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Ischemia is characterized by an imbalance between myocardial oxygen supply and demand. In some situations this imbalance is caused by a reduction of blood flow and oxygen supply secondary to increased coronary vascular tone, intracoronary platelet aggregation, or thrombus formation. • This condition, termed supply ischemia or low-flow ischemia, is responsible for myocardial infarction and most episodes of unstable angina. • In other instances, usually in the presence of chronic coronary obstruction, exercise, tachycardia, or emotion leads to an increase in coronary blood flow that is insufficient to meet the rise in myocardial oxygen demand. This condition is termed demand ischemia or high-flow ischemia. It is responsible for many episodes of chronic stable angina. • Typically, myocardial ischemia results from both an increase in oxygen demand and a reduction in myocardial oxygen supply. For example, although exercise leads to an overall increase in coronary blood flow, most of the additional flow is distributed toward the subepicardium, whereas subendocardial blood flow may even drop below its resting level. The ischemia of the subendocardium is then caused by both an increase in myocardial oxygen demand and a reduction in regional blood flow.
Low-flow ischemia, in contrast to high-flow ischemia or hypoxia, is characterized not only by oxygen deprivation but also by inadequate removal of metabolites consequent to reduced perfusion and by loss of vascular turgor. Coronary flow and coronary perfusion pressure augment left ventricular systolic performance (Gregg effect) and reduce left ventricular diastolic distensibility (Salisbury effect). Buildup of tissue metabolites, especially inorganic phosphate, reduces calcium sensitivity of myofilaments, thereby diminishing contractility. Accordingly, in patients with low-flow ischemia, left ventricular systolic performance is lower and left ventricular diastolic distensibility greater than when the same patients were exposed to high-flow ischemia or hypoxia. • Myocardial ischemia may be manifest as anginal discomfort, breathlessness, deviation of the ST segment on the electrocardiogram, reduced uptake of a tracer substance in myocardial perfusion images, or regional or global impairment of ventricular function.
Regolazione del flusso coronaricoConcetti generali • Il flusso coronarico è prevalentemente diastolico • I determinanti del flusso sono il gradiente pressorio e le resistenze coronariche • Il gradiente è dato dalla differenza tra pressione aortica (in diastole) e pressione diastolica in ventricolo sinistro • Esiste una pressione critica di chiusura
Autoregolazione coronarica Flusso massimo Flusso a riposo Riserva coronarica Flusso coronarico totale (ml/m’) 0 100 200 300 25 50 75 100 125 150 Pressione arteriosa (mm Hg)
Autoregolazione coronarica Ipertensione Flusso massimo Flusso x 100 g di Ventricolo ipertrofico Flusso x 100 g di Ventricolo normale Riserva coronarica Flusso a riposo Flusso coronarico totale (ml/m’) 0 100 200 300 50 75 100 125 150 175 200 Pressione arteriosa (mm Hg)
MECHANISMS OF AUTOREGULATION • NITRIC OXIDE. • Evidence suggests a role for NO in coronary autoregulation. Inhibition of NO raises the lower autoregulatory threshold by about 15 mm Hg. The involvement of NO may be related to the ability of the endothelium to sense changes in perfusion pressure through pressure-sensitive ion channels. • MYOGENIC CONTROL. • Arteriolar smooth muscle reacts to increased intraluminal pressure by contracting. The consequent augmentation of resistance tends to return blood flow toward normal despite the higher perfusion pressure. This regulatory mechanism, referred to as myogenic control, is an important mechanism in some vascular beds. Their contribution to autoregulation is relatively small.
NITRIC OXIDE (NO). • This substance increases blood flow during metabolic stimuli. NO production is augmented in response to metabolic stimuli by at least two mechanisms. Hypoxia is a stimulus to release of NO from the endothelium. Furthermore, NO is a principal mediator of flow-mediated dilation. Although hypoxia may initiate hyperemia, flow-mediated dilation sustains and amplifies it. • OTHER METABOLIC MEDIATORS. • Inhibition of the synthesis of vasodilator prostaglandins and inhibition of K+ATP channels also reduces metabolic vasodilation. A loss or inhibition of one mediator is compensated for by upregulation of others. Although the inhibition of K+ATP channels, adenosine, and NO individually has at most a modest effect on the increase in coronary blood flow during exercise in dogs, inhibition of all three simultaneously nearly abolishes the flow increase.
Endotelio: un organo con 2 funzioni Prostaciclina Glycocalice Adenosina Glycocalice EDRF NO Eparina Adenosina Antitrombina III Azione Antiadesione piastrinica Repulsione neutrofili Trombomodulina Azione dilatante Azione Anticoagulante ENDOTHELIAL Cellula endoteliale CELL Azione Procoagulante Azione costrittrice Adesione Proadesione piastrinica Attrazione neutrofili Angiotensina II Fattore IX Endotelina ICAM-1 Fattore X Selectina P Fattore VIII di Von Willebrand
Fattori di derivazione endoteliale Fattori di rilasciamento endotelio-derivati: EDRF • Ossido d’azoto (NO) • Fattore iperpolarizzante endotelio-derivato (EDHF) • Prostaciclina Fattori di contrazione endotelio-derivati: EDCF • Anione superossido • Trombossano • Endoperossidi • Endotelina
Patologia della liberazione di EDRF • Quando le cellule endoteliali scompaiono, vengono rimpiazzate da nuove cellule rigenerate. Tali cellule sono meno capaci di produrre EDRF. • Diversi studi hanno dimostrato una tendenza localizzata ad una esagerata vasocostrizione che è una caratteristica precoce della malattia coronarica nell’uomo. Vanhoutte P, Boulanger MC: “L’endotelio: un ruolo fondamentale nella fisiopatologia cardiovascolare” 1994
L’Endotelio e il tono vascolare 1980: Furchgott e Zawadski scoprono che l’endotelio è essenziale per la vasodilatazione dell’acetilcolina ACETILCOLINA -5 -6 -7 -9 -9 -8 -8 -7 -6 -5 INTATTO DENUDATO 1986: il gruppo di Ignarro e quello di Moncada identificano nel NO (ossido di azoto) il fattore vasodilatante endotelio-dipendente
Transmural Distribution of Myocardial Blood Flow Cross-section of the left ventricular wall in diastole and systole. Factors involved in the susceptibility of the subendocardium to the development of ischemia include the greater dependence of this region on diastolic perfusion and the greater degree of shortening, and therefore of energy expenditure, of this region during systole.
Ischemia subendocardica • Il flusso subendocardico è leggermente maggiore del flusso subepicardico a riposo (rapporto =1,16) • Tuttavia il gradiente di perfusione è minore, e le forze compressive sono maggiori • Ne deriva che questo flusso maggiore è ottenuto per vasodilatazione arteriolare, cioè con riduzione della riserva coronarica
Epicardial coronary stenoses are associated with reductions in the subendocardial to subepicardial flow ratio. Severe pressure-induced left ventricular hypertrophy, as well as heart failure with elevated left ventricular end-diastolic pressure, may also reduce the endocardial-to-epicardial flow ratio. When the markedly elevated left ventricular end-diastolic pressure in heart failure is corrected, subendocardial coronary flow reserve is restored and the endocardial-to-epicardial flow ratio is normalized. Reduction of myocardial oxygen demand, for example by beta blockers, also decreases epicardial blood flow and increases perfusion pressure and thereby flow to the ischemic subendocardial region. Subendocardial ischemia
Effects of Coronary Stenoses • As blood traverses a stenosis, pressure (energy) is lost. Principles of fluid dynamics have been applied to estimate this pressure loss and validated in animals models as well as in patients. Although the formulas are complex, they can been simplified as follows: • where DP is the pressure drop across a stenosis in millimeters of mercury (mm Hg), Q is the flow across the stenosis in milliliters per second, and dsten is the minimal diameter of the stenosis lumen in millimeters
Energy losses across a stenosis. The pressure gradient due to friction losses within the stenosis (DP) is directly proportional to blood flow (Q), whereas separation losses at the exit to the stenosis due to formation of eddies increase with blood flow squared (Q2). Separation losses predominate at high blood flows.
Relation between pressure reduction across a stenosis (DP) and flow through the stenosis (Q)
Relationship between resting (dashed line) and maximal coronary blood flow (solid line) and percentage of diameter stenosis
Riserva coronarica • La riserva coronarica è il rapporto tra il flusso massimale (ottenibile con la vasodilatazione massimale) e il flusso a riposo • Normalmente questo rapporto è circa uguale a 4 • La riserva coronarica comincia a diminuire significativamente per stenosi di circa 60-70%
Valutazione della riserva coronarica • Stimolo alla vasodilatazione massimale (adenosina, dipiridamolo) • Misurazione del flusso coronarico • Diretta: flussimetri intracoronarici • Indiretta: • Ecodoppler • Fractional flow reserve
FFR myo SU DA ADENOSINA i.c 0.84 BASALE 0.86
Coronary Collateral Vessels • COLLATERAL FORMATION (ARTERIOGENESIS) • Preexisting collaterals are normally closed and nonfunctional, because no pressure gradient exists between the arteries they connect. After coronary occlusion, the distal pressure drops precipitously and preexisting collaterals open virtually instantly. The transformation of preexisting collaterals into mature collaterals is called arteriogenesis is characterized by inflammation and cellular proliferation. • MECHANISMS PROMOTING COLLATERAL GROWTH • SHEAR STRESS. • Pressure gradients across preexisting rudimentary collaterals augment blood flow velocity and shear stress. Shear stress induces widespread functional changes in the endothelium, many of which reflect new gene expression. • INFLAMMATION.
Coronary Collateral Vessels (2) • ALTRI FATTORI • Gravità della stenosi • Ipossia • Altri fattori di rischio • Attività fisica • SIGNIFICATO FUNZIONALE • La capacità del circolo collaterale non supera il 50% di quella del circolo nativo (corrisponde quindi ad una stenosi del 70-80%)
Conseguenze metaboliche dell’ischemia • Metabolismo anaerobico: produzione di acido lattico per glicolisi • Deplezione di ATP • Perdita di potassio
Conseguenze emodinamiche dell’ischemia • Alterazioni reversibili: fino a 20-30 m’ • Cascata ischemica: • Disfunzione diastolica • Disfunzione sistolica • Alterazioni ECG • Dolore anginoso • Tempo di recupero inversamente proporzionale alla profondità dell’ischemia • Stunning • Hibernation
Schematic diagram of stunned myocardium During coronary occlusion, a wall motion abnormality of the left ventricle is present in the region supplied by the occluded artery. With relief of ischemia and reestablishment of coronary blood flow, there is a persistent wall motion abnormality despite reperfusion and viable myocytes. There is then gradual improvement in function that requires hours to days for recovery.
Two possible additive components of postischemic dysfunction: (1) reperfusion-induced pathology, which can be restored through the use of a therapeutic intervention such as an antioxidant or calcium-limiting agent given transiently at the time of reperfusion; and (2) ischemic pathology from which the heart is slowly recovering. These may be additive to each other and to any additional reperfusion-induced component that is not amenable to the chosen intervention.
Hibernating myocardium • The term hibernating myocardium refers to the presence of impaired resting left ventricular function, owing to reduced coronary blood flow that can be restored toward normal by revascularization. • Hibernation was first noted in patients with coronary artery disease who had no evidence of ongoing ischemia yet whose left ventricular function improved after coronary artery bypass grafting. • Even akinetic segments can occasionally regain systolic contraction after revascularization. • Hibernating myocardium is present in approximately one third of patients with coronary artery disease and impaired left ventricular function.
Forme cliniche della cardiopatia ischemica • Angina da sforzo • Sindromi ischemiche acute • Con sopraslivellamento del tratto ST (infarto miocardico acuto) • Senza sopraslivellamento sel tratto ST • Angina instabile • Infarto non-Q • Cardio(mio)patia ischemica cronica
LE DIVERSE SEDI DEL DOLORE TORACICO 1: posizione del cuore nel torace 2: angina di petto 3: irradiazione nell’attacco card. 4: sede correlata ad emozioni e stati ansiosi Da: M Caccavale. Inervista sul cuore e dintorni, 1984. Adn Kronos, Roma
ALCUNE POSSIBILI SEDI ED IRRADIAZIONI DEL DOLORE TORACICO DI ORIGINE ESOFAGEA Sleisenger MH, Fordtran JS: Trattato di gastroenterologia, Piccin Ed, Padova
EMANAZIONE SIMPATICA E PARASIMPATICA DEL CUORE ED EMBRICAZIONE DELL’INNERVAZIONE CARDIACA E SPLANCNICA da: S Dalla Volta. La cardiopatia ischemica: dalla teoria alla clinica
GRECO agcon:cappio, capestro, laccio kardia:cuore, bocca dello stomaco Liddel Scott. Le Monnier LATINO angor:stringimento, angoscia, pena cardiacus:di stomaco Castiglioni Mariotti. Loescher INGLESE heart burn:bruciore di stomaco Hazon. Garzanti ITALIANO cardias: sbocco dell’esofago nello stomaco angere: affliggere, angosciare
DOLORE TORACICO DI TIPO ANGINOSO ED ATTRIBUZIONE DELLA SINTOMATOLOGIA ALL’ESOFAGO Pazienti% origine esofagea Delmonico et al., 1968 117 10 Brand et al., 1977 43 46 Dart et al., 1980 98 17 Ferguson et al., 1981 72 18 Kline et al., 1981 16 31 De Meester et al., 1982 50 46 Katz et al., 1989 16 31 Schofield et al., 1989 52 48 Nevens et al., 1991 37 50 Voskuil et al., 1996 28 36 Frøbert et al., 1996 46 25 Chauhan et al., 1996 32 66 Fass et al., 1998 37 62 Ho et al., 1998 80 46 Börjesson et al., 1998 20 35 Romand et al., 1999 43 44 Netzer et al., 1999 303 54
Summary • Angina pectoris is a discomfort in the chest or adjacent areas caused by myocardial ischemia. • Anginal “equivalents” (i.e., symptoms of myocardial ischemia other than angina), such as dyspnea, faintness, fatigue, and eructations, are common, particularly in the elderly. • Nocturnal angina should raise the suspicion of sleep apnea. • Chest discomfort while walking in the cold, uphill, or after a meal is suggestive of angina. • Features suggesting the absence of angina pectoris include pleuritic pain, pain localized to the tip of one finger, pain reproduced by movement or palpation of the chest wall or arms, and constant pain lasting many hours or, alternatively, very brief episodes of pain lasting seconds. Pain radiating into the lower extremities is also a highly unusual manifestation of angina pectoris. • Typical angina pectoris is relieved within minutes by rest or by the use of nitroglycerin.
Differential diagnosis of chest pain according to location where pain starts. Serious intrathoracic or subdiaphragmatic diseases are usually associated with pains that begin in the left anterior chest, left shoulder, or upper arm, the interscapular region, or the epigastrium. The scheme is not all inclusive (e.g., intercostal neuralgia occurs in locations other than the left, lower anterior chest area).
Fisiopatologia • Abitualmente placca aterosclerotica stabile che crea stenosi critica • Angina da eccesso di domanda o da riduzione di offerta • Angina a soglia fissa/soglia variabile • Angina mista • Non c’è correlazione tra gravità del sintomo e gravità della malattia • L’ischemia può essere silente
