Lower leg and foot contributions to turnout in female pre-professional dancers: A 3D kinematic analysis.

Turnout is a central element of classical ballet which involves sustained external rotation of the lower limbs during dance movements. Lower leg and foot compensation mechanisms which are often used to increase turnout have been attributed to the high incidence of lower limb injury in dancers. Evaluation of dancers' leg posture is needed to provide insight into the lower limb kinematic strategies used to achieve turnout. The primary purpose of this study was to use 3D kinematic analyses to determine the lower leg and foot compensations that are incorporated by female university dancers to accentuate their turnout. Active and passive external tibiofemoral rotation (TFR) was also measured. A moderate-strong negative relationship was observed between hip external rotation (HER) and foot abduction in the three first position conditions. A moderate negative relationship was found between passive TFR and foot abduction in all first position conditions. Our findings suggest dancers are more likely to pronate, than rotate the knee to compensate for limited HER. Dancers with a limited capacity to pronate may force additional rotation via the knee. Ongoing research would benefit from more in-depth analyses of the foot/ankle complex using a multi-segment foot model.

An exploratory, open-label, randomized, multicenter study to investigate the pharmacodynamics of a glycoengineered antibody (imgatuzumab) and cetuximab in patients with operable head and neck squamous cell carcinoma.

BACKGROUND: In addition to inhibiting epidermal growth factor receptor (EGFR) signaling, anti-EGFR antibodies of the IgG1 'subtype' can induce a complementary therapeutic effect through the induction of antibody-dependent cell-mediated cytotoxicity (ADCC). Glycoengineering of therapeutic antibodies increases the affinity for the Fc-gamma receptor, thereby enhancing ADCC. PATIENTS AND METHODS: We investigated the changes in immune effector cells and EGFR pathway biomarkers in 44 patients with operable, advanced stage head and neck squamous cell carcinoma treated with two preoperative doses of either glycoengineered imgatuzumab (GA201; 700 or 1400 mg) or cetuximab (standard dosing) in a neoadjuvant setting with paired pre- and post-treatment tumor biopsies. RESULTS: Significant antitumor activity was observed with both antibodies after just two infusions. Metabolic responses were seen in 23 (59.0%) patients overall. One imgatuzumab-treated patient (700 mg) achieved a 'pathological' complete response. An immediate and sustained decrease in peripheral natural killer cells was consistently observed with the first imgatuzumab infusion but not with cetuximab. The functionality of the remaining peripheral natural killer cells was maintained. Similarly, a pronounced increase in circulating cytokines was seen following the first infusion of imgatuzumab but not cetuximab. Overall, tumor-infiltrating CD3+ cell counts increased following treatment with both antibodies. A significant increase from baseline in CD3+/perforin+ cytotoxic T cells occurred only in the 700-mg imgatuzumab group (median 95% increase, P < 0.05). The most prominent decrease of EGFR-expressing cells was recorded after treatment with imgatuzumab (700 mg, -34.6%; 1400 mg, -41.8%). The post-treatment inflammatory tumor microenvironment was strongly related to baseline tumor-infiltrating immune cell density, and baseline levels of EGFR and pERK in tumor cells most strongly predicted therapeutic response. CONCLUSIONS: These pharmacodynamic observations and relationship with efficacy are consistent with the proposed mode of action of imgatuzumab combining efficient EGFR pathway inhibition with ADCC-related immune antitumor effects. CLINICAL TRIAL REGISTRATION NUMBER: NCT01046266 (ClinicalTrials.gov).

Single-leg squats can predict leg alignment in dancers performing ballet movements in "turnout".

The physical assessments used in dance injury surveillance programs are often adapted from the sports and exercise domain. Bespoke physical assessments may be required for dance, particularly when ballet movements involve "turning out" or external rotation of the legs beyond that typically used in sports. This study evaluated the ability of the traditional single-leg squat to predict the leg alignment of dancers performing ballet movements with turnout. Three-dimensional kinematic data of dancers performing the single-leg squat and five ballet movements were recorded and analyzed. Reduction of the three-dimensional data into a one-dimensional variable incorporating the ankle, knee, and hip joint center positions provided the strongest predictive model between the single-leg squat and the ballet movements. The single-leg squat can predict leg alignment in dancers performing ballet movements, even in "turned out" postures. Clinicians should pay careful attention to observational positioning and rating criteria when assessing dancers performing the single-leg squat.

The cholecystokinin CCK2 receptor antagonist, JNJ-26070109, inhibits gastric acid secretion and prevents omeprazole-induced acid rebound in the rat.

BACKGROUND AND PURPOSE: JNJ-26070109 [(R)4-bromo-N-[1-(2,4-difluoro-phenyl)-ethyl]-2-(quinoxaline-5-sulfonylamino)-benzamide] is a novel antagonist at cholecystokinin CCK(2) receptors with good pharmacokinetic properties and represents a novel mechanism for the treatment of gastro-oesophageal reflux disease (GORD). The purpose of the present study was to determine whether chronic treatment with JNJ-26070109 could prevent, as well as treat, acid rebound in rats. EXPERIMENTAL APPROACH: A chronic fistula was surgically inserted into the stomach of rats to enable the measurement of acid secretion under basal, pentagastrin and histamine-stimulated conditions. JNJ-26070109 and omeprazole were administered separately and in combination. KEY RESULTS: Sustained administration of omeprazole alone and in combination with JNJ-26070109 inhibited gastric acid secretion by >90%. However, 3 days after withdrawing treatment, there was a rebound hypersecretion by ∼1.5-fold in omeprazole-treated animals. No such acid rebound was observed with JNJ-26070109 alone or with co-administration of JNJ-26070109 and omeprazole. The anti-trophic effects of JNJ-26070109 in the gastric mucosal paralleled the effects on acid rebound. Administration of JNJ-26070109 for 3 days after cessation of omeprazole prevented the occurrence of acid rebound. Interestingly, chronic, but not acute, treatment with JNJ-26070109 also inhibited histamine-stimulated acid secretion. CONCLUSIONS AND IMPLICATIONS: Chronic administration of JNJ-26070109 effectively inhibited gastric acid secretion and suppressed proton pump inhibitor (PPI)-induced acid rebound in the rat. This work advances the field by demonstrating that modest doses of a competitive CCK(2) receptor antagonist have significant and functionally important anti-trophic actions in the gastric mucosa. These properties make JNJ-26070109 a suitable candidate for clinical investigation for the treatment of GORD.

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies.

R306465 is a novel hydroxamate-based histone deacetylase (HDAC) inhibitor with broad-spectrum antitumour activity against solid and haematological malignancies in preclinical models. R306465 was found to be a potent inhibitor of HDAC1 and -8 (class I) in vitro. It rapidly induced histone 3 (H3) acetylation and strongly upregulated expression of p21waf1,cip1, a downstream component of HDAC1 signalling, in A2780 ovarian carcinoma cells. R306465 showed class I HDAC isotype selectivity as evidenced by poor inhibition of HDAC6 (class IIb) confirmed by the absence of downregulation of Hsp90 chaperone c-raf protein expression and tubulin acetylation. This distinguished it from other HDAC inhibitors currently in clinical development that were either more potent towards HDAC6 (e.g. vorinostat) or had a broader HDAC inhibition spectrum (e.g. panobinostat). R306465 potently inhibited cell proliferation of all main solid tumour indications, including ovarian, lung, colon, breast and prostate cancer cell lines, with IC50 values ranging from 30 to 300 nM. Haematological cell lines, including acute lymphoblastic leukaemia, acute myeloid leukaemia, chronic lymphoblastic leukaemia, chronic myeloid leukaemia, lymphoma and myeloma, were potently inhibited at a similar concentration range. R306465 induced apoptosis and inhibited angiogenesis in cell-based assays and had potent oral in vivo antitumoral activity in xenograft models. Once-daily oral administration of R306465 at well-tolerated doses inhibited the growth of A2780 ovarian, H460 lung and HCT116 colon carcinomas in immunodeficient mice. The high activity of R306465 in cell-based assays and in vivo after oral administration makes R306465 a promising novel antitumoral agent with potential applicability in a broad spectrum of human malignancies.

Activation of cardiac endothelium as a compensatory component in endotoxin-induced cardiomyopathy: role of endothelin, prostaglandins, and nitric oxide.

BACKGROUND: In view of growing evidence of an important endothelial paracrine regulation of cardiac function, the present study investigated the role of cardiac endothelium-derived endothelin-1 (ET-1), prostaglandins, and nitric oxide (NO) during endotoxin-induced cardiomyopathy in rabbits. METHODS AND RESULTS: Immunohistochemical studies showed a marked transient coinduction of the inducible isoforms of NO synthase (NOS-2) and cyclooxygenase (COX-2) in endocardial endothelium and coronary arteriolar endothelium of hearts 12 hours after intravenous administration of lipopolysaccharide (LPS+12h); staining for both isoforms was much weaker 24 hours later (LPS+36h). Nitrotyrosine localization was similar to that of NOS-2, suggesting a NOS-2-related endothelial formation of peroxynitrite in septic hearts. Contractile performance of papillary muscles was depressed in both LPS-treated groups. In the LPS+12h group, however, isometric twitches were significantly prolonged (482+/-14 versus 420+/-14 ms in the saline-treated group, P<0.005). This twitch prolongation was completely reversed by simultaneous administration of BQ-123 and indomethacin to block endogenous ET-1 and prostaglandins, respectively. In addition, in the LPS+12h group, myocardial inotropic responsiveness to exogenous ET-1 was enhanced (P<0.01). CONCLUSIONS: Cardiac endothelial activation and myocardial sensitization to endothelium-derived mediators may be part of an adaptive response in the early (12 hours) stages of septic cardiomyopathy.

Transferrin-mediated uptake of aluminium by human parathyroid cells results in reduced parathyroid hormone secretion.

BACKGROUND: The present study investigates whether aluminium-transferrin (Al-Tf) uptake by Tf receptor-mediated endocytosis induces hypoparathyroidism and thus might contribute to the increasing prevalence of adynamic bone disease (ABD) in the current dialysis population. METHODS AND RESULTS: Human parathyroid glands as well as in vitro cultured human parathyroid cells were shown to express Tf receptors. Five-day-old cultures of parathyroid cells were incubated for 48 h in serum-free DMEM/F12 supplemented with 12 microM apo-Tf: 12 microM Tf to which 150 microg/l Al or 150 microg/l Al-citrate (Al-ci) was bound. The amount of Al taken up by the parathyroid cells either as Al-Tf or Al-ci did not differ. However, incubation of cell cultures with Al-Tf showed a significant proportional decrease (mean+/-SEM, -23.1+/-4.5%) in iPTH secretion as compared to the reference apo-Tf cultures. Al-ci did not suppress PTH secretion (+3.4+/-6.5%). The Al uptake after incubation with Al-Tf was found to be dose-dependent. With regard to iPTH secretion, a tendency toward a dose response relationship was observed. Northern blot analysis of parathyroid cells incubated in 12 microM apo-Tf or 12 microM Al-Tf demonstrated that the PTH mRNA synthesis was unaffected by the Tf-mediated uptake of Al. These observations suggest an effect of Al on PTH release rather than on PTH synthesis. Since the cytoskeleton can play an important role in the release of secretory vesicles, the influence of Al on the structure of actin, beta-tubulin and vimentin was investigated by confocal microscopy. Comparison of cultures incubated with apo-Tf and Al-Tf revealed no difference in the organization of these cytoskeletal proteins in relation to the inhibitory effect of Al-Tf on PTH secretion. CONCLUSION: In summary, data in the present paper demonstrate that the (i) human parathyroid gland/parathyroid cells exhibit Tf receptors; (ii) Al-Tf complex is taken up by the parathyroid gland in a dose-dependent manner; and (iii) uptake of Al by Tf receptor-mediated endocytosis reduces the secretion of PTH but not its synthesis. These in vitro findings allow us to suggest that Tf receptor-mediated uptake of Al might, besides other factors such as vitamin D, high calcium dialysate or CaCO(3) intake, play a role in the development of hypoparathyroidism associated with ABD. The exact mechanism by which Al-Tf suppresses iPTH secretion remains to be elucidated.

Improvement of endocardial and vascular endothelial function on myocardial performance by captopril treatment in postinfarct rat hearts.

Background-Endocardial (EE) and myocardial capillary vascular endothelial (myocap VE) cells have been shown to modulate the contractile characteristics of myocardium in a calcium-dependent manner. We evaluated the endothelial-myocardial interaction in the rat postinfarction myocardial infarction (MI) model and the effects of captopril. Methods and Results-Wistar rats were divided into 4 groups treated for 4 weeks: (1) control; (2) infarcted controls (left anterior coronary artery ligation); (3) infarcted+captopril 2 g/L in drinking water; and (4) infarct+captopril+triton intracoronary injection. Coronary VE function was evaluated by infusion of serotonin in Langendorff preparations (n=31), and the myocardial contractile characteristics were investigated by use of isolated papillary muscles (n=44). Cardiac mRNA for endothelial constitutive nitric oxide synthase (ecNOS) was measured, and its cellular location was evaluated by immunohistochemistry. Serotonin-induced increase in coronary flow was decreased in infarct controls compared with controls (4.6% versus 53.4%, P<0.01) but not in the 2 infarct+captopril groups. Intracoronary triton injection decreased serotonin-induced coronary flow in the infarct+captopril+triton group. All MI groups had decreased total tension in isolated papillary muscles. EE removal by triton immersion decreased total tension in all groups except for infarct controls (3.3 versus 3.2 g/mm(2)). Cardiac ecNOS mRNA decreased in the control infarct group but remained normal in the infarct+captopril group. Conclusions-Chronic postinfarction endothelium-induced coronary vasodilatation is impaired, and both EE and myocap VE dysfunction contribute to myocardial depression. Captopril use prevents these abnormalities and the reduction of cardiac ecNOS mRNA.

Cardiac endothelium and myocardial function.

Endocardial endothelium and vascular endothelium of myocardial capillaries share common features as modulators of cardiac performance, rhythmicity and growth. Growing evidence suggests differences between these two cardiac endothelial cell types with regard to developmental, morphological and functional properties. A major difference probably resides in the way and extent by which these endothelial cells perceive and transmit signals.

Role of polymorphonuclear leukocytes in collar-induced intimal thickening in the rabbit carotid artery.

In this study, the involvement of polymorphonuclear leukocytes (PMNs) in the development of intimal thickening was investigated. A fibromuscular intima was induced by placing a silicone collar around the rabbit carotid artery for 3 days or 2 weeks; the contralateral artery was sham operated. Rabbits received placebo treatments (groups 1 and 3), granulocyte-colony stimulating factor (group 2; G-CSF, 20 microg x kg(-1) x d(-1), delivered by subcutaneous osmotic pumps), or an anti-CD18 monoclonal antibody (group 4; 1.5 mg/kg i.v.). The G-CSF treatment raised the peripheral PMN count 5- to 12-fold but had no effect on intimal thickening on day 3, 12, or 14. A single injection of anti-CD18 prevented PMN extravasation 6 hours after collar implantation without influencing intimal hyperplasia on day 14. Repeated daily administration of anti-CD18 strongly bound to CD18 on peripheral PMNs and inhibited both PMN-dependent plasma extravasation in the skin and accumulation of CD14-immunoreactive leukocytes in the intima and media. However, anti-CD18 did not suppress early intimal thickening or accumulation of alpha-smooth muscle actin-immunoreactive cells by day 3. It thus appears that the PMN influx in the intima and media evoked by the perivascular collar is of little functional relevance to the subsequent smooth muscle cell migration and intimal thickening in this model.

Vascular endothelial dysfunction contributes to myocardial depression in ischemia-reperfusion in the rat.

Endocardial and vascular myocardial capillary endothelium has been shown to modulate the contractile characteristics of myocardium by altering myofibrillar affinity for calcium. Although the release of endothelial-derived substances that modify myocardial contractility has been shown to be altered in certain physiologic and pathologic situations, until now no study has evaluated whether the direct modulatory effects of endothelium on its subjacent myocardium were altered in pathologic situations and contributed to loss of contractile function. This study was designed to evaluate whether the direct contractile modulatory effects of endocardial and (or) vascular endothelium were altered and whether these alterations contributed to contractile dysfunction in a model of ischemia-reperfusion. Sixty-two perfused rat hearts as Langendorff preparations were randomized to no intervention, intracoronary Triton X100 injection (to render vascular endothelium dysfunctional), ischemia (30 min)-reperfusion (20 min), and ischemia-reperfusion followed by intracoronary Triton X100 injection. Coronary endothelial-dependent vascular reactivity and vascular smooth muscle reactivity were assessed by serotonin and sodium nitroprusside, respectively. Myocardial damage was assessed by coronary effluent creatine phosphokinase and by morphologic studies. Papillary muscles were then excised and contractile characteristics evaluated at varying extracellular calcium concentration prior to and after endocardial endothelial removal with Triton X100. All three interventions eliminated all coronary vascular response to serotonin but did not modify response to nitroprusside. Creatine phosphokinase values rose only in hearts with ischemia-reperfusion, and only minor morphologic changes occurred, mostly in hearts with ischemia-reperfusion. Papillary muscles from hearts with intracoronary Triton X100 injection had lower contractile indices compared with normal controls (total tension 4.0 vs. 4.6 g/mm2, p < 0.01) and an abbreviation of contraction duration. Increasing extracellular calcium concentration from to 0.7 to 3.25 mM eliminated these differences. Similar but more marked decreases in contractile indices and twitch duration were noted in the two ischemia-reperfusion groups, but consistent with some myocardial damage being present, increasing extracellular calcium concentration to 3.25 or 7 mM did not fully eliminate these differences. In both ischemia-reperfusion groups and the intracoronary Triton X100 group, the relative increase in total tension with increasing extracellular calcium concentrations was similar (35 to 38%) and greater than that of the control group (25%), consistent with dysfunction of vascular endothelium contributing to myocardial dysfunction in the three intervention groups. Endocardial endothelial removal had a similar effect in all four groups, suggesting that dysfunction of endocardial endothelium does not play a role in this model. We conclude that vascular but not endocardial endothelial dysfunction contributes to the myocardial dysfunction that occurs during ischemia-reperfusion injury.

Exposure to oxidized low-density lipoprotein in vivo enhances intimal thickening and selectively impairs endothelium-dependent dilation in the rabbit.

OBJECTIVES: Based on in vitro studies, oxidized low-density lipoprotein (oxLDL) has been implicated in atherogenesis and the associated deficiency in endothelium-dependent relaxation. The aim of this study was to investigate the effects of in vivo exposure to oxLDL on intimal thickening and relaxing behaviour. METHODS: Intimal thickening was evoked by the placement of silicone collars around the carotid arteries of the rabbit for 3 or 14 days. OxLDL (Cu(2+)-oxidized, 7 micron/h) or the vehicle phosphate-buffered saline (PBS) was infused in the collars via subdermally implanted osmotic minipumps. RESULTS: The collared vessels receiving PBS developed discrete intimal thickening after 14 days (intima/media (I/M) ratio 11 +/- 2%). OxLDL infusion resulted in intimal thickening after 3 days and significantly enhanced the intimal thickness by 14 days (I/M ratio 98 +/- 16%). Collaring alone for 3 or 14 days and 3 days exposure to oxLDL did not impair the endothelium-dependent relaxations to acetylcholine or calcium ionophore, nor to the NO donors glyceryl trinitrate (GTN) and S-nitroso-N-acetylpenicillamine (SNAP). However, the sensitivity to acetylcholine was decreased after exposure to oxLDL for 14 days (-logEC50 oxLDL 6.95 +/- 0.11 vs. 7.52 +/- 0.11 collar alone) and the maximal relaxation to the endothelium-dependent agonist was reduced by 50%, this in the presence of a virtually intact endothelium. Complete relaxation was still obtained with the nitric oxide donors. CONCLUSION: Our results show for the first time that local vascular exposure to oxLDL in vivo promotes intimal thickening and inhibits endothelium-dependent dilation, thereby supporting an active role for oxLDL in the morphological and functional changes observed in atherosclerotic blood vessels.

Nonuniformity of endothelial constitutive nitric oxide synthase distribution in cardiac endothelium.

Endocardial endothelium and endothelium of coronary vessels produce NO. Histochemical methods have suggested that coronary arterial endothelial cells contain more endothelial constitutive NO synthase (ecNOS) than does coronary venous endothelium. We have further investigated the distribution of ecNOS in cardiac endothelium using immunofluorescence and en face confocal microscopy of rat heart. In endocardial endothelium, confocal microscopy revealed distinct ecNOS labeling of peripheral cell borders, cytoplasmic labeling, and labeling of the Golgi complexes. Labeling of the cell borders and of the Golgi complexes was confirmed by double staining for ecNOS and for platelet and endothelial cell adhesion molecule or Golgi 58k protein, respectively. Cytoplasmic labeling was strongest in coronary arterial endothelium. The size of the ecNOS-labeled Golgi complexes decreased from coronary arterial endothelial cells (8.63 +/- 0.39 microm2, mean +/- SE of 5 rats) to endocardial endothelium (7.07 +/- 0.61 microm2) and to coronary venous endothelium (3.65 +/- 0.20 microm2). In addition, pixel intensity of ecNOS labeling was higher in arterial endothelial cells than in venous endothelial cells. Endothelium of myocardial capillaries also contained small ecNOS-labeled Golgi complexes. No correlation was observed between endothelial cell surface area and Golgi complex size. Caveolin-1 labeling was strongest in capillaries and did not coincide completely with ecNOS labeling in endocardial and venous endothelium. These results suggest that endocardial and coronary arterial endothelium in the rat have a higher synthetic activity and might express more ecNOS than is expressed by cardiac venous and capillary endothelium. The observed heterogeneity in ecNOS distribution might be related to the specific mechanochemical environment and function of each endothelial compartment.

Local application of LDL promotes intimal thickening in the collared carotid artery of the rabbit.

Oxidized LDL (oxLDL) has been implicated in atherogenesis on the basis of in vitro studies and is present in atherosclerotic lesions. The aim of this study was to investigate the effects of LDL and oxLDL on intimal thickening in vivo. Intimal thickening was evoked by the placement of silicone collars around the carotid arteries of rabbits for 2 weeks. The collars were connected to osmotic minipumps containing LDL (7 micrograms h-1, n = 16 arteries), oxLDL (Cu2+ oxidized, 7 micrograms h-1, n = 16), or phosphate-buffered saline (5 microL h-1, n = 16). Segments proximal to the collars served as controls. Collar placement without lipoprotein application resulted in the appearance of alpha-SMC actin-immunoreactive cells in the intima, thereby increasing the intimal thickness from 5 +/- 1 to 26 +/- 5 microns. The perivascular infusion of LDL or oxLDL within the collar significantly enhanced the development of the intima ninefold and sevenfold, respectively. The large intimas resulting from lipoprotein exposure were infiltrated by macrophages and T lymphocytes, and the intimal collagen area was increased from 5 +/- 2% in the discrete collar-induced intima to approximately 20% in the lipoprotein-evoked lesions. In conclusion, the local vascular application of LDL, oxidized in vitro or possibly in vivo, elicited an inflammatory-fibroproliferative response characteristic of arteriosclerotic lesions, thereby demonstrating an active role for this class of lipoproteins in the disease process.

Endocardial endothelium in the avascular heart of the frog: morphology and role of nitric oxide.

Endocardial endothelial morphology and the physiological modulatory role of nitric oxide (NO) were studied in an in vitro preparation of the working intact heart of the frog Rana esculenta, which lacks coronary vasculature and is thus devoid of a coronary vascular endothelium. En face confocal scanning laser microscopy of samples of perfused fixed hearts demonstrated the presence of NO synthase as a cytoplasmic constituent of the endocardial endothelial cells. Stroke volume (as a measure of performance in paced frog hearts) and stroke work (as an index of systolic function) increased by approximately 5 % after inhibition of the NO-cGMP pathway with 10(-4 )mol l-1 NG-nitro-l-arginine methyl ester and by approximately 8 % after inhibition with 10(-6 )mol l-1 Methylene Blue. In contrast, stroke volume and stroke work decreased by approximately 22 % after activation of the NO-cGMP pathway with sodium nitroprusside (10(-4 )mol l-1), while 3-morpholinosydnonimine (5x10(-8) to 10(-5 )mol l-1) caused a decrease of between 15 and 30 % and 8-bromo-cGMP (10(-6 )mol l-1) a decrease of approximately 8 %. These responses were significantly attenuated after exposure of the ventricular luminal to Triton X-100 (0.05 %, 0.1 ml), which itself increased performance (by over 10 %) without detectable morphological changes. These results show that the endocardial endothelium of Rana esculenta produces amounts of NO sufficient to modulate ventricular performance.

Endocardial endothelial dysfunction and heart failure.

Like vascular endothelium, the EE plays a role in transendothelial transport, in coagulant and thrombotic processes, and in interactions with inflammatory cells. In addition, EE is involved in the modulation of cardiac performance of subjacent myocardium. EE dysfunction includes insufficient as well as excessive performance of any of its multiple functions. Dysfunction can progress from a disturbed modulation of myocardial performance and an imbalance in the release of growth factors to changes in EE cytoskeletal organization, with concomitant changes in transendothelial permeability, and in extreme cases, to loss of endothelial integrity and frank denudation. Structural and functional impairment of EE and of endocardial interstitial cells may be primary or secondary to the disease. Mechanical stress, various hormones and cytokines can initiate EE dysfunction. EE dysfunction may influence the development of cardiac failure in endo(myo)cardial fibrosis (Loeffler's endocarditis and carcinoid syndrome) and in dilated cardiomyopathy. Although Bouillaud, in 1836, was referring to endocarditis when stating: (quote: see text) his statement may presently find a much broader field of applicability in cardiology.

The cardiac endothelium: functional morphology, development, and physiology.

Cardiac endothelial cells, regardless of whether they are from endocardial or from coronary (micro)vascular origin, directly modulate performance of the subjacent cardiomyocytes, resulting in control of the onset of ventricular relaxation and rapid filling of the heart. This review summarizes major features of the morphology, embryology, and comparative physiology of cardiac endothelial cells as well as the experimental observations on how cardiac endothelial cells affect the mechanical performance of the heart. As for the underlying mechanisms of the interaction between cardiac endothelial cells and cardiomyocytes, two working hypotheses have been postulated over the past years; (1) interaction mediated through a trans-endothelial physicochemical gradient for various ions (active blood-heart barrier), and (2) interaction mediated through the release by the cardiac endothelial cells of various cardioactive substances, eg, nitric oxide, endothelin, and prostacyclin. These two mechanisms may act in concert or in parallel.

Vascular-derived myocardial contractile factor: positive myocardial inotropic substance released from medial layer of the canine aorta.

Interactions between the various cell types that make up the cardiovascular system are known to play an important role in maintaining homeostasis. One area about smooth muscle cells that has received little attention, despite the production of a wide variety of mediators by smooth muscle cells, is their effect on myocardial function. In this study, the myocardial contractile effects of four different types of dog aortic strips on rabbit papillary muscles were evaluated. Of these, medial vascular smooth muscle strips most consistently (65% of the time) produced a "vascular-derived contractile factor" (VDCF), which caused a 15% increase in isometric twitch tension and a 24% increase in isotonic twitch shortening with no change in twitch configuration. Endovascular strips with or without intact endothelium and complete aortic rings had less consistent effects. Vascular-derived contractile factor was stable after freezing at -80 degrees C, its activity was not modified by a broad spectrum peptidase, but it was heat-labile. The angiotensin II blocker, losartan, did not modify its effects. However, incubation with indomethacin did reduce, but did not eliminate, the contractile effects of vascular strips. The addition of alpha 1- and beta-blockers did not further modify the effects of VDCF. Endocardial endothelial removal increased the effects of VDCF. No correlation existed between endothelin levels and the contractile effects of vascular strips. It is concluded that VDCF is produced by the medial layer of large vessels but its exact cellular origin is uncertain. These findings expand the ever-increasing understanding of the inter-relationship between the structures that make up the cardiovascular system, and open the door to new studies evaluating the inter-relationship of vessels and myocardium.

Endothelin-mediated positive inotropic effect induced by reactive oxygen species in isolated cardiac muscle.

Cardiac endothelium, both coronary and endocardial, produces a number of inotropic molecules. Changes in cardiac endothelial function by substances in the superfusing blood may thus participate in the control of muscle-pump performance of the heart. Reactive oxygen species (ROS) have been implicated in normal and pathological vascular physiology by influencing vascular endothelial function. Therefore, we examined the influence of ROS on endocardial endothelial modulation of myocardial performance. Right ventricular cat papillary muscles were briefly (15 s) exposed to electrolysis-generated ROS. Peak total isometric twitch tension and peak rate of tension development increased by 7.8 +/- 0.7% (P < .05) and 9.7 +/- 1.5% (P < .05), respectively (n = 12). Isometric twitch duration was slightly increased (time from stimulus to half isometric relaxation, +2.7 +/- 0.6%; P < .05). ROS scavengers such as ascorbic acid (n = 6), superoxide dismutase and catalase (n = 8), or catalase alone (n = 6), but not superoxide dismutase alone (n = 6), blocked the inotropic effect. Interestingly, the positive inotropic effect was completely blocked by selectively damaging endocardial endothelium (Triton X-100, 0.5%, 1-s immersion, n = 7) before ROS generation and by preincubating the muscles with the endothelin-A receptor antagonist BQ 123 (n = 11). Preincubation with NG-nitro-L-arginine methyl ester and indomethacin (n = 5) or with atenolol (n = 6) did not influence the inotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphoregulatory interactions of endocardial endothelium and extracellular material in the heart.

The endocardium forms the inner lining of the cavities of the heart. The luminal surface of the cardiac wall is subjected to considerable cyclical physico-chemical forces. These forces can have structural and physiological consequences both for the endocardial endothelium and for the subjacent interstitial tissue. In the latter tissue space, the extracellular matrix (ECM) plays a dominant role during cardiogenesis. For example, this role becomes evident from the influence of fibronectin in the directional migration of proendocardial cells and in the formation of a trabeculated heart. In particular, the complex processes occurring in the valves of the developing heart illustrate a spatiotemporally regulated expression of ECM components and adhesion molecules. In the adult heart, the endocardial interstitial tissue consists of a thin basal lamina, a reticular lamina and a fibroelastic layer which contains some fibroblasts, smooth muscle cells and a heterogeneous population of nerve fibers. Unlike in arteries, elastic fiber in the fibroelastic layer of ventricular endocardium do not constitute an elastic lamina. Differences in thickness of the endocardium between atria and ventricles, as well as the diffuse and focal endocardial fibrosis during ageing have been related to mechanical stress and local turbulence of flow. Although endocardial fibrosis is a common pathological finding in various cardiomyopathies, our knowledge on the structural organization and on the pathogenetic role of ECM is very limited, mainly by the lack of suitable experimental models.