ANGINA PECTORIS Che cos Dolore toracico costrittivo angor o anginadolore come morsa che stringe per ischemia miocard

1. 1 ANGINA PECTORIS Che cos��? Dolore toracico costrittivo (angor o angina=dolore come morsa che stringe) per ischemia miocardica dovuta nella maggioranza dei casi ad aterosclerosi coronarica

2. Pathophysiology of Acute Coronary Syndromes Slide 4 Pathophysiology of ACS Various factors affect the risk that an atherosclerotic plaque will rupture, including the tensile strength of the fibrous cap and the shear stresses to which it is subjected. Unstable plaques at high risk of rupture typically have a large lipid core, a thin cap and contain large numbers of macrophages, but relatively few smooth muscle cells. Rupture or fissure of the plaque exposes the thrombogenic core of the lesion and leads to adhesion and aggregation of platelets and thrombus formation. A large fissure typically results in the formation of a large thrombus that completely occludes the coronary artery, causing acute MI, characterized by persistent ST-segment elevation and subsequent development of new Q waves on the electrocardiogram (ECG). A smaller fissure may result in a mural thrombus that partially or transiently occludes the artery, causing acute myocardial ischemia without persistent ST-segment elevation. The clinical diagnosis is unstable angina, or if there is biochemical evidence of myocardial damage, non-Q-wave MI. ACS is a classic example of atherothrombosis (plaque rupture and thrombus formation). Slide 4 Pathophysiology of ACS Various factors affect the risk that an atherosclerotic plaque will rupture, including the tensile strength of the fibrous cap and the shear stresses to which it is subjected. Unstable plaques at high risk of rupture typically have a large lipid core, a thin cap and contain large numbers of macrophages, but relatively few smooth muscle cells. Rupture or fissure of the plaque exposes the thrombogenic core of the lesion and leads to adhesion and aggregation of platelets and thrombus formation. A large fissure typically results in the formation of a large thrombus that completely occludes the coronary artery, causing acute MI, characterized by persistent ST-segment elevation and subsequent development of new Q waves on the electrocardiogram (ECG). A smaller fissure may result in a mural thrombus that partially or transiently occludes the artery, causing acute myocardial ischemia without persistent ST-segment elevation. The clinical diagnosis is unstable angina, or if there is biochemical evidence of myocardial damage, non-Q-wave MI. ACS is a classic example of atherothrombosis (plaque rupture and thrombus formation).

3. 3 Angina pectoris Da che cosa � causata? Ischemia del miocardio: apporto di sangue temporaneamente insufficiente rispetto alle necessit� metaboliche fabbisogno di sangue e quindi di O2 aumenta se aumenta lavoro del cuore: - sforzo fisico - digestione - emozione - stress - esposizione al freddo - passaggio da posizione eretta a sdraiata (aumento ritorno venoso)

4. 4 Angina pectoris Che cos��? ischemia: apporto di sangue insufficiente rispetto alle necessit� metaboliche Apporto diminuisce per ostacolo al flusso ostacolo se riduzione calibro art. > 70% ? flusso ad una zona localizzata con alterazione metabolismo e quindi funzione DOLORE (accumulo metaboliti da sofferenza cellulare)

5. 5 Cause di angina pectoris ateroma coronarico con stenosi (restringimento) lume valvulopatie aortiche stenosi aortica insufficienza aortica

6. 6 Dolore tipico di angina pectoris retrosternale,mediano, costrittivo, opprimente, irradiato alle braccia,collo mandibola provocato da sforzo (riproducibile con stessa entit� di sforzo) o emozione Durata < 30 m� cessa con riposo ( riduzione lavoro cuore) e con nitroglicerina sublinguale

7. 7 INFARTO ACUTO DEL MIOCARDIO occlusione acuta delle coronarie con persistente ? flusso ematico coronarico sofferenza grave del miocardio fino a morte cellule ovvero necrosi

8. 8 INFARTO ACUTO DEL MIOCARDIO Cause ateroma riduce calibro vaso placca si fessura ? trombo occludente area del miocardio privata di irrorazione di sangue e quindi di O2 (arterie terminali) cellule miocardiche: sofferenza reversibile e poi irreversibile con morte necrosi di tutto lo spessore di parete:transmurale localizzato: nell�area irrorata da arteria colpita

9. 9 Infarto acuto del miocardio Dolore retrosternale, mediano, costrittivo, opprimente, irradiato al le braccia, collo mandibola, intenso accompagnato da nausea e senso di angoscia durata > 30 m�, non cessa con riposo n� con nitroglicerina sublinguale

10. 10 Infarto acuto del miocardio alle volte sintomi atipici: dolore dorsale sintomi digestivi ( specie infarto inferiore) Sudorazione profusa oppure sincopi, tachicardia ventricolare, insufficienza vn. Sn. Improvvisa, edema polmonare, morte improvvisa

11. 11 COMPLICANZE DI INFARTO ACUTO DEL MIOCARDIO Precoci a livello delle cellule: danno reversibile e poi irreversibile 1- perdita attivit� contrattile tanto maggiore quanto maggiore � area infartuata se si perde > 25-30% ? insufficienza vn. Sn acuta con edema polmonare 2- ischemia muscoli papillari disfunzione valvolare ? insufficienza mitralica acuta 3- alterazione eccitabilit� con rischio di aritmie ? Fibrillazione ventricolare: fatale o blocco atrio-ventricolare per danno nodo del seno 4- tessuto necrotico � fragile ? rischio rottura di cuore

12. 12 COMPLICANZE DI INFARTO ACUTO DEL MIOCARDIO Tardive: 1 - perdita attivit� contrattile: quanto maggiore � area infartuata se si perde > 25-30% ? insufficienza vn. Sn cronica 2 - alterazione eccitabilit� con rischio di aritmie ? tachicardie o fibrillazione vn con morte improvvisa

13. 13 Conseguenze di infarto acuto del miocardio Tardive: 3 - trasformazione in cicatrice fibrosa area cicatriziale non pi� mobile perdita attivit� contrattile ? dilatazione ? aneurisma post-infartuale 4 - trombosi intracardiaca: su aree poco o non mobili: ? embolie periferiche 5- recidiva angina, infarto

14. 14 Trattamento: immediato ricovero ospedale in unit� di terapia intensiva coronarica scopo: ripristinare al pi� presto perviet� vaso occluso con lisi del trombo = trombolisi oppure con angioplastica coronarica trattamento di complicanze precoci soprattutto aritmie potenzialmente fatali

15. 15 Trattamento: scopo: ripristinare al pi� presto perviet� vaso occluso con ripresa della irrorazione ematica dell�area ischemica 1- lisi (dissoluzione) del trombo = trombolisi Sommistrazione farmaci trombolitici o fibrinolitici per via endovenosa

16. 16 Trattamento:copo: ripristinare al pi� presto perviet� vaso occluso Angioplastica Percutanea Transluminale Coronarica

17. 17 Trattamento: scopo: ripristinare al pi� presto perviet� vaso occluso angioplastica transluminale percutanea coronarica + stent coronarici

18. 18 Trattamento: scopo: ripristinare perviet� vaso By- pass aorto coronarico

19. 19 RUOLO DEL LABORATORIO NELL�INFARTO ACUTO DEL MIOCARDIO: DIAGNOSI Diagnosi richiede almeno 2 di 3 criteri: 1- sintomi tipici 2- alterazioni dell�ECG (elettrocardiogramma) 3-aumento degli indici di necrosi miocardica ovvero enzimi cardiaci o markers cardiaci The ideal marker of myocardial injury would provide early diagnosis, assessment of the success of reperfusion after thrombolytic therapy, detection of re-occlusion and re-infarctions, determination of infarct size, and detection of perioperative MI during cardiac or noncardiac surgery. Acceptable biochemical markers of ischemic heart disease are now considered to include myoglobin, CK-MB, total CK, and cardiac troponins T and I. The ideal marker of myocardial injury would provide early diagnosis, assessment of the success of reperfusion after thrombolytic therapy, detection of re-occlusion and re-infarctions, determination of infarct size, and detection of perioperative MI during cardiac or noncardiac surgery. Acceptable biochemical markers of ischemic heart disease are now considered to include myoglobin, CK-MB, total CK, and cardiac troponins T and I.

20. 20 INDICI DI NECROSI MIOCARDICA Il miocardio contiene fasci di fibre muscolari striate composte da proteine contrattili (actina e miosina), proteine regolatorie (troponine and tropomiosina), e proteine che sono richieste per la conversione dell�energia chimica in lavoro (contrazione), ovvero mioglobina; ed enzimi quali creatina chinasi e lattico deidrogenasi. The myocardium contains bundles of striated muscle fibers that are composed of cardiac-specific contractile proteins (actin and myosin), regulatory proteins (troponins and tropomyosin), and proteins that are required for the conversion of chemical energy into work (muscle contraction), i.e., myoglobin; and the enzymes creatine kinase and lactate dehydrogenase. Cardiac tissue injury may cause these proteins to be released into the circulation; they therefore serve as biochemical markers of cardiac injury. Some of these cardiac markers are also useful for the noninvasive assessment of thrombolytic therapy undertaken in attempts to dissolve the obstruction in the blood vessel. Restoration of blood flow (reperfusion) causes high concentrations of previously trapped markers to be washed out of the affected area and released into the circulation. A rapid rise of the markers during the 60- to 90-minute period after initiation of thrombolytic therapy signals successful reperfusion. Absence of a characteristic rise alerts the clinician to consider alternative therapies. � The myocardium contains bundles of striated muscle fibers that are composed of cardiac-specific contractile proteins (actin and myosin), regulatory proteins (troponins and tropomyosin), and proteins that are required for the conversion of chemical energy into work (muscle contraction), i.e., myoglobin; and the enzymes creatine kinase and lactate dehydrogenase. Cardiac tissue injury may cause these proteins to be released into the circulation; they therefore serve as biochemical markers of cardiac injury. Some of these cardiac markers are also useful for the noninvasive assessment of thrombolytic therapy undertaken in attempts to dissolve the obstruction in the blood vessel. Restoration of blood flow (reperfusion) causes high concentrations of previously trapped markers to be washed out of the affected area and released into the circulation. A rapid rise of the markers during the 60- to 90-minute period after initiation of thrombolytic therapy signals successful reperfusion. Absence of a characteristic rise alerts the clinician to consider alternative therapies. �

21. 21 INDICI DI NECROSI MIOCARDICA Dopo infarto del miocardio alcune proteine cellulari passano in circolo dal muscolo danneggiato o necrotico per alterazione della permeabilit� delle membrane cellulari Queste proteine servono come markers biochimici di lesione cardiaca. La velocit� di passaggio in circolo di queste proteine dipende dalla sede, peso molecolare e flusso ematico e linfatico The myocardium contains bundles of striated muscle fibers that are composed of cardiac-specific contractile proteins (actin and myosin), regulatory proteins (troponins and tropomyosin), and proteins that are required for the conversion of chemical energy into work (muscle contraction), i.e., myoglobin; and the enzymes creatine kinase and lactate dehydrogenase. Cardiac tissue injury may cause these proteins to be released into the circulation; they therefore serve as biochemical markers of cardiac injury. Some of these cardiac markers are also useful for the noninvasive assessment of thrombolytic therapy undertaken in attempts to dissolve the obstruction in the blood vessel. Restoration of blood flow (reperfusion) causes high concentrations of previously trapped markers to be washed out of the affected area and released into the circulation. A rapid rise of the markers during the 60- to 90-minute period after initiation of thrombolytic therapy signals successful reperfusion. Absence of a characteristic rise alerts the clinician to consider alternative therapies. � The myocardium contains bundles of striated muscle fibers that are composed of cardiac-specific contractile proteins (actin and myosin), regulatory proteins (troponins and tropomyosin), and proteins that are required for the conversion of chemical energy into work (muscle contraction), i.e., myoglobin; and the enzymes creatine kinase and lactate dehydrogenase. Cardiac tissue injury may cause these proteins to be released into the circulation; they therefore serve as biochemical markers of cardiac injury. Some of these cardiac markers are also useful for the noninvasive assessment of thrombolytic therapy undertaken in attempts to dissolve the obstruction in the blood vessel. Restoration of blood flow (reperfusion) causes high concentrations of previously trapped markers to be washed out of the affected area and released into the circulation. A rapid rise of the markers during the 60- to 90-minute period after initiation of thrombolytic therapy signals successful reperfusion. Absence of a characteristic rise alerts the clinician to consider alternative therapies. �

22. 22 INDICI DI NECROSI MIOCARDICA Il marker ideale di lesione miocardica dovrebbe consentire: Diagnosi precoce Valutazione del successo della riperfusione dopo trombolisi (riperfusione comporta aumento dei livelli dei markers che vengono trasportati in circolo dall�area ischemica. Un aumento rapido durante il 60-90 min. dopo terapia trombolitica inidca riperfusione ottenuta) Valutazione della ri-occlusione e del re-infarto Valutazione dell�estensione dell�infarto Valutazione dell�infarto peri-operatorio durante chirurgia cardiaca e non cardiaca. The myocardium contains bundles of striated muscle fibers that are composed of cardiac-specific contractile proteins (actin and myosin), regulatory proteins (troponins and tropomyosin), and proteins that are required for the conversion of chemical energy into work (muscle contraction), i.e., myoglobin; and the enzymes creatine kinase and lactate dehydrogenase. Cardiac tissue injury may cause these proteins to be released into the circulation; they therefore serve as biochemical markers of cardiac injury. Some of these cardiac markers are also useful for the noninvasive assessment of thrombolytic therapy undertaken in attempts to dissolve the obstruction in the blood vessel. Restoration of blood flow (reperfusion) causes high concentrations of previously trapped markers to be washed out of the affected area and released into the circulation. A rapid rise of the markers during the 60- to 90-minute period after initiation of thrombolytic therapy signals successful reperfusion. Absence of a characteristic rise alerts the clinician to consider alternative therapies. � The myocardium contains bundles of striated muscle fibers that are composed of cardiac-specific contractile proteins (actin and myosin), regulatory proteins (troponins and tropomyosin), and proteins that are required for the conversion of chemical energy into work (muscle contraction), i.e., myoglobin; and the enzymes creatine kinase and lactate dehydrogenase. Cardiac tissue injury may cause these proteins to be released into the circulation; they therefore serve as biochemical markers of cardiac injury. Some of these cardiac markers are also useful for the noninvasive assessment of thrombolytic therapy undertaken in attempts to dissolve the obstruction in the blood vessel. Restoration of blood flow (reperfusion) causes high concentrations of previously trapped markers to be washed out of the affected area and released into the circulation. A rapid rise of the markers during the 60- to 90-minute period after initiation of thrombolytic therapy signals successful reperfusion. Absence of a characteristic rise alerts the clinician to consider alternative therapies. �

23. 23 DIAGNOSI DI INFARTO ACUTO DEL MIOCARDIO E� possibile misurare queste proteine nel plasma per avere indicazione su presenza ed entit� del danno cellulare Creatina (fosfo)chinasi (CK o CPK) Creatina (fosfo)chinasi isoenzima (CK-MB) Troponine cardiache T (cTnT) e I (cTnI) Mioglobina Latticodeidrogenasi Oggi anche metodi su sangue intero al letto del malato The myocardium contains bundles of striated muscle fibers that are composed of cardiac-specific contractile proteins (actin and myosin), regulatory proteins (troponins and tropomyosin), and proteins that are required for the conversion of chemical energy into work (muscle contraction), i.e., myoglobin; and the enzymes creatine kinase and lactate dehydrogenase. Cardiac tissue injury may cause these proteins to be released into the circulation; they therefore serve as biochemical markers of cardiac injury. Some of these cardiac markers are also useful for the noninvasive assessment of thrombolytic therapy undertaken in attempts to dissolve the obstruction in the blood vessel. Restoration of blood flow (reperfusion) causes high concentrations of previously trapped markers to be washed out of the affected area and released into the circulation. A rapid rise of the markers during the 60- to 90-minute period after initiation of thrombolytic therapy signals successful reperfusion. Absence of a characteristic rise alerts the clinician to consider alternative therapies. � The myocardium contains bundles of striated muscle fibers that are composed of cardiac-specific contractile proteins (actin and myosin), regulatory proteins (troponins and tropomyosin), and proteins that are required for the conversion of chemical energy into work (muscle contraction), i.e., myoglobin; and the enzymes creatine kinase and lactate dehydrogenase. Cardiac tissue injury may cause these proteins to be released into the circulation; they therefore serve as biochemical markers of cardiac injury. Some of these cardiac markers are also useful for the noninvasive assessment of thrombolytic therapy undertaken in attempts to dissolve the obstruction in the blood vessel. Restoration of blood flow (reperfusion) causes high concentrations of previously trapped markers to be washed out of the affected area and released into the circulation. A rapid rise of the markers during the 60- to 90-minute period after initiation of thrombolytic therapy signals successful reperfusion. Absence of a characteristic rise alerts the clinician to consider alternative therapies. �

24. 24 MARKERS DI NECROSI MIOCARDICA CREATINA FOSFOCHINASI (CK o CPK) Creatina chinasi MB (isoenzyme - CK-MB)  Il ruolo fisiologico � mantenere una adeguata riserva di creatina fosforilata, che � necessaria per ripristinare i livelli di ATP esauriti durante la contrazione muscolare. CK � composta da 2 subunit� B ed M (B- brain: cervello e M o muscolo). ciascuna con peso molecolare di 43 kDa . Enzyme CK has three isoforms composed of two chains (M and B chains), MM, MB and BB. The MB fraction is found predominantly in cardiac muscle. It is important to show both a rise in the serum concentration of CK-MB, and a rise in the ratio of CK-MB to total CK to diagnose MI. Furthermore, it is important to obtain serial samples for CK-MB and total CK from a patient with suspected MI to demonstrate a rise or fall in isoenzyme concentration. Typically, CK-MB begins to rise 4-8 hours after the MI, peaks within the first 24 hours, and can be used to establish the diagnosis of the MI. The CK-MB returns to normal range after 48-72 hours. Enzyme CK has three isoforms composed of two chains (M and B chains), MM, MB and BB. The MB fraction is found predominantly in cardiac muscle. It is important to show both a rise in the serum concentration of CK-MB, and a rise in the ratio of CK-MB to total CK to diagnose MI. Furthermore, it is important to obtain serial samples for CK-MB and total CK from a patient with suspected MI to demonstrate a rise or fall in isoenzyme concentration. Typically, CK-MB begins to rise 4-8 hours after the MI, peaks within the first 24 hours, and can be used to establish the diagnosis of the MI. The CK-MB returns to normal range after 48-72 hours.

25. 25 MARKERS DI NECROSI MIOCARDICA CREATINA FOSFOCHINASI (CK o CPK) Tre isoenzimi risultano dall�accoppiamento di due differenti subunit� (B- brain: cervello e M o muscolo). CK-MM predomina nel muscolo scheletrico (~ 99% della CK totale) e muscolo cardiaco (~ 55% della CK totale) CK-BB predomina nel cervello (> 90% della CK totale) CK-MB � prevalente nel muscolo cardiaco (fino al ~ 45% della CK totale). Enzyme CK has three isoforms composed of two chains (M and B chains), MM, MB and BB. The MB fraction is found predominantly in cardiac muscle. It is important to show both a rise in the serum concentration of CK-MB, and a rise in the ratio of CK-MB to total CK to diagnose MI. Furthermore, it is important to obtain serial samples for CK-MB and total CK from a patient with suspected MI to demonstrate a rise or fall in isoenzyme concentration. Typically, CK-MB begins to rise 4-8 hours after the MI, peaks within the first 24 hours, and can be used to establish the diagnosis of the MI. The CK-MB returns to normal range after 48-72 hours. Enzyme CK has three isoforms composed of two chains (M and B chains), MM, MB and BB. The MB fraction is found predominantly in cardiac muscle. It is important to show both a rise in the serum concentration of CK-MB, and a rise in the ratio of CK-MB to total CK to diagnose MI. Furthermore, it is important to obtain serial samples for CK-MB and total CK from a patient with suspected MI to demonstrate a rise or fall in isoenzyme concentration. Typically, CK-MB begins to rise 4-8 hours after the MI, peaks within the first 24 hours, and can be used to establish the diagnosis of the MI. The CK-MB returns to normal range after 48-72 hours.

26. 26 Markers di necrosi miocardica CREATINA FOSFOCHINASI (CK o CPK) aumenta entro 4-8 h e torna al normale dopo 48-72 h Ma Non specifica per il muscolo cardiaco Aumenta anche dopo danno del muscolo scheletrico (ad es. traumi, iniezioni IM x 2-3 volte) CPK isoenzima MB: pi� specifico per miocardio

27. 27 Markers di necrosi miocardica CREATINA FOSFOCHINASI (CK o CPK) CPK isoenzima MB: pi� specifico per miocardio Dopo infarto , livelli elevati di CK-MB appaiono entro 3 - 8 ore con picco tra 9-30 ore livelli tornano alla normalit� dopo 48-72 ore. E� importante mostrare aumento sia CK-MB, e un aumento del rapporto tra CK-MB e CK totale per la diagnosi di infarto. E� inoltre necessario avere prelievi seriati per CK-MB e CK totale in un paziente con sospetto IMA per dimostrare salita o diminuzione nella concentrazioni dell�isoenzima.

28. 28 Troponin I is the subunit of the troponin complex that binds actin and inhibits actomyosin ATPase activity in the absence of calcium (http://sbweb.med.harvard. edu/~bcmp/sm_gergely.gif). Three isoforms of troponin I have been described, one cardiac (cTnI), and two skeletal muscle (slow twitch, sTnI, and fast twitch, fTnI) . Each of the three TnI isoforms is encoded by different genes located on different chromosomes. cTnI gene locus maps to 19q13.4. cTnI (MW 24 kDa) and is a unique protein that is different form either fTnI or sTnI (MW 19.8 kDa) because of the presence of additional 31 amino acids at the N-terminal region. Unlike CK-MB, cardiac troponins are not found in serum from healthy people. These facts make cTnI an excellent biochemical marker for detection of myocardial injury. cTnI has been shown to be a very sensitive and specific marker for acute MI. It can be detected within 4-8 hrs after the onset of symptoms. Therefore, cTnI does not provide an earlier detection of AMI than CK-MB. cTnI peaks between 14-36 hrs after onset of AMI and remains elevated for 5-7 days after AMI. Due to long duration of increase of cTnI following onset of chest pain, it could replace LD-2 isoenzyme for the detection of late presenting AMI patients. Additionally, recent studies demonstrate that cTnI is more sensitive than the LD1/LD2 ratio. The time course of cTnI is affected by re-perfusion, which leads to a more rapid increase, a higher rate of increase, and earlier peak values. This dependence of troponin time course on reperfusion can be used for monitoring the effectiveness of reperfusion therapy. cTnI seems to be of value in determining whether elevations of CK-MB are indicative of myocardial injury or represent skeletal muscle damage in patients with neuromuscular disorders. Troponin I in patients with coronary syndromes permits the early identification of patients with increased risk of MI and cardiac death. Many studies have determined the importance of increased cTnI for the detection of cardiac injury in several patient groups that have often shown falsely increased CK-MB. These groups have included patients with chest and muscle trauma, with cocaine-associated chest pain, in the critically ill, intensive care patients, and in patients with renal disease. cTnI has proved to be a diagnostic and prognostic marker for myocardial damage with high diagnostic sensitivity and specificity. It is a powerful tool for risk stratification and management of patients with unstable angina, even in the presence of normal CK and CK-MB values. Recently, some newer biochemical markers of myocardial injury are being used. One of earliest markers is myoglobin, which is very sensitive but, in certain clinical settings, lacks specificity. An example of that is Case 1, where muscle (not just myocardial) injury would case a myoglobin level increase that would be difficult to interpret. Additional difficulties are present in patients with renal failure, where use of serum myoglobin/carbonic anhydrase III has been advocated by some authors, as myoglobin itself is not reliable enough. Its diagnostic value is primarily due to its early appearance. These 2 cases demonstrates that cardiac enzyme measurements are a necessary part of the full evaluation of patients with suspected cardiac events, and that such test results can be used for diagnostic purposes as well as for follow up and confirmation of clinical diagnosis. Troponin I is the subunit of the troponin complex that binds actin and inhibits actomyosin ATPase activity in the absence of calcium (http://sbweb.med.harvard. edu/~bcmp/sm_gergely.gif). Three isoforms of troponin I have been described, one cardiac (cTnI), and two skeletal muscle (slow twitch, sTnI, and fast twitch, fTnI) . Each of the three TnI isoforms is encoded by different genes located on different chromosomes. cTnI gene locus maps to 19q13.4. cTnI (MW 24 kDa) and is a unique protein that is different form either fTnI or sTnI (MW 19.8 kDa) because of the presence of additional 31 amino acids at the N-terminal region. Unlike CK-MB, cardiac troponins are not found in serum from healthy people. These facts make cTnI an excellent biochemical marker for detection of myocardial injury. cTnI has been shown to be a very sensitive and specific marker for acute MI. It can be detected within 4-8 hrs after the onset of symptoms. Therefore, cTnI does not provide an earlier detection of AMI than CK-MB. cTnI peaks between 14-36 hrs after onset of AMI and remains elevated for 5-7 days after AMI. Due to long duration of increase of cTnI following onset of chest pain, it could replace LD-2 isoenzyme for the detection of late presenting AMI patients. Additionally, recent studies demonstrate that cTnI is more sensitive than the LD1/LD2 ratio. The time course of cTnI is affected by re-perfusion, which leads to a more rapid increase, a higher rate of increase, and earlier peak values. This dependence of troponin time course on reperfusion can be used for monitoring the effectiveness of reperfusion therapy. cTnI seems to be of value in determining whether elevations of CK-MB are indicative of myocardial injury or represent skeletal muscle damage in patients with neuromuscular disorders. Troponin I in patients with coronary syndromes permits the early identification of patients with increased risk of MI and cardiac death. Many studies have determined the importance of increased cTnI for the detection of cardiac injury in several patient groups that have often shown falsely increased CK-MB. These groups have included patients with chest and muscle trauma, with cocaine-associated chest pain, in the critically ill, intensive care patients, and in patients with renal disease. cTnI has proved to be a diagnostic and prognostic marker for myocardial damage with high diagnostic sensitivity and specificity. It is a powerful tool for risk stratification and management of patients with unstable angina, even in the presence of normal CK and CK-MB values. Recently, some newer biochemical markers of myocardial injury are being used. One of earliest markers is myoglobin, which is very sensitive but, in certain clinical settings, lacks specificity. An example of that is Case 1, where muscle (not just myocardial) injury would case a myoglobin level increase that would be difficult to interpret. Additional difficulties are present in patients with renal failure, where use of serum myoglobin/carbonic anhydrase III has been advocated by some authors, as myoglobin itself is not reliable enough. Its diagnostic value is primarily due to its early appearance. These 2 cases demonstrates that cardiac enzyme measurements are a necessary part of the full evaluation of patients with suspected cardiac events, and that such test results can be used for diagnostic purposes as well as for follow up and confirmation of clinical diagnosis.

29. 29 Markers di necrosi miocardica CPK isoenzima MB Misurazione CPK totale e CPK �MB: Se CPK_MB > 2.5% del CPK totale : indicativo di danno miocardico si eseguono determinazioni seriate del CPK-MB: picco a 20 ore dall�infarto miocardico e poi decremento Utile per diagnosi di infarto miocardico acuto nelle prime 48-72 ore

30. 30 Markers di necrosi miocardica Quantit� di proteina totale: correlata con estensione tessuto leso, picco dei livelli si correla solo debolmente con entit� lesione miocardica Si esegue misurazione seriata di CPK ed CPK MB per valutare andamento ed eventuale ricanalizzazione che si accompagna a picco precoce

31. 31

32. 32

33. 33 cTnT and cTnI encoded by individual genes producing unique amino acid sequences hence immunoassays developed for them. Cardiac troponin I (cTnI)1�4,6,8,10 Troponin is a complex consisting of three single-chain polypeptides: troponin-I, which prevents muscle contraction in the absence of calcium; troponin-T, which connects the troponin complex to tropomyosin; and troponin-C, which binds calcium. Together with tropomyosin and under the influence of calcium, troponin regulates muscle contraction. The cardiac muscle-specific isoform cTnI (24 kDa) exhibits approximately 60 percent homology with the skeletal isoforms (sTnI), and has a unique 31 amino acid extension of the N-terminus.1,10 After myocardial infarction, elevated cTnI levels appear within 3 to 6 hours. Levels peak within 14 to 20 hours, and return to normal after 5 to 7 days.6 cTnI becomes elevated later than myoglobin and, like CK-MB, does not meet the criteria for an early marker. However, the longer return to normal extends the time frame over which this marker can be used beyond the 48-hour postinfarction limitation of CK-MB. Serial determinations of cTnI are also useful for assessing reperfusion following thrombolysis cTnT and cTnI encoded by individual genes producing unique amino acid sequences hence immunoassays developed for them. Cardiac troponin I (cTnI)1�4,6,8,10 Troponin is a complex consisting of three single-chain polypeptides: troponin-I, which prevents muscle contraction in the absence of calcium; troponin-T, which connects the troponin complex to tropomyosin; and troponin-C, which binds calcium. Together with tropomyosin and under the influence of calcium, troponin regulates muscle contraction. The cardiac muscle-specific isoform cTnI (24 kDa) exhibits approximately 60 percent homology with the skeletal isoforms (sTnI), and has a unique 31 amino acid extension of the N-terminus.1,10 After myocardial infarction, elevated cTnI levels appear within 3 to 6 hours. Levels peak within 14 to 20 hours, and return to normal after 5 to 7 days.6 cTnI becomes elevated later than myoglobin and, like CK-MB, does not meet the criteria for an early marker. However, the longer return to normal extends the time frame over which this marker can be used beyond the 48-hour postinfarction limitation of CK-MB. Serial determinations of cTnI are also useful for assessing reperfusion following thrombolysis

34. 34 cTnT and cTnI encoded by individual genes producing unique amino acid sequences hence immunoassays developed for them. Cardiac troponin I (cTnI)1�4,6,8,10 Troponin is a complex consisting of three single-chain polypeptides: troponin-I, which prevents muscle contraction in the absence of calcium; troponin-T, which connects the troponin complex to tropomyosin; and troponin-C, which binds calcium. Together with tropomyosin and under the influence of calcium, troponin regulates muscle contraction. The cardiac muscle-specific isoform cTnI (24 kDa) exhibits approximately 60 percent homology with the skeletal isoforms (sTnI), and has a unique 31 amino acid extension of the N-terminus.1,10 After myocardial infarction, elevated cTnI levels appear within 3 to 6 hours. Levels peak within 14 to 20 hours, and return to normal after 5 to 7 days.6 cTnI becomes elevated later than myoglobin and, like CK-MB, does not meet the criteria for an early marker. However, the longer return to normal extends the time frame over which this marker can be used beyond the 48-hour postinfarction limitation of CK-MB. Serial determinations of cTnI are also useful for assessing reperfusion following thrombolysis cTnT and cTnI encoded by individual genes producing unique amino acid sequences hence immunoassays developed for them. Cardiac troponin I (cTnI)1�4,6,8,10 Troponin is a complex consisting of three single-chain polypeptides: troponin-I, which prevents muscle contraction in the absence of calcium; troponin-T, which connects the troponin complex to tropomyosin; and troponin-C, which binds calcium. Together with tropomyosin and under the influence of calcium, troponin regulates muscle contraction. The cardiac muscle-specific isoform cTnI (24 kDa) exhibits approximately 60 percent homology with the skeletal isoforms (sTnI), and has a unique 31 amino acid extension of the N-terminus.1,10 After myocardial infarction, elevated cTnI levels appear within 3 to 6 hours. Levels peak within 14 to 20 hours, and return to normal after 5 to 7 days.6 cTnI becomes elevated later than myoglobin and, like CK-MB, does not meet the criteria for an early marker. However, the longer return to normal extends the time frame over which this marker can be used beyond the 48-hour postinfarction limitation of CK-MB. Serial determinations of cTnI are also useful for assessing reperfusion following thrombolysis

35. 35 Markers di necrosi miocardica TROPONINE CARDIACHE T (cTnT) e I (cTnI): troponin I (cTnI) cardiaca Isoforma specifica per il miocardio (24 kDa) ha circa il 60% di omologia per le isoforme scheletrice (sTnI) In contrasto con tutti gli altri markers cardiaci compresa la cTnT, cTnI non � espressa dal muscolo scheletrico leso o in rigerazione cTnI non aumenta in paz. Con malattie scheletrica o renale Markers con elevatissima specificit� per il miocardio Consente distinzione da altre condizioni con aumento di markers di lesione muscolare The most important characteristic of cTnI, however, is its apparent absolute cardiac specificity. In contrast to all other known cardiac markers including cTnT, cTnI is not expressed in fetal, diseased or regenerating skeletal muscle.4,11 cTnI is not increased in patients with skeletal muscle or renal disease, and the absolute cardiac specificity of this marker allows its use for the diagnosis of perioperative myocardial infarction. Furthermore, this extraordinary cardiac specificity of cTnI has resolved risk stratification difficulties when interpretation of results for other cardiac markers was severely confounded by conditions unrelated to AMI.12 Among patients with acute coronary syndromes, cTnI levels have been reported to provide prognostic information useful for the early identification of patients with an increased risk of unstable angina progressing to AMI and death.5,13 The most important characteristic of cTnI, however, is its apparent absolute cardiac specificity. In contrast to all other known cardiac markers including cTnT, cTnI is not expressed in fetal, diseased or regenerating skeletal muscle.4,11 cTnI is not increased in patients with skeletal muscle or renal disease, and the absolute cardiac specificity of this marker allows its use for the diagnosis of perioperative myocardial infarction. Furthermore, this extraordinary cardiac specificity of cTnI has resolved risk stratification difficulties when interpretation of results for other cardiac markers was severely confounded by conditions unrelated to AMI.12 Among patients with acute coronary syndromes, cTnI levels have been reported to provide prognostic information useful for the early identification of patients with an increased risk of unstable angina progressing to AMI and death.5,13

36. 36 Markers di necrosi miocardica TROPONINE CARDIACHE T (cTnT) e I (cTnI): Diversa sequenza aminoacidica rispetto a forme scheletriche Test con anticorpi monoclonali cTnT e cTnI: non sono presenti in circolo e sono specifici per miocardio cTnI: pi� specifica perch� cTnT pu� aumentare anche in malattie renali o traumi muscolari The most important characteristic of cTnI, however, is its apparent absolute cardiac specificity. In contrast to all other known cardiac markers including cTnT, cTnI is not expressed in fetal, diseased or regenerating skeletal muscle.4,11 cTnI is not increased in patients with skeletal muscle or renal disease, and the absolute cardiac specificity of this marker allows its use for the diagnosis of perioperative myocardial infarction. Furthermore, this extraordinary cardiac specificity of cTnI has resolved risk stratification difficulties when interpretation of results for other cardiac markers was severely confounded by conditions unrelated to AMI.12 Among patients with acute coronary syndromes, cTnI levels have been reported to provide prognostic information useful for the early identification of patients with an increased risk of unstable angina progressing to AMI and death.5,13 The most important characteristic of cTnI, however, is its apparent absolute cardiac specificity. In contrast to all other known cardiac markers including cTnT, cTnI is not expressed in fetal, diseased or regenerating skeletal muscle.4,11 cTnI is not increased in patients with skeletal muscle or renal disease, and the absolute cardiac specificity of this marker allows its use for the diagnosis of perioperative myocardial infarction. Furthermore, this extraordinary cardiac specificity of cTnI has resolved risk stratification difficulties when interpretation of results for other cardiac markers was severely confounded by conditions unrelated to AMI.12 Among patients with acute coronary syndromes, cTnI levels have been reported to provide prognostic information useful for the early identification of patients with an increased risk of unstable angina progressing to AMI and death.5,13

37. 37 Markers di necrosi miocardica TROPONINE CARDIACHE T (cTnT) e I (cTnI): troponin I (cTnI) cardiaca Dopo infarto acuto, livelli elevati compaiono entro 3 - 6 ore Picco entro 14-20 ore Ritornano al normale dopo 5-7 gg cTnI aumenta dopo mioglobina e non � marker precoce di lesione Ma il calo pi� lento consente di superare il limite delle 48 ore della CK-MB per la diagnosi di IMA The most important characteristic of cTnI, however, is its apparent absolute cardiac specificity. In contrast to all other known cardiac markers including cTnT, cTnI is not expressed in fetal, diseased or regenerating skeletal muscle.4,11 cTnI is not increased in patients with skeletal muscle or renal disease, and the absolute cardiac specificity of this marker allows its use for the diagnosis of perioperative myocardial infarction. Furthermore, this extraordinary cardiac specificity of cTnI has resolved risk stratification difficulties when interpretation of results for other cardiac markers was severely confounded by conditions unrelated to AMI.12 Among patients with acute coronary syndromes, cTnI levels have been reported to provide prognostic information useful for the early identification of patients with an increased risk of unstable angina progressing to AMI and death.5,13 The most important characteristic of cTnI, however, is its apparent absolute cardiac specificity. In contrast to all other known cardiac markers including cTnT, cTnI is not expressed in fetal, diseased or regenerating skeletal muscle.4,11 cTnI is not increased in patients with skeletal muscle or renal disease, and the absolute cardiac specificity of this marker allows its use for the diagnosis of perioperative myocardial infarction. Furthermore, this extraordinary cardiac specificity of cTnI has resolved risk stratification difficulties when interpretation of results for other cardiac markers was severely confounded by conditions unrelated to AMI.12 Among patients with acute coronary syndromes, cTnI levels have been reported to provide prognostic information useful for the early identification of patients with an increased risk of unstable angina progressing to AMI and death.5,13

38. 38

39. 39 Markers di necrosi miocardica TROPONINE CARDIACHE T (cTnT) e I (cTnI): Livelli di cTnI: rimangono elevati per 7-10 gg dopo infarto acuto del miocardio cTnT: rimane elevate per 10-14 gg meno utili per diagnosi fase acuta infarto MIOGLOBINA: rilasciata in circolo nelle prime ore ma rapidamente eliminata dal rene e non � specifica per miocardio

40. 40 Troponin I is the subunit of the troponin complex that binds actin and inhibits actomyosin ATPase activity in the absence of calcium (http://sbweb.med.harvard. edu/~bcmp/sm_gergely.gif). Three isoforms of troponin I have been described, one cardiac (cTnI), and two skeletal muscle (slow twitch, sTnI, and fast twitch, fTnI) . Each of the three TnI isoforms is encoded by different genes located on different chromosomes. cTnI gene locus maps to 19q13.4. cTnI (MW 24 kDa) and is a unique protein that is different form either fTnI or sTnI (MW 19.8 kDa) because of the presence of additional 31 amino acids at the N-terminal region. Unlike CK-MB, cardiac troponins are not found in serum from healthy people. These facts make cTnI an excellent biochemical marker for detection of myocardial injury. cTnI has been shown to be a very sensitive and specific marker for acute MI. It can be detected within 4-8 hrs after the onset of symptoms. Therefore, cTnI does not provide an earlier detection of AMI than CK-MB. cTnI peaks between 14-36 hrs after onset of AMI and remains elevated for 5-7 days after AMI. Due to long duration of increase of cTnI following onset of chest pain, it could replace LD-2 isoenzyme for the detection of late presenting AMI patients. Additionally, recent studies demonstrate that cTnI is more sensitive than the LD1/LD2 ratio. The time course of cTnI is affected by re-perfusion, which leads to a more rapid increase, a higher rate of increase, and earlier peak values. This dependence of troponin time course on reperfusion can be used for monitoring the effectiveness of reperfusion therapy. cTnI seems to be of value in determining whether elevations of CK-MB are indicative of myocardial injury or represent skeletal muscle damage in patients with neuromuscular disorders. Troponin I in patients with coronary syndromes permits the early identification of patients with increased risk of MI and cardiac death. Many studies have determined the importance of increased cTnI for the detection of cardiac injury in several patient groups that have often shown falsely increased CK-MB. These groups have included patients with chest and muscle trauma, with cocaine-associated chest pain, in the critically ill, intensive care patients, and in patients with renal disease. cTnI has proved to be a diagnostic and prognostic marker for myocardial damage with high diagnostic sensitivity and specificity. It is a powerful tool for risk stratification and management of patients with unstable angina, even in the presence of normal CK and CK-MB values. Recently, some newer biochemical markers of myocardial injury are being used. One of earliest markers is myoglobin, which is very sensitive but, in certain clinical settings, lacks specificity. An example of that is Case 1, where muscle (not just myocardial) injury would case a myoglobin level increase that would be difficult to interpret. Additional difficulties are present in patients with renal failure, where use of serum myoglobin/carbonic anhydrase III has been advocated by some authors, as myoglobin itself is not reliable enough. Its diagnostic value is primarily due to its early appearance. These 2 cases demonstrates that cardiac enzyme measurements are a necessary part of the full evaluation of patients with suspected cardiac events, and that such test results can be used for diagnostic purposes as well as for follow up and confirmation of clinical diagnosis. Troponin I is the subunit of the troponin complex that binds actin and inhibits actomyosin ATPase activity in the absence of calcium (http://sbweb.med.harvard. edu/~bcmp/sm_gergely.gif). Three isoforms of troponin I have been described, one cardiac (cTnI), and two skeletal muscle (slow twitch, sTnI, and fast twitch, fTnI) . Each of the three TnI isoforms is encoded by different genes located on different chromosomes. cTnI gene locus maps to 19q13.4. cTnI (MW 24 kDa) and is a unique protein that is different form either fTnI or sTnI (MW 19.8 kDa) because of the presence of additional 31 amino acids at the N-terminal region. Unlike CK-MB, cardiac troponins are not found in serum from healthy people. These facts make cTnI an excellent biochemical marker for detection of myocardial injury. cTnI has been shown to be a very sensitive and specific marker for acute MI. It can be detected within 4-8 hrs after the onset of symptoms. Therefore, cTnI does not provide an earlier detection of AMI than CK-MB. cTnI peaks between 14-36 hrs after onset of AMI and remains elevated for 5-7 days after AMI. Due to long duration of increase of cTnI following onset of chest pain, it could replace LD-2 isoenzyme for the detection of late presenting AMI patients. Additionally, recent studies demonstrate that cTnI is more sensitive than the LD1/LD2 ratio. The time course of cTnI is affected by re-perfusion, which leads to a more rapid increase, a higher rate of increase, and earlier peak values. This dependence of troponin time course on reperfusion can be used for monitoring the effectiveness of reperfusion therapy. cTnI seems to be of value in determining whether elevations of CK-MB are indicative of myocardial injury or represent skeletal muscle damage in patients with neuromuscular disorders. Troponin I in patients with coronary syndromes permits the early identification of patients with increased risk of MI and cardiac death. Many studies have determined the importance of increased cTnI for the detection of cardiac injury in several patient groups that have often shown falsely increased CK-MB. These groups have included patients with chest and muscle trauma, with cocaine-associated chest pain, in the critically ill, intensive care patients, and in patients with renal disease. cTnI has proved to be a diagnostic and prognostic marker for myocardial damage with high diagnostic sensitivity and specificity. It is a powerful tool for risk stratification and management of patients with unstable angina, even in the presence of normal CK and CK-MB values. Recently, some newer biochemical markers of myocardial injury are being used. One of earliest markers is myoglobin, which is very sensitive but, in certain clinical settings, lacks specificity. An example of that is Case 1, where muscle (not just myocardial) injury would case a myoglobin level increase that would be difficult to interpret. Additional difficulties are present in patients with renal failure, where use of serum myoglobin/carbonic anhydrase III has been advocated by some authors, as myoglobin itself is not reliable enough. Its diagnostic value is primarily due to its early appearance. These 2 cases demonstrates that cardiac enzyme measurements are a necessary part of the full evaluation of patients with suspected cardiac events, and that such test results can be used for diagnostic purposes as well as for follow up and confirmation of clinical diagnosis.

41. 41 Biomarker indicators of MI Troponin is preferred biomarker for dx of MI cTnT or cTnI > 99th %ile on any determination CK-MB > 99th %ile on two successivemeasurements or > 2X ULN on any sample Diagnosis MI?

42. 42 Criteria: Biochemical Markers for Detecting Myocardial Necrosis Increased cardiac troponin defined as measurement >99th percentile of reference group Max concentration of cTnT or cTnI exceeding the decision limit (99th percentile for reference control group) at least once during initial 24h after index event. Acceptable imprecision (%CV) at 99th percentile should be defined as ?10%

43. 43 Markers di necrosi miocardica in caso di infarto acuto del miocardio aumentano tutti i markers con andamento diverso In caso di angina pectoris o angina instabile: CPK e CPK-MB nella norma mentre possono aumentare cTnT o cTnI indicativi di microinfarti e di prognosi peggiore oggi non si misura pi� LDH