fibrin fiber width in plasma clots formed ex vivo, while having no effect on fiber density. Mass spectrometry analysis of a recombinant apo(a) species containing the Met variant revealed sulfoxide modification of the Met residue. Conclusions Our data suggest that the I4399M variant differs structurally from wild-type apo(a), which may underlie key differences related to its effects on fibrin clot architecture and fibrinolysis.

Timely administration of AICA riboside reduces reperfusion injury in rabbits.

OBJECTIVE: Agents which promote increased interstitial adenosine levels may be cardioprotective. The aim of this study was to evaluate the ability of 5-amino-1-beta-D- ribofuranosylimidazole-4-carboxamide (AICAr), an adenosine regulating agent, to limit infarct size when given before ischaemia, before coronary reperfusion, or postreperfusion in a rabbit preparation of ischaemia-reperfusion injury. METHODS: The left coronary artery was occluded for 30 min and subsequently the ischaemic bed was reperfused for 180 min. Infarct size and risk zone size were delineated by tetrazolium staining and microsphere autoradiography, respectively. Four groups were studied: controls (n = 13), AICAr (2.5 mg.kg-1.min-1 intravenously for 5 min followed by 0.5 mg.kg-1.min-1 for 60 min) beginning either 5 min before coronary occlusion (n = 11), 5 min before coronary reperfusion (n = 11), or at 25 min coronary reperfusion (n = 10). Lignocaine was not given in these experiments. RESULTS: Infarct size, normalised to risk zone, was significantly reduced with AICAr given 5 min before coronary reperfusion, at 35.0(SEM 4.4)% v 51.8(3.9)% in controls; p = 0.03. Cardioprotection was not observed when AICAr was given either 5 min before coronary occlusion [44.2(4.8)%] or 25 min postreperfusion [45.9(3.2)%]. CONCLUSIONS: These findings support the hypothesis that adenosine regulating agents, such as AICAr, can modulate infarct size in this rabbit preparation of ischaemia-reperfusion injury.

Nitric oxide bioavailability affects cardiovascular regulation dependent on cardiac nerve status.

The sympathetic nervous system and nitric oxide (NO) contribute to regulation of vascular tone, blood flow regulation and cardiac function. Intrinsic cardiac neurons are tonically influenced by locally released NO and exogenous NO donors; however, the role of intact central neural connections remains controversial. We investigated the effects of S-nitroso-N-acetylpenicillamine (SNAP) administered into an intracoronary artery near the ventral interventricular ganglionated plexus (VIVGP) to evaluate distribution of myocardial blood flow (MBF) and ventricular function in normal and acute cardiac decentralized dogs. MBF was measured with microspheres during infusion of SNAP (100µM, IC) after systemic administration of 7-nitroindazole (nNOS blocker) followed by N(ω)-nitro-L-arginine methyl ester (LN; non-selective NOS blocker). Cardiac dynamics were not significantly affected by cardiac decentralization; several of these parameters (aortic systolic and diastolic pressures) were significantly increased after systemic administration of LN. Overall SNAP administered to the VIVGP increased blood flow in the anterior LV wall (vs. posterior LV wall) without affecting other cardiodynamic factors. In cardiac decentralized dogs subepicardial blood flow to the anterior LV wall during LN+SNAP was diminished resulting in a significantly higher inner:outer blood flow ratio (index of blood flow uniformity across the LV wall). LV function was not affected by acute cardiac decentralization; however, LV ejection fraction decreased markedly after LN (reduced NO bioavailability). These results validate earlier claims that reduced NO bioavailability imposes an upper limit on myocardial blood flow regulation and its transmural distribution. These effects are exacerbated after disconnection of intrinsic cardiac neurons from intact central neuron connections.

Renocardiac syndromes: physiopathology and treatment stratagems.

PURPOSE OF REVIEW: Bidirectional inter-organ interactions are essential for normal functioning of the human body; however, they may also promote adverse conditions in remote organs. This review provides a narrative summary of the epidemiology, physiopathological mechanisms and clinical management of patients with combined renal and cardiac disease (recently classified as type 3 and 4 cardiorenal syndrome). Findings are also discussed within the context of basic research in animal models with similar comorbidities. SOURCES OF INFORMATION: Pertinent published articles were identified by literature search of PubMed, MEDLINE and Google Scholar. Additional data from studies in the author's laboratory were also consulted. FINDINGS: The prevalence of renocardiac syndrome throughout the world is increasing in part due to an aging population and to other risk factors including hypertension, diabetes and dyslipidemia. Pathogenesis of this disorder involves multiple bidirectional interactions between the kidneys and heart; however, participation of other organs cannot be excluded. Our own work supports the hypothesis that the uremic milieu, caused by kidney dysfunction, produces major alterations in vasoregulatory control particularly at the level of the microvasculature that results in impaired oxygen delivery and blood perfusion. LIMITATIONS: Recent clinical literature is replete with articles discussing the necessity to clearly define or characterize what constitutes cardiorenal syndrome in order to improve clinical management of affected patients. Patients are treated after onset of symptoms with limited available information regarding etiology. While understanding of mechanisms involved in pathogenesis of inter-organ crosstalk remains a challenging objective, basic research data remains limited partly because of the lack of animal models. IMPLICATIONS: Preservation of microvascular integrity may be the most critical factor to limit progression of multi-organ disorders including renocardiac syndrome. More fundamental studies are needed to help elucidate physiopathological mechanisms and for development of treatments to improve clinical outcomes.

OBJECTIFS DE LA RÉVISION: Les interactions bidirectionnelles entre organes adjacents sont essentielles au bon fonctionnement du corps humain mais sont aussi susceptibles de provoquer des conditions adverses sur des organes plus éloignés. Cette revue offre un compte rendu sommaire de l'épidémiologie, des mécanismes physiopathologiques et du traitement clinique des patients atteints à la fois d'insuffisance rénale et de cardiopathie, ou tel que récemment désignés, atteints du syndrome cardiorénal de type 3 ou de type 4. La revue examine également des résultats obtenus en recherche fondamentale en utilisant des modèles animaux présentant des cas similaires de comorbidité. SOURCES: Les articles pertinents ont été répertoriés à la suite d'une recherche dans la littérature sur PubMed, MEDLINE et « Google Scholar ¼. Des données complémentaires provenant  d'études du laboratoire de recherche de l'auteur ont aussi été consultées. CONSTATATIONS: Le vieillissement de la population en plus de facteurs de risque incluant l'hypertension, le diabète et la dyslipidémie augmente en partie la prévalence du syndrome cardiorénal à travers le monde. La pathogenèse de ce désordre implique de multiples interactions bidirectionnelles entre le cœur et les reins; cependant, la participation d'organes périphériques n'est tout de même pas à exclure. Nos travaux soutiennent l'hypothèse selon laquelle l'environnement urémique résultant de la dysfonction rénale serait responsable d'altérations majeures dans la régulation de la pression, particulièrement au niveau des microvaisseaux. En résultent une perfusion sanguine altérée et une distribution insuffisante d'oxygène vers les organes. LIMITES DE L'ÉTUDE: La littérature clinique récente comporte de nombreux articles traitant de la nécessité d'identifier et de caractériser de façon plus élaborée les causes du syndrome cardiorénal dans la perspective d'améliorer le traitement clinique des patients qui en sont atteints. Par contre, puisqu'il existe encore très peu d'informations sur l'étiologie du syndrome cardiorénal, les patients ne sont pris en charge qu'après son apparition. Qui plus est, la compréhension des mécanismes impliqués dans la pathogenèse résultant des interactions entre organes demeure un objectif difficile à atteindre, en partie parce que la recherche fondamentale est limitée étant donné la rareté des modèles animaux pour cette pathologie. CONSÉQUENCES: À la lumière des données disponibles à ce jour, il apparait que la préservation de l'intégrité du système vasculaire, particulièrement au niveau des microvaisseaux, est un facteur-clé pour restreindre le développement de désordres impliquant plusieurs organes tel le syndrome cardiorénal. Davantage d'études en recherche fondamentale sont requises pour faire la lumière sur les mécanismes physiopathologiques de ce syndrome et développer des traitements efficaces pour en améliorer les résultats cliniques.

The risk of stroke in patients with first-ever retinal vs hemispheric transient ischemic attacks and high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial.

BACKGROUND: The prognosis of amaurosis fugax has been considered to be favorable compared with that of hemispheric transient ischemic attacks. However, this has remained uncertain for patients with significant carotid stenosis as the assessment of progression of the disease has been confounded when patients undergo carotid endarterectomy. In the North American Symptomatic Carotid Endarterectomy Trial, patients with high-grade (70% to 99%) carotid stenosis were randomized to receive either medical or surgical treatment, thus making an unconfounded analysis possible. METHOD: We identified 129 medically treated patients with high-grade carotid stenosis who had their first-ever transient ischemic attack as the entry event into the trial. Fifty-nine patients with retinal transient ischemic attacks (RTIAs) were compared with 70 patients with hemispheric transient ischemic attacks (HTIAs). RESULTS: Patients with HTIAs were older, with a higher prevalence of most risk factors for stroke. Average time of delay from the onset of transient ischemic attacks to medical treatment was longer for patients with RTIAs than for patients with HTIAs (48.5 vs 15.2 days). Kaplan-Meier estimates of the risk of ipsilateral stroke at 2 years were 16.6% +/- 5.6% for patients with RTIAs and 43.5% +/- 6.7% for patients with HTIAs (P = .002 for the difference in risk between RTIAs and HTIAs). From corresponding Cox's proportional hazards regression analyses, the risk of ipsilateral stroke ranged from 11.2% to 28.9% for patients with RTIAs and from 37.4% to 96.3% for patients with HTIAs across stenoses, spanning 75% to 95%. Overall, the relative risk of ipsilateral stroke (HTIAs compared with RTIAs) was 3.23 (95% confidence interval, 1.47 to 7.12), regardless of the degree of high-grade stenosis. CONCLUSION: To our knowledge, this study is the first report on the expected outcome for medically treated patients with high-grade (70% to 99%) carotid stenosis in whom the first-ever event was either an RTIA or HTIA. The presence of RTIAs carries a considerable risk of ipsilateral strokes, particularly at higher degrees of stenosis. However, in comparison with HTIAs, patients with RTIAs still have a better prognosis.

Outcome of asymptomatic patients with carotid disease. Asymptomatic Cervical Bruit Study Group.

Asymptomatic cervical atherosclerosis carries a variable risk of vascular events. We sought to identify patients with asymptomatic cervical bruits who may be at increased risk of developing ischemic events. We conducted a prospective multicenter cohort study of neurologically asymptomatic patients presenting a cervical bruit. Patients had biannual neurologic and carotid duplex evaluation. Association between ultrasonographic findings and vascular events, adjusting for common risk factors, was evaluated. Seven hundred fifteen patients were followed on average for 3.6 years. Mean age was 65 years. At initial visit, 357 subjects had a > or = 50% stenosis. Overall, 237 events occurred in 177 patients. Annual rate of all primary vascular events in patients with > or = 50% stenosis was 11.0% versus 4.2% in those with < 50% stenosis (p < 0.001). Annual rate of stroke and vascular death was 5.5% in the > or = 50% group compared with 1.9% in the < 50% group (p < 0.001). Yearly rate of unheralded ischemic stroke was 4.2% in subjects with > or = 80% stenosis and 1.4% in those with stenosis < 80% (p < 0.001). A stroke or TIA was ipsilateral to a > or = 80% stenosis in 66% of patients. Progression of carotid stenosis particularly to more than 80% was associated both with a higher rate of ipsilateral neurologic events and overall combined vascular events. Our data suggest that severity of carotid stenosis is the main risk factor predicting occurrence of neurologic and other vascular events. Yearly rate of ipsilateral stroke with > or = 50% carotid stenosis is low (1.4%) and most are nondisabling. Progression to > or = 80% or occlusion is associated with worse outcome.

AMF-R tubules concentrate in a pericentriolar microtubule domain after MSV transformation of epithelial MDCK cells.

Autocrine motility factor receptor (AMF-R) is localized to an intracellular microtubule-associated membranous organelle, the AMF-R tubule. In well-spread untransformed MDCK epithelial cells, the microtubules originate from a broad perinuclear region and AMF-R tubules extend throughout the cytoplasm of the cells. In Moloney sarcoma virus (mos)-transformed MDCK (MSV-MDCK) cells, microtubules accumulate around the centrosome, forming a microtubule domain rich in stabilized detyrosinated microtubules. AMF-R tubules are quantitatively associated with this pericentriolar microtubule domain and the rough endoplasmic reticulum and lysosomes also co-distribute with the pericentriolar mass of microtubules. The Golgi apparatus is closely associated with the microtubule organizing center (MTOC) within the juxtanuclear mass of AMF-R tubules, and no co-localization of AMF-R tubules with the Golgi marker beta-COP could be detected by confocal microscopy. After nocodazole treatment and washout, microtubule nucleation occurs exclusively at the centrosome of MSV-MDCK cells, and only after microtubule extension to the cell periphery does the microtubule cytoskeleton reorganize to generate the pericentriolar microtubule domain after 30-60 min. AMF-R tubules dispersed by nocodazole treatment concentrate in the pericentriolar region in parallel with the reorganization of the microtubule cytoskeleton. MSV transformation of epithelial MDCK cells results in the stabilization of a pericentriolar microtubule domain responsible for the concentration and polarized distribution of AMF-R tubules.

Comparison of the efficacy and safety of flunarizine to propranolol in the prophylaxis of migraine.

This study was designed to compare flunarizine, a cerebro-specific calcium channel antagonist, and propranolol in the prophylaxis of migraine with or without aura. Following a 1 month single-blind placebo baseline period, 94 patients were equitably randomised under double-blind conditions to take flunarizine 10 mg daily or propranolol 80 mg twice daily for 4 months. Both treatments led to a significant reduction in the frequency of migraines and use of rescue analgesics with a significantly greater decrease in number of attacks for flunarizine after 1 and 4 months. Neither treatment affected the severity nor duration of migraines. Overall, 67% of flunarizine patients and 51% of propranolol patients responded positively. Propranolol significantly reduced blood pressure and heart rate; flunarizine had no effect on cardiovascular function. Weight gain was noted with both treatments. Flunarizine is at least as effective as propranolol in the prophylactic treatment of migraine and may have a better safety profile.

Canadian guidelines for intravenous thrombolytic treatment in acute stroke. A consensus statement of the Canadian Stroke Consortium.

BACKGROUND: The thromobolytic drug, tissue plasminogen activator (tPA) has been approved in the United States for the treatment of acute ischemic stroke amid controversy and concern about the balance of risk and benefit. The Canadian Stroke Consortium (CSC), a national network of neurologists who collaborate on joint projects in stroke medicine, including clinical trials and consensus statements, has developed guidelines for the use of tPA in Canada. METHODS AND RESULTS: The CSC Board of Directors wrote a preliminary report based on existing publications, including randomized drug trials and the report of a special committee struck by the Stroke Council of the American Heart Association. This draft was circulated to the CSC membership-at-large for suggestions or amendments, to produce this final draft. CONCLUSIONS: The present guidelines have been devised to represent a Canadian viewpoint of management. The Health Protection Branch of the Ministry of Health of Canada has not yet produced an evaluation. Further modification of these guidelines may be necessary when more data from clinical trials and experience with the drug become available.

[The young adult at work : development according to social class.]. / Le jeune adulte au travail : son développement selon les classes sociales.

The objective of the present study is to describe the comparative occupational experience of adults from 23-27 years of age and from 28-32 years according to whether they belong to the middle, comfortable or disfavoured socio-economic class. To accomplish this, we interviewed 161 subjects from 23-32 years in the number 03 administrative region (Quebec). Subjects were randomly chosen and divided according to variables of socio-economic class, sex and work sector. Results indicate that the 23-27 years old adults is busy with a "landing" on the job market. Depending on the class, this "landing" is primarily attentive (middle class), discreet (disfavoured class) or manifest (confortable class). The 28-32 years old adult is searching for a promising path. Depending on the case, this search is worthy optional (middle class), oriented towards the viable conditions of the milieu (disfavoured class) or very ambitious (comfortable class).

Inverse relation of autocrine motility factor receptor and E-cadherin expression following MDCK epithelial cell transformation.

Autocrine motility factor interacts with its cell surface receptor (AMF-R) to stimulate tumor cell motility. To study AMF-R expression following transformation of polarized epithelial MDCK cells, we have used the invasive Moloney sarcoma virus transformed MDCK (MSV-MDCK) cell population. Decreased E-cadherin expression of the transformed MSV-MDCK clones is associated with both increased cellular motility and increased AMF-R expression. Increased AMF-R expression is due to MSV transformation as differentially motile MSV-MDCK clones, which either retain low E-cadherin, exhibit equivalent high levels of AMF-R. Loss of the polarized epithelial phenotype and increased cellular motility following transformation of MDCK cells is thus associated with a shift from a high E-cadherin/low AMF-R to a low E-cadherin/low AMF-R phenotype.

Variations in bacitracin susceptibility observed in Staphylococcus and Micrococcus species.

Bacitracin susceptibility was evaluated as a laboratory method to differentiate staphylococci from micrococci. A total of 317 staphylococcal isolates and 108 micrococcal isolates were each tested for susceptibility to bacitracin by a disk-diffusion method using disks of three different potencies (0.04, 2.0, and 10.0 U) and a broth dilution method to obtain MICs. When a growth inhibition zone diameter breakpoint of greater than 10 mm was used to establish susceptibility with a 0.04-U disk, all micrococci were bacitracin susceptible and 94.6% of the staphylococci were resistant. Testing with disks of higher potency did not improve the specificity of the disk-diffusion method.

Myocardial blood flow regulation relative to left ventricle pressure and volume in anesthetized dogs.

The influence of left ventricle pressure and volume changes on coronary blood flow was investigated in eight anesthetized dogs. Coronary artery pressure-flow relationships were determined at two levels of left ventricular pressure and volume. The distribution of blood flow within the myocardium was also determined when these relationships varied. Reducing left ventricle pressures and volumes increased heart rate. Rate-pressure product, diastolic coronary pressure, myocardial O2 consumption, total, subendocardial and subepicardial flow decreased. Hematocrit and blood gas data were unchanged. The pressure-flow relationships were shifted leftward (p = 0.001) but the range of autoregulation was not altered. At low left ventricle pressures and volumes, the lower coronary artery pressure limit was shifted leftward (from 75 to 45 mm Hg (1 mm Hg = 133.3 Pa)), while total, subendocardial, and subepicardial blood flow did not change compared with the control. Below the lower coronary artery pressure limit, subendocardial but not subepicardial flow decreased, resulting in maldistribution of flow across the left ventricular wall. When coronary pressure was reset between control and the lower coronary artery pressure limit, subendocardial flow was restored. These results show that the lower coronary artery pressure limit can be shifted leftward while the distribution of blood flow across the left ventricular wall is preserved.