Vernieri Fabrizio. Emicrania e disfunzione endoteliale. ASMaD 2011
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Vernieri Fabrizio. Emicrania e disfunzione endoteliale. ASMaD 2011
- 1. Corso di Aggiornamento CEFALEA E MALATTIA CEREBROVASCOLARE Ospedale S. Eugenio - Roma, 25 marzo 2011 Emicrania e Disfunzione Endoteliale Fabrizio Vernieri Neurologia, Università Campus Bio-Medico di Roma
- 3. L’endotelio vascolare Rilascia molecole per mantenere l’omeostasi ed il tono vascolare ‘ more than just a passive interface between the blood and the vessel wall’
- 5. Disfunzione endoteliale A pathological condition characterized by an imbalance between vasodilatating and vasoconstricting substances Flammer & Luscher, 2010
- 6. Regulatory Functions of the Endothelium Normal Dysfunction Vasodilation Vasoconstriction NO, PGI2, EDHF, BK, C-NP ROS, ET-1, TxA2, A-II, PGH2 Thrombolysis Thrombosis Platelet Disaggregation NO, PGI2 Adhesion Molecules CAMs, P,E Selectins Antiproliferation NO, PGI2, TGF- , Hep Growth Factors ET-1, A-II, PDGF, ILGF, ILs Lipolysis Inflammation ROS, NF- B PAI-1, TF- α , Tx-A2 tPA, Protein C, TF-I, vWF LPL Vogel R
- 7. Endothelial permeability Platelet adhesion Leukocyte adhesion and migration
- 8. Methods for exploring endothelial function Guerci et al., Diabetes Metab 2001; 27: 425-434
- 9. Assessment of coronary vascular function
- 10. Cerebrovascular reactivity to L-Arginine Pretnar-Oblak et al., Stroke 2006
- 11. Corretti et al. Journal of the American College of Cardiology 2002 Flow mediated dilation (FMD) X 100 (Shear rate) Diametro post – Diametro basale Diametro basale FMD Picco di flusso post Diametro basale Shear rate FMD = FMD =
- 16. Juonala et al., 2004 Yan et al., 2005
- 17. Chen et al. 2006
- 18. Emicrania e reattività endoteliale De Hoon et al, Cephalalgia 2006 Silva et al, Headache 2007
- 19. Headache 2007
- 20. Floris H. Vanmolkot, Luc M. Van Bortel and Jan N. de Hoon. Neurology 2007;68;1563-1570
- 21. 2010, 10: 119
- 22. Perko et al, Cephalalgia 2011
- 24. “ Migraine patients seem to have an arterial super-sensitivity to NO, that may be explained also by an autonomic dysfunction. Lacking a functional autonomic control, cerebral vessels would become over-sensible to NO as well as to other chemical stimuli, such as CO2.”
- 26. Thomsen LL et al. Cephalalgia 1993, 13; 395-9
- 27. Reattività vasomotoria cerebrale ed emicrania con aura Vedi anche: Thie et al., 1990; Harer & Von Kummer, 1991; Fiermonte et al., 1995
- 28. Reattività vasomotoria cerebrale (VMR) VMR= (V CO 2 -V rest /V rest )*100
- 29. Cerebral VMR, THC and oxygen% increases were significantly greater on the predominant compared with the non-predominant migraine side, with both sides of patients without side predominance and with controls. These findings suggest altered autoregulation in MA patients, possibly secondary to impaired cerebrovascular autonomic control. Cephalalgia 2009
- 31. Migraine and ischaemic vascular events. Kurth, Cephalalgia 2007 Emicrania e Stroke: rischio relativo
- 32. Emicrania e Stroke: RR nelle donne MacClellan et al., Stroke 2007 Studio caso-controllo, in 386 ♀ affette da stroke dai 15 ai 49 aa 1.5 OR di stroke (95% CI, 1.1 to 2.0), in assenza di fattori di rischio vascolari
- 33. Aura emicranica e stroke: fisiopatologia Hadjikhani et al., PNAS, 2001
- 34. KRUIT et al.
- 35. Silvestrini et al., Headache 2004
- 36. Emicrania, omocisteinemia e MTHFR Pezzini et al., Stroke, 2007 Headache 2007
- 37. Lee et al.
- 38. Emicrania e stroke: meccanismi fisopatologici comuni Modificato da Tietijen et al., Cephalalgia, 2007 ↑ PAF ↑ VWF NO metabolism PFO dissection
- 39. Grazie per l’attenzione Claudia Altamura Paola Palazzo Paola Maggio Riccardo Altavilla [email_address]
Editor's Notes
- Endothelium-derived vasoactive substances. Endothelial nitric oxide synthase is induced by shear stress and a variety of receptors and leads to a release of nitric oxide (NO), which exerts relaxation of vascular smooth muscle cells and other important effects such as antiproliferation and inhibition of thrombocyte aggregation and leukocyte adhesion. Other endothelium-derived relaxing factors including endotheliumderived hyperpolarisating factor (EDHF) and prostacyclin (PGI2) are also shown. ACE denotes angiotensin-converting enzyme, Ach, acetylcholine; AI, angiotensin I, AII, angiotensin II, AT1, angiotensin 1 receptor; Bk, bradykinin; COX, cyclooxygenase; ECE, ET-converting enzyme; EDHF, endotheliumderived hyperpolarizing factor; ETA and ETB, endothelin A and B receptors; ET-1, endothelin-1, L-Arg, L-arginine; PGH2, prostaglandin H2; ROS, reactive oxygen species; S1, serotoninergic receptor; TH, thromboxane receptor; Thr, Thrombin; TXA2, thromboxane; 5-HT, serotonin. In the past the endothelium was believed to represent a simple semipermeable membrane covering the endoluminal part of all blood vessels. However, in recent years, abundant research on the endothelium and its function has brought to light its impressive and indeed indispensable physiological functions, especially in maintaining the homeostasis of vascular tone and structure. Loss of function of the endothelium not only makes the vessel prone to vasoconstriction, but also leads to atherothrombotic changes such as proliferation of vascular smooth muscle, expression of proinflammatory molecules and thrombosis. Moreover, in humans endothelial dysfunction is one of the first detectable vascular alteration in the evolution of atherosclerosis, and its presence also correlates well with future cardiovascular events. The endothelium represents the inner layer of the vessel wall. It is a continuous and smooth monolayer of cells providing a nonthrombogenic surface with highly selective permeability properties. In total, it represents a surface area of about 4000 to 7000 m2. The endothelium controls vascular permeability and actively regulates the exchange of molecules in response to environmental and molecular signals (fig. 1) [2]. Moreover, healthy endothelial cells are crucial in the prevention of thrombotic events. A feature of note is that endothelial cells express antiplatelet and anticoagulant molecules [3], whereas dysfunctional cells make the vessel prone to thrombotic events with tissue factor playing an important role [4]. However, the endothelium is able to do much more; indeed, it is known to be a highly complex organ able to respond to a broad variety of endogenous and exogenous stimuli which also synthesizes and releases a vast amount of vasoactive substances. Many endothelium-derived relaxing factors (EDRF) have been characterised chemically in recent years; most of them are released in response to an increase in intracellular calcium. The most studied EDRF molecules are nitric oxide (NO), prostacyclin (PGI2) and endothelialderived hyperpolarisation factors (EDHF). Furthermore, there are also important endothelial-derived constricting factors (EDCF), endothelin-1 (ET-1) representing the most potent molecule. Given these important physiological (inter)actions of endothelial mediators, prompt repair of damaged or apoptotic cells by endothelial progenitor cells is essential. Thus, these cells are not only important for angiogenesis, but also prompt repair of defects in the endothelial lining of the vessel wall (for review see [5]). In the course of further research, NO has not only been shown to have vasodilatory properties. Indeed, it also prevents platelet adhesion and aggregation, as well as leukocyte adhesion and migration into the arterial wall and inhibits smooth muscle cell proliferation, all key events in the development of atherosclerosis [8–13]. NO is a highly diffusible small molecule and is synthesised by NO synthase (NOS) from L-arginine. It is released by endothelial cells mainly in response to shear stress, but also by many other molecules such as acetylcholine, bradykinin, thrombin, and ADP among others, leading to a relaxation of vascular smooth muscle cells
- The term endothelial dysfunction is widely used to describe any form of abnormal activity of the endothelium. An imbalance of the above-mentioned vasoactive substances due to endothelium dysfunction affects vascular function negatively. Most commonly, endothelium dysfunction is characterised by an impaired NO bioavailability due to reduced production of NO by NOS or increased breakdown by reactive oxygen species [71]. In the early stages, endothelial function may be partly maintained by compensatory upregulation of prostacyclin and/or EDHF. Endothelial dysfunction has been documented in almost every condition associated with atherosclerosis and cardiovascular disease. ROS might interact with NO and reduce its bioavailability, and might directly damage cellular structures via the production of peroxynitrate. Hence oxidative stress is probably one of the major mechanisms in the development of endothelial dysfunction, if not its major contributor. Endothelial function therefore represents an integrated index of both the overall cardiovascular risk factor burden and the sum of all vasculoprotective factors in a given individual [91]. Although studies often report endothelial dysfunction as a loss of the vasodilator capacity, the term encompasses a generalized defect in all the homeostatic mechanisms. When endothelial dysfunction becomes evident, there is vasoconstriction, increased leukocyte adherence, upregulation of adhesion molecules, increased chemokine secretion and cell permeability, enhanced LDL oxidation, cytokine production, platelet activation, mitogenesis, thrombosis, impaired coagulation, vascular inflammation, vascular smooth muscle cell proliferation and migration, and atherosclerosis [5] .
- Il distretto arterioso periferico possiede la capacità di rispondere ad un aumento del flusso ematico ( shear stress ) con una vasodilatazione FMD Questo fenomeno sembra mediato dal rilascio di ossido nitrico (NO) da parte dell’endotelio Il rilascio di NO è dipendente dall’attivazione di canali del potassio, dall’entrata del calcio dentro la cellula e dall’attivazione calcio-dipendente della NO sintetasi (eNOS) Lo studio della FMD permette, quindi, di studiare la funzione endoteliale in maniera ripetibile e non invasiva Viene effettuato a livello dell’arteria brachiale, insonata al di sopra del gomito Lo shear stress viene generato da uno sfigmomanometro, posizionato solitamente al di sopra della fossa antecubitale, che viene gonfiato ad una pressione superiore di almeno 50 mmHg rispetto alla PA sistolica per 5 min La massima vasodilatazione avviene dopo circa 60 sec dal rilascio dello sfigmomanometro Le tre misurazioni devono essere eseguite sempre nello stesso momento del ciclo cardiaco (misurato mediante ECG), preferenzialmente alla fine della diastole (inizio dell’onda R all’ECG) Studio della vasodilatazione endotelio-indipendente (NMD) We evaluated endothelial function by measuring the change in forearm blood flow induced by flow mediated dilation [16,17]; measurements were performed according to guidelines [18]. All examinations were performed by a single experienced vascular sonographer, who was unaware of the subjects’ clinical background, using an ultrasound system (Aplio 80 CV, Toshiba) with a broadband 8-14 MHz transducer. In our lab coefficient of variation for FMD repeated measurements is 15%. Because of circadian variations of peripheral vascular tone, the FMD investigation was performed on all patients between 8 and 9 AM in a quiet, temperature controlled room (22°C to 24°C). All subjects were studied after a 12-hour overnight fast. Smokers refrained from smoking in the 12 hours preceding the study. Vasoactive drugs were discontinued in the same time period. Female subjects were investigated during the first week of menstrual cycle [19]. Patients were headache-free for at least 15 days at the moment of the examination. No patient had a migraine attack in the five days subsequent the examination. With the patient in the supine position, the right brachial artery was scanned over a longitudinal section, 3-5 cm above the elbow. Depth and gain settings were optimized to identify the lumen-to-vessel wall interface. The FMD was assessed by measuring the change in brachial artery diameter after 50, 60 and 70 seconds of reactive hyperemia, compared with baseline measurements, after deflation of a cuff placed around the forearm that had been inflated to 50 mm Hg above systolic blood pressure for 5 minutes (figure 1). Arterial diameter was determined as the internal dimension of the vessel wall from the anterior-to-posterior interface between the lumen and the intima. The mean diameter was calculated from three measurements of arterial diameter performed at end-diastole incident with the R wave on a continuously recorded ECG. The response of the vessel diameter to reactive hyperemia (FMD) was expressed as a percent change relative to the diameter before cuff inflation. However, FMD depends on the shear stress on the blood vessels, which is directly related to the velocity and the viscosity of the blood but inversely related to the vessel diameter. Vesselswith different diameters may have the same flow but substantially different levels of shear stress and thus a different degree of stimuli for FMD. In other words, FMD values derived from subjects with a comparable endothelial function but with different vessel diameters may results dissimilar. To avoid this bias, FMD raw values need to be corrected for flow velocity and diameter. A shear rate was then estimated as velocity divided by diameter [20]. Peak shear rate, estimated as peak flow velocity divided by baseline diameter, was calculated to quantify the FMD stimulus in each subject. FMD responses were normalized by dividing the maximal percentage change in diameter by the peak shear rate [20].
- This increased sensitivity to GNT could reflect increased sensitivity to NO, a view which is supported by increased arterial vasodilatation during GNT infusion in migraineurs.