Chaotic advection in blood flow

In this paper we argue that the effects of irregular chaotic motion of particles transported by blood can play a major role in the development of serious circulatory diseases. Vessel wall irregularities modify the flow field, changing in a nontrivial way the transport and activation of biochemically active particles. We argue that blood particle transport is often chaotic in realistic physiological conditions. We also argue that this chaotic behavior of the flow has crucial consequences for the dynamics of important processes in the blood, such as the activation of platelets which are involved in the thrombus formation.

Influence of left ventricular size and hemodynamics on the systolic longitudinal myocardial Doppler velocity response to stress

Background Systolic myocardial Doppler velocity accurately identifies coronary artery disease. However, these velocities may be affected by age, hemodynamic responses to stress, and left ventricular cavity size. We sought to examine the influences of these variables on myocardial velocity during dobutamine stress in patients with normal wall motion. Methods One hundred seventy-nine consecutive patients with normal dobutamine echocardiograms were studied. Color myocardial tissue Doppler data were obtained at rest and peak stress, and peak systolic myocardial velocity (PSV) was measured in all basal and midventricular segments. Velocities at rest and peak stress were compared with left ventricular diastolic and systolic volumes, blood pressure, heart rate, and age by Pearson correlation and interdecile analysis by use of analysis of variance. Results The only clinical variable correlating with velocity was age; PSV showed only mild correlation with age at rest (r(2) = 0.01, P = .001) and peak stress (r(2) = 0.02, P = .001), but the normal peak velocity was significantly different between the extremes of age (<44 years and >74 years). There was very weak correlation of PSV with systolic and diastolic blood pressure (r(2) < 0.01), heart rate (r(2) < 0.01), systemic vascular resistance (r(2) = 0.08), and left ventricular volumes (r(2) < 0.01). Conclusions Peak systolic velocity during dobutamine stress is relatively independent of hemodynamic factors and left ventricular cavity size. The extremes of age may influence peak systolic Doppler velocities. These results suggest that peak systolic velocity may be a robust quantitative measure during dobutamine echocardiography across most patient subgroups.

Exhaled nitric oxide in high-altitude pulmonary edema: role in the regulation of pulmonary vascular tone and evidence for a role against inflammation.

High-altitude pulmonary edema (HAPE) is a life-threatening condition occurring in predisposed subjects at altitudes above 2,500 m. It is not clear whether, in addition to hemodynamic factors and defective alveolar fluid clearance, inflammation plays a pathogenic role in HAPE. We therefore made serial measurements of exhaled pulmonary nitric oxide (NO), a marker of airway inflammation, in 28 HAPE-prone and 24 control subjects during high-altitude exposure (4,559 m). To examine the relationship between pulmonary NO synthesis and pulmonary vascular tone, we also measured systolic pulmonary artery pressure (Ppa). In the 13 subjects who developed HAPE, exhaled NO did not show any tendency to increase during the development of lung edema. Throughout the entire sojourn at high altitude, pulmonary exhaled NO was roughly 30% lower in HAPE-prone than in control subjects, and there existed an inverse relationship between Ppa and exhaled NO (r = -0.51, p < 0.001). These findings suggest that HAPE is not preceded by airway inflammation. Reduced exhaled NO may be related to altered pulmonary NO synthesis and/or transport and clearance, and the data in our study could be consistent with the novel concept that in HAPE-prone subjects, a defect in pulmonary epithelial NO synthesis may contribute to exaggerated hypoxic pulmonary vasoconstriction and in turn to pulmonary edema.

Perfusion computed tomography-guided subacute endovascular reperfusion in a patient with carotid occlusion.

Most patients with symptomatic internal carotid artery occlusion have a single minor or major hemispheric stroke. A minority of patients have ipsilateral retinal ischemia, recurrent strokes, or transient ischemic attacks. Whereas spontaneous carotid recanalization is rare, acute surgical recanalization has been attempted, with mixed results. Recently, acute endovascular recanalization has been performed and described as feasible and relatively safe. We describe a patient with symptom recurrence related to hemodynamic factors after occlusion of the carotid artery who was successfully treated 14 days after symptom onset.

Congenital heart disease affects local gyrification in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2DS) is a common genetic condition associated with cognitive and learning impairments. In this study, we applied a three-dimensional method for quantifying gyrification at thousands of points over the cortical surface to imaging data from 44 children, adolescents, and young adults with 22q11.2DS (17 males, 27 females; mean age 17y 2mo [SD 9y 1mo], range 6-37y), and 53 healthy participants (21 males, 32 females; mean age 15y 4mo [SD 8y 6mo]; range 6-40y). Several clusters of reduced gyrification were observed, further substantiating the pattern of cerebral alterations presented by children with the syndrome. Comparisons within 22q11.2DS demonstrated an effect of congenital heart disease (CHD) on cortical gyrification, with reduced gyrification at the parieto-temporo-occipital junction in patients with CHD, as compared with patients without CHD. Reductions in gyrification can resemble mild polymicrogyria, suggesting early abnormal neuronal proliferation or migration and providing support for an effect of hemodynamic factors on brain development in 22q11.2DS. The results also shed light on the pathophysiology of acquired brain injury in other populations with CHD.

Rein et tabac : revue de la littérature et mise au point [Kidney and smoking: literature review and focus].

Smoking remains a major public health problem. It is associated with a considerable number of deaths in the world's population. Smoking is just like high blood pressure, an independent predictor of progression to any primary renal disease and renal transplant patients. It seems that smoking cessation slows the progression of kidney disease in smokers. The literature data are sometimes contradictory about it because of some methodological weaknesses. However, experimental models highlight the harmful effects of tobacco by hemodynamic and non-hemodynamic factors. The conclusion is that a major effort should be further produced by the nephrology community to motivate our patients to stop smoking.

Influence de l’agrégation érythrocytaire sur la migration axiale de microparticules simulant des plaquettes sanguines

Lors du phénomène d’hémostase primaire ou de thrombose vasculaire, les plaquettes sanguines doivent adhérer aux parois afin de remplir leur fonction réparatrice ou pathologique. Pour ce faire, certains facteurs rhéologiques et hémodynamiques tels que l’hématocrite, le taux de cisaillement local et les contraintes de cisaillement pariétal, entrent en jeu afin d’exclure les plaquettes sanguines de l’écoulement principal et de les transporter vers le site endommagé ou enflammé. Cette exclusion pourrait aussi être influencée par l’agrégation de globules rouges qui est un phénomène naturel présent dans tout le système cardiovasculaire selon les conditions d’écoulement. La dérive de ces agrégats de globules rouges vers le centre des vaisseaux provoque la formation de réseaux d’agrégats dont la taille et la complexité varient en fonction de l’hématocrite et des conditions de cisaillement présentes. Il en résulte un écoulement bi-phasique avec un écoulement central composé d’agrégats de globules rouges avoisinés par une région moins dense en particules où l’on peut trouver des globules rouges singuliers, des petits rouleaux de globules rouges et une importante concentration en plaquettes et globules blancs. De ce fait, il est raisonnable de penser que plus la taille des agrégats qui occupent le centre du vaisseau augmente, plus il y aura de plaquettes expulsées vers les parois vasculaires. L'objectif du projet est de quantifier, in vitro, la migration des plaquettes sanguines en fonction du niveau d’agrégation érythrocytaire présent, en faisant varier l’hématocrite, le taux de cisaillement et en promouvant l’agrégation par l’ajout d’agents tels que le dextran à poids moléculaire élevé. Cependant, le comportement non Newtonien du sang dans un écoulement tubulaire peut être vu comme un facteur confondant à cause de son impact sur l’organisation spatiale des agrégats de globules rouges. De ce fait, les études ont été réalisées dans un appareil permettant de moduler, de façon homogène, la taille et la structure de ces agrégats et de quantifier ainsi leur effet sur la migration axiale des plaquettes. Du sang de porc anti coagulé a été ajusté à différents taux d’hématocrite et insérer dans un appareil à écoulement de Couette, à température ambiante. Les plaquettes sanguines, difficilement isolables in vitro sans en activer certains ligands membranaires, ont été remplacées par des fantômes en polystyrène ayant un revêtement de biotine. La quantification de la migration de ces fantômes de plaquettes a été réalisée grâce à l’utilisation de membranes biologiques fixées sur les parois internes de l’entrefer du rhéomètre de Couette. Ces membranes ont un revêtement de streptavidine assurant une très forte affinité d’adhésion avec les microparticules biotynilées. À 40% d’hématocrite, à un cisaillement de 2 s-1, 566 ± 53 microparticules ont été comptées pour un protocole préétabli avec du sang non agrégeant, comparativement à 1077 ± 229 pour du sang normal et 1568 ± 131 pour du sang hyper agrégeant. Les résultats obtenus suggèrent une nette participation de l’agrégation érythrocytaire sur le transport des fantômes de plaquettes puisque l’adhésion de ces derniers à la paroi du rhéomètre de Couette augmente de façon quasi exponentielle selon le niveau d’agrégation présent.

Effet du bosentan sur les niveaux d'inflammation systémique et rénale chez des patients avec néphropathie diabétique traités par bloqueurs de récepteurs de l'angiotensine II

Outre les facteurs métaboliques et hémodynamiques, l’inflammation est actuellement considérée comme un facteur pathogénique potentiel de la néphropathie diabétique (ND), pouvant contribuer à l’initiation et à la progression de la maladie. Les mécanismes menant au développement de l’inflammation rénale dans la ND sont encore peu connus, bien qu’une augmentation d’activité des systèmes rénine angiotensine (RAS) et de l’endothéline (ET) semble y contribuer. L’objectif général de cette étude mono-centre, à double aveugle, randomisée et incluant un groupe placebo était de démontrer que l’inhibition simultanée du RAS et du système de l’ET chez des patients avec ND induisait des effets rénoprotecteurs et anti-inflammatoires supérieurs à ceux observés par blocage du RAS seul. L’objectif spécifique de notre étude était d’évaluer la possibilité que l’administration d’un bloqueur des récepteurs de l’ET-1, le bosentan, à des patients atteints de ND et traités par bloqueurs des récepteurs de l’angiotensine II (BRA), réduisait, chez ces derniers, la protéinurie et les marqueurs inflammatoires systémiques et rénaux. Ce travail constitue un rapport d’un cas clinique et illustre les résultats obtenus suite à l’administration pendant 16 semaines du bosentan chez un patient diabétique de type 2 avec néphropathie clinique traité au long cours par BRA. Le protocole de recherche comprenait 6 visites médicales à 4 semaines d’intervalle, la première visite (V1) correspondant au recrutement du patient, la deuxième visite (V2) constituant le temps 0 de l’étude et la dernière visite (V6) représentant la fin de l’étude. Des échantillons de sang et d’urine étaient prélevés à 3 reprises soit à V2, V4 c’est-à-dire 8 semaines après le début du traitement et à V6 soit 16 semaines après le début du traitement pour mesure des taux sériques et urinaires de divers facteurs pro-inflammatoires incluant l’ET-1, le facteur de nécrose tumorale alpha (TNF-α), l’interleukine-6 (IL-6), le facteur chémoattractant des monocytes-1 (MCP-1), la molécule d’adhésion intracellulaire-1 (ICAM-1), la molécule d’adhésion vasculaire-1 (VCAM-1) et la protéine C-réactive (CRP). Un profil lipidique était aussi déterminé au début et à la fin de l’étude. La fonction rénale était mesurée aux visites V1, V2, V4 et V6 par détermination du taux de filtration glomérulaire (TFG) et de l’excrétion urinaire d’albumine (UAE). Des tests biochimiques de routine étaient aussi faits à chaque visite. La corrélation entre les paramètres inflammatoires et rénaux sous étude et la filtration glomérulaire était enfin déterminée. Nos résultats chez ce sujet ont démontré que le bosentan réduisait l’UAE de 32 % et 35% aux semaines 8 et 16, et ce, sans affecter la pression artérielle ou la filtration glomérulaire. L'effet anti-protéinurique du bosentan était associé à une réduction des concentrations urinaires de VCAM-1, ICAM-1, IL-6, TNF-α et d’ET-1 ainsi qu’à une diminution des concentrations sériques de TNF-α. Le changement dans la protéinurie était corrélé de manière positive avec les changements des niveaux urinaires de VCAM-1 (r=0.86), ICAM-1 (r=0.88), ET-1 (r=0.94), et du TNF-α (r=0.96) ainsi qu’avec les changements des niveaux sériques de TNF-α (r=0.98). Ces données suggèrent que l’inhibition du système de l’ET induit dans la ND des effets rénoprotecteurs additifs à ceux observés par blocage du RAS seul. Ils supportent le concept que l’activation du système de l’ET au niveau rénal, par ses effets inflammatoires, puisse jouer un rôle important dans la pathogenèse de la ND. L’effet anti-inflammatoire et anti-protéinurique du bosentan constitue une découverte intéressante susceptible d’engendrer dans le futur une alternative thérapeutique et préventive dans la prise en charge de la ND.

[Kidney and smoking: literature review and focus]

Smoking remains a major public health problem. It is associated with a considerable number of deaths in the world's population. Smoking is just like high blood pressure, an independent predictor of progression to any primary renal disease and renal transplant patients. It seems that smoking cessation slows the progression of kidney disease in smokers. The literature data are sometimes contradictory about it because of some methodological weaknesses. However, experimental models highlight the harmful effects of tobacco by hemodynamic and non-hemodynamic factors. The conclusion is that a major effort should be further produced by the nephrology community to motivate our patients to stop smoking.

Mechanotransduction pathway activation in familial thoracic aortic aneurysms and dissections

Thoracic aortic aneurysms and dissections (TAAD) are autosomal dominantly inherited in 19% of patients. Mapping studies determined that the disease is genetically heterogeneous with multiple loci and genetic mutations accounting for familial TAAD. However, regardless of the specific mutation, resulting pathology is consistently medial degeneration, characterized by increased proteoglycans and loss of elastic fibers. We tested the hypothesis that genetic mutations leading to familial TAAD alter common pathways in aortic smooth muscle cells (SMCs). Identification of mutations at R460 in TGFBR2 reveals a 5% contribution to TAAD, however downstream analysis of Smad2 phosphorylation in the TGF-β pathway is not commonly altered in familial or sporadic disease when compared to controls. Expression profiling using Illumina's Sentrix HumanRef 8 Expression Beadchip array was done on RNA isolated from SMCs explanted from 6 patients with inherited TAAD with no identified mutation and 3 healthy controls obtained from the International Institute for the Advancement of Medicine. Significant increases in expression of proteoglycan genes in patients' SMCs, specifically lumican, podocan, and decorin were confirmed using Q-PCR and tissue immunofluorescence. NCI's Ingenuity Pathway Analysis predicted alterations in the ERK, insulin receptor and SAPK/JNK pathways (p<0.001), which SMCs activate in response to cyclic stretch. Immunoblotting indicated increased phosphorylation of ERK and GSK-3β, a protein from the insulin receptor pathway, in explanted patient SMCs, also confirmed by increased immunoreactivity against phosphorylated ERK and GSK-3β in the sub-intimal SMCs from patient tissue compared to controls. To determine if mechanotransduction pathway activation was responsible for the medial degeneration a specific inhibitor of GSK-3β, SB216763 was incubated with control cells and significantly increased the expression levels of proteoglycans. Mechanical strain was also applied to control SMCs confirming pathways stimulation with stretch. Incubation with pathway inhibitors against insulin receptor and ERK pathways identify, for the first time that stretch induced GSK-3β phosphorylation may increase proteoglycan expression, and ERK phosphorylation may regulate the expression of MMP2, a protein known to degrade elastic fibers. Furthermore, specific mutations in SMC-specific β-myosin heavy chain and α-actin, in addition to upregulation of pathways activated by cyclic stretch suggest that SMC response to hemodynamic factors, play a role in this disease. ^

Hemodynamic, morphometric and autonomic patterns in hypertensive rats - renin-angiotensin system modulation

BACKGROUND: Spontaneously hypertensive rats develop left ventricular hypertrophy, increased blood pressure and blood pressure variability, which are important determinants of heart damage, like the activation of renin-angiotensin system. AIMS: To investigate the effects of the time-course of hypertension over 1) hemodynamic and autonomic patterns (blood pressure; blood pressure variability; heart rate); 2) left ventricular hypertrophy; and 3) local and systemic Renin-angiotensin system of the spontaneously hypertensive rats. METHODS: Male spontaneously hypertensive rats were randomized into two groups: young (n=13) and adult (n=12). Hemodynamic signals (blood pressure, heart rate), blood pressure variability (BPV) and spectral analysis of the autonomic components of blood pressure were analyzed. LEFT ventricular hypertrophy was measured by the ratio of LV mass to body weight (mg/g), by myocyte diameter (μm) and by relative fibrosis area (RFA, %). ACE and ACE2 activities were measured by fluorometry (UF/min), and plasma renin activity (PRA) was assessed by a radioimmunoassay (ng/mL/h). Cardiac gene expressions of Agt, Ace and Ace2 were quantified by RT-PCR (AU). RESULTS: The time-course of hypertension in spontaneously hypertensive rats increased BPV and reduced the alpha index in adult spontaneously hypertensive rats. Adult rats showed increases in left ventricular hypertrophy and in RFA. Compared to young spontaneously hypertensive rats, adult spontaneously hypertensive rats had lower cardiac ACE and ACE2 activities, and high levels of PRA. No change was observed in gene expression of Renin-angiotensin system components. CONCLUSIONS: The observed autonomic dysfunction and modulation of Renin-angiotensin system activity are contributing factors to end-organ damage in hypertension and could be interacting. Our findings suggest that the management of hypertensive disease must start before blood pressure reaches the highest stable levels and the consequent established end-organ damage is reached.

Factors associated with arterial stiffness in children aged 9-10 years

OBJECTIVE To analyze the factors associated with stiffness of the great arteries in prepubertal children.METHODS This study with convenience sample of 231 schoolchildren aged 9-10 years enrolled in public and private schools in Vitória, ES, Southeastern Brazil, in 2010-2011. Anthropometric and hemodynamic data, blood pressure, and pulse wave velocity in the carotid-femoral segment were obtained. Data on current and previous health conditions were obtained by questionnaire and notes on the child’s health card. Multiple linear regression was applied to identify the partial and total contribution of the factors in determining the pulse wave velocity values.RESULTS Among the students, 50.2% were female and 55.4% were 10 years old. Among those classified in the last tertile of pulse wave velocity, 60.0% were overweight, with higher mean blood pressure, waist circumference, and waist-to-height ratio. Birth weight was not associated with pulse wave velocity. After multiple linear regression analysis, body mass index (BMI) and diastolic blood pressure remained in the model.CONCLUSIONS BMI was the most important factor in determining arterial stiffness in children aged 9-10 years.

Embolization for multicompartmental bleeding in patients in hemodynamically unstable condition: prognostic factors and outcome.

PURPOSE: To determine prognostic factors and evaluate outcomes of transcatheter arterial embolization in severely injured patients in hemodynamically unstable condition with multicompartmental bleeding.¦MATERIALS AND METHODS: Between June 2000 and May 2008, 36 consecutive patients treated with transcatheter arterial embolization for major retroperitoneal bleeding associated with at least one additional source of bleeding were retrospectively reviewed. Mean Injury Severity Score (ISS) was 49.4 ± 15.8. Univariate and multivariate analyses were performed to identify parameters associated with failure of embolization, need for additional surgery to control bleeding, and fatal outcome at 30 d.¦RESULTS: Embolization was technically successful in 35 of 36 patients (97.2%) and resulted in immediate and sustained (> 24 h) hemodynamic improvement in 29 (80.5%). Additional hemostatic surgery was necessary after embolization in six patients (16.6%). Fifteen patients (41.6%) died within 30 d. Failure to restore hemodynamic stability was correlated with the rate of administration of packed red blood cells (P = .014), rate of administration of fresh frozen plasma (FFP; P = .031), and systolic blood pressure (SBP) immediately before embolization (P = .002). The need for additional surgery was correlated with FFP administration rate before embolization (P = .0002) and hemodynamic success (P = .003). Death was correlated with Glasgow Coma Scale score at admission (P = .001), ISS (P = .014), New Injury Severity Score (P = .016), number of injured sites (P = .012), SBP before embolization (P = .042), need for vasopressive drugs before embolization (P = .037), and hemodynamic success (P = .0004).¦CONCLUSIONS: In patients in hemodynamically unstable condition, transcatheter arterial embolization effectively controls bleeding and improves hemodynamic stability. Immediate survival is related to hemodynamic condition before embolization, and 30-d mortality is mainly related to associated brain trauma.