Una Patologia Polidistrettuale: l’Aterotrombosi Plinio Fabiani Ospedale San Giovanni di Dio Firenze 3 ottobre 2009 L’aterotrombosi è un processo patologico potenzialmente letale che può interessare l’intero sistema vascolare arterioso. La sua natura progressiva rende conto di come sia messo a repentaglio in maniera imprevedibile il destino a lungo termine dei pazienti a rischio Una Patologia Polidistrettuale: l’Aterotrombosi Plinio Fabiani

What is Atherothrombosis? Atherothrombosis is characterized by a sudden (unpredictable) atherosclerotic plaque disruption (rupture or erosion) leading to platelet activation and thrombus formation Atherothrombosis is the underlying condition that results in events leading to myocardial infarction, ischemic stroke, and vascular death L’aterotrombosi è caratterizzata da un’improvvisa rottura, erosione o fissurazione di una placca aterosclerotica che comporta l’attivazione piastrinica e la formazione del trombo. (“Atherothrombosis”, defined as disruption of an atherosclerotic plaque with superimposed thrombosis1,2 –”underrecognition REACH 2007.pdf” L’immagine a sinistra illustra la rapida progressione dell’aterotrombosi, mostrando una rottura di placca coronarica con trombo ocllusivo sovrapposto. La figura a destra mostra un’erosione di placca con trombosi coronarica acuta. L’aterotrombosi rappresenta la condizione alla base di eventi che conducono all’infartro del miocardio, stroke ischemico e morte vascolare. Le malattie cardiovascolari, cerebrovascolari e vascolari periferiche sono parte di un continuum che condivide la comune fisiopatologia dell’aterotrombosi Plaque rupture1 Plaque erosion2 1. Falk E et al. Circulation 1995; 92: 657–71. 2. Arbustini E et al. Heart 1999; 82: 269–72. References: 1. Falk E et al. Circulation 1995; 92: 657–71. 2. Arbustini E et al. Heart 1999; 82: 269–72.

La due fasi dell’atero-trombosi

Infarto Miocardico Acuto

Atherothrombosis: A Generalized and Progressive Process Unstable angina MI Ischemic stroke/TIA Critical leg ischemia Cardiovasculardeath ACS Atherosclerosis Atherothrombosis Atherothrombosis is the common underlying disease process for MI, ischemic stroke, and vascular death. Acute coronary syndrome (ACS) is a classic example of atherothrombosis (plaque rupture and thrombus formation). ACS (in common with ischemic stroke and critical leg ischemia) is typically caused by rupture or erosion of an atherosclerotic plaque followed by formation of a platelet-rich thrombus. Atherosclerosis is an ongoing process affecting mainly large and medium-sized arteries, which can begin in childhood and progress throughout a person’s lifetime. Stable atherosclerotic plaques may encroach on the lumen of the artery and cause chronic ischemia, resulting in (stable) angina pectoris or intermittent claudication, depending on the vascular bed affected. Unstable atherosclerotic plaques may rupture, leading to the formation of a platelet-rich thrombus that partially or completely occludes the artery and causes acute ischemic symptoms. Stable angina Intermittent claudication Adapted from Stary HC et al. Circulation. 1995; 92: 1355–74, and Fuster V et al. Vasc Med. 1998; 3: 231–9. Reference: 1. Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6.

Secondo il racconto di Cicerone, Damocle è un cortigiano particolarmente adulatore alla corte di Dionigi I di Siracusa, un tiranno del IV secolo a.C.. Nell'aneddoto Damocle sostiene in presenza del tiranno che egli sia una persona estremamente fortunata, potendo disporre di un grande potere e di una grande autorità. Dionigi gli propone, allora, di scambiare con lui i rispettivi ruoli per un giorno, in modo da poter assaporare tale fortuna. Damocle accetta. La sera si tiene un banchetto, durante il quale inizia a tastare con mano i piaceri dell'essere un uomo potente. Solo al termine della cena nota, sopra la sua testa, la presenza di una spada affilata, sostenuta da un esile crine di cavallo. Dionigi l'aveva fatta sospendere sul capo di Damocle perché capisse che la sua posizione di tiranno lo esponeva continuamente a grandi minacce per la sua incolumità. Immediatamente Damocle perde tutto il gusto per i cibi raffinati che sta assumendo, nonché per le bellissime ragazze che gli stanno intorno e chiede al tiranno di voler terminare lo scambio, non volendo più essere così fortunato.

Major Clinical Manifestations of Atherothrombosis Ischemic stroke Transient ischemic attack Myocardial infarction Angina: Stable Unstable Atherothrombosis can be an extensive vascular disease affecting the coronary, cerebral and peripheral circulation. It is a progressive, generalized disorder with many clinical manifestations – either acute or chronic and often multiple in any single patient. Stenosis in an atherosclerotic artery may give rise to angina, a transient ischemic attack (TIA) or intermittent claudication. Atherothrombosis in the coronary arteries is the major cause of acute coronary syndrome (ACS), defined as unstable angina and non Q-wave myocardial infarction. Atherothrombosis of the cerebral arteries may also result in TIA or ischemic stroke. In the peripheral arteries, thrombosis superimposed on atherosclerosis can contribute to the progression of peripheral arterial disease, producing intermittent claudication (leg pain on walking that is relieved by rest) as well as ischemic necrosis and, potentially, loss of the limb. Peripheral arterial disease: Intermittent claudication Rest Pain Gangrene Necrosis Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Reference: 1. Drouet L. Cereobrovasc Dis 2002; 13(suppl 1): 1–6.

The Development of Atherothrombosis – a Generalized and Progressive Process Plaque rupture Platelet activation and aggregation Non-occlusive thrombus Acute syndrome: coronary cerebrovascular peripheral Occlusive Healing and resolution Plaque growth The trigger of an ischemic clinical event is the formation of a platelet-rich thrombus on a disrupted atherosclerotic plaque (i.e. atherothrombosis). Rupture or fissure of a plaque acts as a stimulus for atherothrombosis (thrombus formation superimposed upon atherosclerosis). In the case of an occlusive thrombus, there will be acute ischemic syndrome in the coronary, cerebral or peripheral vascular territory depending on the localization of the atherosclerotic plaque, potentially leading to permanent tissue damage. In the case of a non-occlusive thrombus, ischemic symptoms are temporary. Thrombosis can contribute to plaque growth through formation and resolution of subclinical platelet thrombi. Thrombus formation is a dynamic process in which platelets aggregate but also spontaneously disaggregate, leading to embolization of platelet aggregates from an evolving thrombus. Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Reference: 1. Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6.

Atherothrombosis and Microcirculation Plaque rupture Microvascular obstruction Embolization Through the development of new imaging modalities and specific therapeutics that serve as probes, microvascular obstruction, owing to embolization, has become increasingly recognized as an important sequelae of atherosclerotic and atherothrombotic vascular disease.1 Thrombus formation on an atherosclerotic plaque is a dynamic process in which platelets aggregate but also spontaneously disaggregate, leading to embolization of platelet aggregates from an evolving thrombus, which can lead to inflammation or microvascular obstruction.2 Additionally, particulate matter may also shed from the ruptured atherosclerotic lesion.2 Altogether, the release of microemboli, which occurs while a plaque is active and can last for hours, days or weeks, leads to microvascular obstruction in the myocardium, brain or peripheral tissues, resulting for example in cardiac insufficiency or vascular dementia.2 Adapted from: Topol EJ, Yadav JS. Circulation 2000; 101: 570–80, and Falk E et al. Circulation 1995; 92: 657–71. References: 1. Topol EJ, Yadav JS. Circulation 2000; 101: 570–80. 2. Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6.

Atherothrombosis* is a Leading Cause of Death Worldwide†1 L’aterotrombosi è la condizione sottostante che sfocia in eventi che conducono ad infarto del miocardio, stroke ischemico e morte vascolare. Come tale, è la principale causa di morte nel mondo intero, manifestandosi come malattia cardiovascolare, cardiopatia sichemica ed istus. Altre importanti cause di morte erano (2002) AIDS (5,1%) Malattie respiratorie (6%) Morte violenta (9,1%) Tumori (12,6%) Malattie infettive (17,8%) Mortality (%) *Cardiovascular disease, ischemic heart disease and cerebrovascular disease †Worldwide defined as Member States by WHO Region (African, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific) 1. The World Health Report 2002. Geneva: WHO; 2002. Reference: 1. The World Health Report 2001. Geneva: WHO; 2001.

Identifying Those at Risk of Atherothrombosis1,2 Local factors: Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 Blood flow patterns, vessel diameter, arterial wall structure Systemic conditions History of vascular events Hypertension Hyperlipidemia Hypercoagulable states Homocystinemia Atherothrombosis manifestations (myocardial infarction, stroke, vascular death) Generalised disorders Obesity Diabetes L’aterosclerosi è una malattia che si sviluppa per diverse decadi – fattori di rischio quali fumo, ipertensione, iperlipemia e diabte possono promuoverne lo sviluppo. Questi fattori di rischio sono estremamemnte comuni nelle società occidentali e sono in incremento nei paesi di nuova industrializzazione. L’ipetrensione interessa circa il 40% degli adulti sopra i 40 anni L’obesità si ritrova in circa il 50% della popolazione adulta degli stati uniti Il diabete in circa il 7% dei paesi ad economia occidentale La presenza di fatty streaks arteriose e di placche fibrosi che si possono ritrovare anche al di sotto dei vent’anni di età rappresentano un ulteriore fattore di rischio La presentazione dei multipli fattori di rischio per l’aterotrombosi sottolinea semplicemente l’importanza di una malattia che rappresenta la più importante causa di morte nel mondo. Atherosclerosis is a disease that develops over several decades – risk factors such as smoking, hypertension, hyperlipidemia and diabetes can promote its development.1 These risk factors are extremely common in Western communities and increasingly in the new industrialized nations: hypertension affects about 40% of adults over 40 years of age obesity affects over 50% of the adult population of the US diabetes affects up to 7% of the population in Western communities. The presence of arterial fatty streaks and fibrous plaques, which can be found in individuals in their teens and twenties, is also an indicator of risk.2 This presentation of the multiple risk factors for atherothrombosis simply highlights the importance of a disease that is the leading cause of death worldwide. Genetic Genetic traits Gender Age Lifestyle Smoking Diet Lack of exercise 1. Yusuf S et al. Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. References: 1. Yusuf S et al. Circulation 2001; 104: 2746–53. 2. McNamara JJ et al. JAMA 1971; 216: 1185–7.

Il fumo uccide!

Atherothrombosis is a Systemic Disease: Increased Risk of Stroke in Patients After a Myocardial Infarction1 0.93 1.43 2.08 2.72 3.58 4.17 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 1 2 3 4 5 or more Six month stroke admission rate Number of risk factors Poiché il processo aterosclerotico alla base dell’aterotrombosi è generalizzato e progressivo gli eventi maggiori a carico di un letto vascolare, ad esempio l’infarto del miocardio, sono altamente predittivi del rischio di ulteriori eventi ischemici a carico di altri distretti arteriosi. Per esempio il rischio di ictus dopo IMA è sostanziale, con circa 1 caso su 40 dimessi a 6 mesi di follow-up. Così l’incremento del numero dei fattori di rischio, aumenta l’incidenza di ulteriori eventi ischemici 1. Lichtman JH et al. Circulation 2002; 105: 1082–7. Reference: 1. Lichtman JH et al. Circulation 2002; 105: 1082–7.

Calcificazioni coronariche L’aterosclerosi coronarica è il più comune fattore predisponenete per l’aterostrombosi L’aterosclerosi coronarica è il più comune fattore predisponenete per l’aterostrombosi Le calcificazioni coronariche sono indicative di aterosclerosi avanzata non solo nel letto coronarico, ma anche di malattia cerebrovascolare Coronary atherosclerosis is the most common predisposing factor for atherothrombosis. Coronary calcification is indicative of advanced atherosclerosis not only in the coronary arteries but, in addition, ultimately of cerebrovascular disease.

Atherothrombosis is a Systemic Disease: Long-Term Risk Increase for Stroke As a Function of Coronary Calcification1 3.5 x 3.3 3.0 2.5 2.0 Risk increase 1.5 1.0 1.0 C’è una forte correlazione incremento del calcium score nelle coronarie ed il rischio di ictus a lungo termine, a favore del fatto che l’aterotrombosi rappresenta una malattia progressiva e generalizzata. There is a strong relationship between increased calcium score in the coronary artery and long-term risk of stroke, further elucidating the principle of atherothrombosis as a generalized and progressive disease. 0.5 0.0 0–100 101–500 > 500 Coronary calcium score 1. Vliegenthart R. Stroke 2002; 33: 462–5. Reference: 1. Vliegenthart R. Stroke 2002; 33: 462–5.

Quintiles of carotid artery media thickness Atherothrombosis is a Systemic Disease: Long-term Risk Increase for Myocardial Infarction as a Function of Carotid Intima Media Thickness1 4.0 x 3.61 3.5 3.0 2.5 Risk increase 2.0 1.5 1.0 1.0 Atherosclerosis of the carotid arteries has a strong correlation with stroke – which is to be expected as the brain is the arterial bed it serves. However, carotid artery atherosclerosis is associated with a similar significant risk of atherothrombotic events in the coronary arteries, demonstrating the generalized nature of atherosclerosis and consequently atherothrombosis. 0.5 0.0 1 2 3 4 5 Quintiles of carotid artery media thickness 1. O’Leary DH. N Engl J Med 1999; 340: 14–22. Reference: 1. O’Leary DH. N Engl J Med 1999; 340: 14–22.

Indice di Winsor (braccio/caviglia)

Atherothrombosis is a Systemic Disease: Increase for Myocardial Infarction and Stroke as a Function of ABI Measurement1 2.5 x 2.2 2.0 Risk increase 1.5 While major vessel disease in the central arteries demonstrates a strong and two way association (i.e. coronary to cerebral, carotid to coronary), with the risk of an ischemic event, the relationship might not be so clear between peripheral arterial disease (PAD) and central arterial disease. However, there is a clear association between the extent of PAD and the risk of myocardial infarction (MI) and stroke (although not as strong as for MI and stroke alone). 1.0 1.0 0.8 0.6 0.4 0.2 Ankle-brachial index (ABI) index 1. Dormandy JA, Creager MA. Cerebrovasc Dis 1999; 9(suppl 1): 14. Reference: 1. Dormandy JA, Creager MA. Cerebrovasc Dis 1999; 9(suppl 1): 14.

Causes of Death During Different Time Intervals after First-Ever Stroke1 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% < 30 days 30d–6m 6m–1yr 1–3yr 3–5yr Time Proportion of deaths (%) Unknown Non-vascular Cardiovascular Recurrent stroke Related to first stroke A second study by Hankey of the 5-year survival rates illustrates that as time after first-ever stroke increases, the proportion of cardiovascular death also increases, which supports the generalized nature of atherothrombosis in the vascular system. 1. Hankey GJ. Stroke 2000; 31: 2080–6. Reference: 1. Hankey G. Stroke 2000; 31: 2080–6.

Peripheral arterial disease Manifestations of Atherothrombosis are Commonly Found in More than One Arterial Bed in an Individual Patient*1 Cerebrovascular disease Coronary disease 24.7% 3.8% 11.8% 29.9% 3.3% 7.4% 19.2% A person suffering from any one manifestation of atherothrombosis is at risk of future disabling or life-threatening events caused by the same underlying disease process.1 The CAPRIE trial enrolled 19,185 patients with either established peripheral arterial disease (PAD),2,3 a recent myocardial infarction or recent ischemic stroke in approximately equal distribution. However, based on the baseline characteristics of these patients, many of them already had a prior history of ischemic events. Thus, at study entry ~26% of the patients had ischemic vascular disease in at least two vascular beds, demonstrating the generalized nature of atherothrombosis.3 For example, 11.8% of patients had both coronary disease and PAD, 7.4% had both coronary and cerebrovascular disease, 3.8% had a combination of cerebrovascular disease and PAD, and 3.3% had disease of all three arterial beds.3 Over time this overlap will most probably increase (in the CAPRIE trial more than 2,000 patients experienced a major ischemic event over the mean 1.9 year follow-up, and many others developed other ischemic events such as transient ischemic attack and angina).3 Peripheral arterial disease *Data from CAPRIE study (n=19,185) 1. Coccheri S. Eur Heart J 1998; 19(suppl): P1268. References: 1. Lichtman JH et al. Circulation 2002; 105: 1082–7. 2. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39. 3. Coccheri S. Eur Heart J 1998; 19(suppl): P1268.

Conclusioni L’Aterotrombosi è caratterizzata da un’improvvisa rottura di placca che determina attivazione piastrinica e formazione del trombo1 L’aterotrombosi rappresenta il legame patologico comune a tutte le maggiori manifestazioni cliniche delle malattie vascolari: infarto del miocardio, ictus ischemico ed ateriopatia obliterante periferica2 Pazienti con manifestazioni cliniche di aterotrombosi in un letto vascolare non sono solo a rischio di un evento ricorrente nella stessa distribuzione arteriosa, ma corrono il rischio di eventi ischemici anche in altri letti vascolari3 L’Aterotrombosi è la maggiore causa di mortalità nel mondo intero4 Atherothrombosis is characterized by a sudden plaque disruption leading to platelet activation and thrombus formation.1 Atherothrombosis is a global disease and is the common pathological link between myocardial infarction, ischemic stroke and peripheral arterial disease – the main clinical manifestations of vascular ischemia.2 Patients with a clinical manifestation of atherothrombosis are at risk of subsequent events. Since atherothrombosis often reflects disseminated atherosclerosis, the subsequent events may occur not only in the same arterial distribution but also in other vascular beds.3 The health burden of atherothrombosis is considerable, and the disease is one of the leading causes of death worldwide.4 1. Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. 2. Nenci GG. Eur Heart J 1999; 1(suppl A): A27–A30. 3. Lichtman JH et al. Circulation 2002; 105: 1082–7. 4. The World Health Report 2002. Geneva: WHO; 2002. References: 1. Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. 2. Nenci GG. Eur Heart J 1999; 1(suppl A): A27–A30. 3. Lichtman JH et al. Circulation 2002; 105: 1082–7. 4. The World Health Report 2001. Geneva: WHO; 2001.