Cardiopatia Ischemica
• 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.
Determinanti del consumo di O2
Regolazione del flusso coronarico
Concetti 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
Flusso coronarico totale (ml/m’)
100
200
300
Autoregolazione coronarica
Flusso massimo
Flusso a riposo
0
Riserva coronarica
25
50
75
100
125
150
Pressione arteriosa (mm Hg)
Autoregolazione coronarica
Flusso massimo
Ipertensione
Flusso coronarico totale (ml/m’)
100
200
300
Flusso x 100 g di
Ventricolo normale
Flusso x 100 g di
Ventricolo ipertrofico
Riserva coronarica
0
Flusso a riposo
50
75
100
125
150
175
Pressione arteriosa (mm Hg)
200
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
Eparina
Prostaciclina
Glycocalice
Adenosina
Glycocalice
EDRF
Antitrombina III
Azione
Antiadesione
piastrinica
Trombomodulina
NO
Adenosina
Repulsione
neutrofili
Azione
dilatante
Azione
Anticoagulante
ENDOTHELIA
L CELL
Cellula endoteliale
Azione
Procoagulante
Azione
costrittrice
Adesione
Proadesione
piastrinica
Attrazione
neutrofili
Angiotensina II
Fattore IX
ICAM-1
Fattore X
Fattore VIII di Von
Willebrand
Selectina P
Endotelina
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
-9
-9
-8
-7
-6
-5
-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
Subendocardial ischemia
• 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 enddiastolic pressure in heart failure is corrected, subendocardial
coronary flow reserve is restored and the endocardial-toepicardial 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.
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%
Coronaria destra
Coronaria sinistra OAdx
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
BASALE 0.86
ADENOSINA i.c 0.84
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) reperfusioninduced 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 reperfusioninduced 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.
CHARACTERISTICS OF STUNNING, HIBERNATION, AND ISCHEMIA
PARAMETER
STUNNING
HIBERNATION
TRUE ISCHEMIA
Myocardial
mechanical
function
Reduced
Reduced
Reduced
Coronary blood
flow
Post-ischemic: normal/high
Modestly reduced or low
normal; intermittent
ischemia-reperfusion
Most severely reduced
Myocardial
energy
metabolism
Normal or excessive
Reduced or low normal;
in steady state with
intermittent ischemiareperfusion
Reduced; increasingly
severe as ischemia
proceeds
Duration
Hours to days; late stunning
over weeks
Days to hours to months
Minutes to hours
Outcome
Full spontaneous recovery
Recovery if
revascularized
Myocyte necrosis if
severe ischemia persists
Proposed
change in
metabolic
regulation of
calcium
Cytosolic overload of
calcium in early reperfusion
with damage to contractile
proteins
Possibly just enough
glycolytic ATP to prevent
contracture
Insufficient glycolytic
ATP to prevent ischemic
contracture and
irreversibility
ATP = adenosine triphosphate.
Modified from Opie LH: The multifarious spectrum of ischemic left ventricular dysfunction: Relevance
of new ischemic syndromes. J Mol Cell Cardiol 28:2403–2414, 1966.
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
Angina da sforzo
Netter
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:
kardia:
cappio, capestro, laccio
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:
angere:
sbocco dell’esofago nello stomaco
affliggere, angosciare
DOLORE TORACICO DI TIPO ANGINOSO ED ATTRIBUZIONE
DELLA SINTOMATOLOGIA ALL’ESOFAGO
Pazienti
Delmonico et al., 1968
Brand et al., 1977
Dart et al., 1980
Ferguson et al., 1981
Kline et al., 1981
De Meester et al., 1982
Katz et al., 1989
Schofield et al., 1989
Nevens et al., 1991
Voskuil et al., 1996
Frøbert et al., 1996
Chauhan et al., 1996
Fass et al., 1998
Ho et al., 1998
Börjesson et al., 1998
Romand et al., 1999
Netzer et al., 1999
117
43
98
72
16
50
16
52
37
28
46
32
37
80
20
43
303
% origine esofagea
10
46
17
18
31
46
31
48
50
36
25
66
62
46
35
44
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
Factors influencing the balance between myocardial O2 requirements (left) and supply
(right). Arrows indicate effects of nitrates. In relieving angina pectoris, nitrates exert
favorable effects by reducing O2 requirements and increasing supply. Although a reflex
increase in heart rate would tend to reduce the time for coronary flow, dilation of
collaterals and enhancement of the pressure gradient for flow to occur as the left
ventricular end-diastolic pressure (LVEDP) falls tend to increase coronary flow. AoP =
aortic pressure; NC = no change. (From Frishman WH: Pharmacology of the nitrates in
angina pectoris. Am J Cardiol 56:8I, 1985. By permission of Excerpta Medica.)
Elettrocardiogramma
• A riposo e in assenza di sintomi
l’elettrocardiogramma può essere normale
(spesso è normale)
– Altre alterazioni possono dipendere dalla
malattia di base
• In presenza di sintomi (angina) il segno
fondamentale è la lesione
subendocardica, (sottoslivellamento
del tratto ST)
Elettrogenesi della “lesione”
Acute ischemia may alter ventricular action potentials by inducing lower resting
membrane potential, decreased amplitude and velocity of phase 0, and an
abbreviated action potential duration (pathological early repolarization). These
electrophysiological effects create a voltage gradient between ischemic and normal
cells during different phases of the cardiac electrical cycle. The resulting currents of
injury are reflected on the surface electrocardiogram by deviation of the ST segment
Current-of-injury patterns with acute ischemia. With predominant subendocardial
ischemia (A), the resultant ST vector is directed toward the inner layer of the affected
ventricle and the ventricular cavity. Overlying leads therefore record ST depression.
With ischemia involving the outer ventricular layer (B) (transmural or epicardial
injury), the ST vector is directed outward. Overlying leads record ST elevation.
Reciprocal ST depression can appear in contralateral leads.
Test ergometrico (prova da sforzo)
• Si esegue al cicloergometro o al tapis
roulant (treadmill)
• Esercizio a carichi crescenti
monitorizzando frequenza cardiaca e
pressione arteriosa
• Cessazione dello sforzo se compaiono
sintomi o alterazioni ECG
• Positività: alterazioni del tratto ST (più
spesso sottoslivellamento)
Miocardioscintigrafia da sforzo (o da stress)
Dobutamina
ischemia apice laterale durante stress
Treatment
• 1) identification and treatment of associated
diseases that can precipitate or worsen angina;
• (2) reduction of coronary risk factors;
• (3) application of general and nonpharmacological methods, with particular
attention toward adjustments in life style;
• (4) pharmacological management;
• (5) revascularization by percutaneous catheterbased techniques or by coronary bypass surgery
Mortalità annua x 100000 maschi
Non
fumatore
Ex
fumatore
Fumatore
< 15
15-25
>25
RR
(>25/NF)
BPCO
10
57
127
86
112
225
22,5
(11-42)
Cardiopatia
ischemica
572
678
892
802
892
1025
1,8
(1,6-2)
Miocardiopatie
61
88
125
122
109
173
2,8
(2,1-3,8)
Ipertensione
32
33
44
28
51
60
1,8
(1,2-2,9)
Cerebrovasculopatie
152
158
166
121
231
235
1,5
(1,2-1,9)
Neoplasia
polmonare
14
58
209
105
208
355
25,4
(15-43)
BMJ 1994;309:901-911 (8 October)
Mortality Risk Reduction Associated With Smoking Cessation in Patients
With Coronary Heart Disease. A Systematic Review
Julia A. Critchley, MSc, DPhil; Simon Capewell, MD, FRCPE
JAMA. 2003;290:86-97.
Objective To conduct a systematic review to determine the magnitude of risk reduction achieved by smoking
cessation in patients with CHD.
Data Sources Nine electronic databases were searched from start of database to April 2003, supplemented
by cross-checking references, contact with experts, and with large international cohort studies (identified by
the Prospective Studies Collaboration).
Study Selection Prospective cohort studies of patients who were diagnosed with CHD were included if they
reported all-cause mortality and had at least 2 years of follow-up. Smoking status had to be measured after
CHD diagnosis to ascertain quitting.
Data Extraction Two reviewers independently assessed studies to determine eligibility, quality assessment
of studies, and results, and independently carried out data extraction using a prepiloted, standardized form.
Data Synthesis From the literature search, 665 publications were screened and 20 studies were included.
Results showed a 36% reduction in crude relative risk (RR) of mortality for patients with CHD who quit
compared with those who continued smoking (RR, 0.64; 95% confidence interval [CI], 0.58-0.71).
Results from individual studies did not vary greatly despite many differences in patient characteristics, such
as age, sex, type of CHD, and the years in which studies took place. Adjusted risk estimates did not differ
substantially from crude estimates. Many studies did not adequately address quality issues, such as control
of confounding, and misclassification of smoking status. However, restriction to 6 higher-quality studies had
little effect on the estimate (RR, 0.71; 95% CI, 0.65-0.77). Few studies included large numbers of elderly
persons, women, ethnic minorities, or patients from developing countries.
Conclusions Quitting smoking is associated with a substantial reduction in risk of allcause mortality among patients with CHD. This risk reduction appears to be consistent
regardless of age, sex, index cardiac event, country, and year of study commencement.
Trattamento farmacologico
• Nitrati (Trinitroglicerina e altri)
– In particolare per risolvere l’attacco acuto (via
sublinguale)
• Beta-bloccanti
• Calcioantagonisti
Effects of nitrates in generating NO+ and stimulating guanylate cyclase to cause
vasodilation. Note the role of cysteine cascade in stimulating guanylate cyclase.
Previously, sulfhydryl (SH) depletion was thought to explain nitrate tolerance. Current
emphasis is on the generation of peroxynitrite, which in turn inhibits the conversion of
guanosine triphosphate (GTP) to cyclic guanosine monophosphate (GMP). Note that
mononitrates bypass hepatic metabolism.
The mechanisms of action of the nitrates are complex. These drugs decrease cardiac
demand and may increase coronary blood supply through a variety of actions. It is likely
that the various mechanisms that act to provide relief to angina patients or prevent
myocardial ischemia differ among individuals. LV = left ventricular; RV = right ventricular.
Mechanisms of nitrate tolerance
•
•
•
•
•
•
Depletion of Sulfhydryl Groups.
Neurohormonal Activation.
Plasma Volume Expansion.
Downregulation of Receptors.
Free Radical Generation.
MANAGEMENT.
– The only practical strategy to manage nitrate
tolerance is to prevent it by providing a
“nitrate-free” interval.
INTERACTION WITH
SILDENAFIL.
• The combination of nitrates and sildenafil may
cause serious, prolonged, and potentially lifethreatening hypotension. Nitrate therapy is an
absolute contraindication to the use of sildenafil
and vice versa. Patients who wish to take
sildenafil should be aware of the serious nature
of this adverse drug interaction and be warned
about taking sildenafil within 24 hours of any
nitrate preparation, including short-acting
sublingual nitroglycerin tablets.
Effects of beta blockade on the ischemic heart. Beta blockade has a
beneficial effect on ischemic myocardium unless (1) the preload rises
substantially as in left-sided heart failure or (2) vasospastic angina is present, in
which case spasm may be promoted in some patients. Note the recent proposal
that beta blockade diminishes exercise-induced vasoconstriction.
CANDIDATES FOR USE OF BETA-BLOCKING AGENTS FOR ANGINA
Ideal Candidates
Prominent relationship of physical activity to attacks of angina
Coexistent hypertension
History of supraventricular or ventricular arrhythmias
Previous myocardial infarction
Left ventricular systolic dysfunction
Mild to moderate heart failure symptoms (NYHA functional Class II–III)
Prominent anxiety state
Poor Candidates
Asthma or reversible airway component in chronic lung disease patients
Severe left ventricular dysfunction with severe heart failure symptoms (NYHA functional
Class IV)
History of severe depression
Raynaud's phenomenon
Symptomatic peripheral vascular disease
Severe bradycardia or heart block
Brittle diabetes
NYHA = New York Heart Association.
RECOMMENDED DRUG THERAPY (CALCIUM ANTAGONIST VS. BETA BLOCKER) IN PATIENTS WHO HAVE ANGINA IN CONJUNCTION WITH
OTHER MEDICAL CONDITIONS
CLINICAL CONDITION
RECOMMENDED DRUG
CARDIAC ARRHYTHMIA OR CONDUCTION DISTURBANCE
Sinus bradycardia
Nifedipine or amlodipine
Sinus tachycardia (not caused by cardiac failure)
Beta blocker
Supraventricular tachycardia
Beta blocker (verapamil)
Atrioventricular block
Nifedipine or amlodipine
Rapid atrial fibrillation (with digitalis)
Verapamil or beta blocker
Ventricular arrhythmia
Beta blocker
LEFT VENTRICULAR DYSFUNCTION
Heart failure
Beta blocker
MISCELLANEOUS MEDICAL CONDITIONS
Systemic hypertension
Beta blocker (calcium antagonist)
Severe preexisting headaches
Beta blocker (verapamil or diltiazem)
COPD with bronchospasm or asthma
Nifedipine, amlodipine, verapamil, or diltiazem
Hyperthyroidism
Beta blocker
Raynaud's syndrome
Nifedipine or amlodipine
Claudication
Calcium antagonist
Severe depression
Calcium antagonist
COPD = chronic obstructive pulmonary disease. (alternatives in parentheses)
TABLE 37–3. EFFECTS OF ANTIANGINAL AGENTS ON INDICES OF MYOCARDIAL OXYGEN SUPPLY AND DEMAND*
BETA-ADRENOCEPTOR BLOCKERS
ISA
INDEX
NITRATES
No
Yes
Cardioselective
CALCIUM ANTAGONISTS
No
Yes
Nifedipine
Verapamil
Ditiazem
0




0
0
SUPPLY
Coronary resistance
Vascular tone

0
Intramyocardial diastolic tension

0
0
Coronary collateral circulation
0
0
0
0
0()
0
0
Preload

0
0
Afterload (peripheral vascular resistance)

Duration of diastole
()
()
()
DEMAND
Intramyocardial systolic tension
0

0

Contractility
0(
)




(
)
Heart rate
0(
)

0


0(
)
†

(
)
(
)
†
(
(
)
†
)
TABLE 37–3. EFFECTS OF ANTIANGINAL AGENTS ON INDICES OF MYOCARDIAL OXYGEN SUPPLY AND DEMAND*
BETA-ADRENOCEPTOR BLOCKERS
ISA
INDEX
NITRATES
No
Yes
Cardioselective
CALCIUM ANTAGONISTS
No
Yes
Nifedipine
Verapamil
Ditiazem
0




0
0
SUPPLY
Coronary resistance
Vascular tone

0
Intramyocardial diastolic tension

0
0
Coronary collateral circulation
0
0
0
0
0()
0
0
Preload

0
0
Afterload (peripheral vascular resistance)

Duration of diastole
()
()
()
DEMAND
Intramyocardial systolic tension
0

0

Contractility
0(
)




(
)
Heart rate
0(
)

0


0(
)
†

(
)
(
)
†
(
(
)
†
)
*
= Increase;  = decrease; 0 = little or no definite effect. The number of arrows represents the relative intensity of effect. Symbols in parentheses indicate reflex-mediated
effects.
†Effect of calcium entry on left ventricular contractility, as assessed in the intact animal model. The net effect on left ventricular performance is variable since it is influenced by
alterations in afterload, reflex cardiac stimulation, and the underlying state of the myocardium.
ISA = intrinsic sympathomimetic activity.
From Shub C, Vlietstra RE, McGoon MD: Selection of optimal drug therapy for the patient with angina pectoris. Mayo Clin Proc 60:539, 1985. By permission of the Mayo
Foundation.
Prognosi in terapia medica
• La prognosi è riservata
• In 15 mesi:
– Mortalità: 4%
– Infarto miocardico: 7%
– Remissione spontanea: 11%
• Importante il ruolo di:
– Funzione ventricolare sinistra
– Estensione dell’ischemia inducibile
Graphs showing survival for
medically treated CASS
patients. A, Patients with one-,
two-, or three-vessel disease
and an ejection fraction of 50
to 100 percent stratified by the
number of diseased vessels
(DISVES). B, Patients with
one-, two-, or three-vessel
disease and an ejection
fraction of 35 to 49 percent
stratified by the number of
diseased vessels. C, Patients
with one-, two-, or three-vessel
disease and an ejection
fraction of 0 to 34 percent
stratified by the number of
diseased vessels.
Indicazioni alla rivascolarizzazione
• Mediante angioplastica: presenza di una o più
stenosi critiche, preferibilmente senza
coinvolgimento della discendente anteriore
(indicazioni “quoad valetudinem”)
• Mediante bypass aortocoronarico (indicazioni
“quad vitam”):
– Malattia del Tronco comune (>50%)
– Malattia di tre vasi
– Malattia di due vasi con coinvolgimento della
discendente anteriore prossimale
Adjusted hazard (mortality) ratios
comparing coronary artery bypass
grafting (CABG) and medical
therapy for nine coronary anatomy
severity groups (GR) according to
the number of vessels diseased
(VD), the presence or absence of
a 95 percent proximal stenosis (95
percent), and involvement of the
left anterior descending coronary
artery (LAD). B, Adjusted hazard
(mortality) ratios comparing CABG
and percutaneous transluminal
angioplasty (PTCA) for nine
coronary anatomy groups
according to the number of
vessels diseased, the presence or
absence of a 95 percent proximal
stenosis, and LAD involvement.
Two-year cumulative mortality rates for three treatment strategies. Significant differences
were seen between revascularization and angina-guided strategies (P<.005) and
between revascularization and ischemia-guided strategies (P<.05). Angina-guided and
ischemia-guided strategies were not significantly different from each other (P=.34).
Asymptomatic Cardiac Ischemia Pilot (ACIP) Study Two-Year Follow-up : Outcomes of Patients Randomized to
Initial Strategies of Medical Therapy Versus Revascularization. Circulation, Apr 1997; 95: 2037 - 2043.
Angina instabile
Angina instabile / Nomenclatura
• Unstable angina lies in the center of the spectrum of clinical
conditions caused by myocardial ischemia. These range from
chronic stable angina pectoris to the acute coronary
syndromes.
• The latter, in turn, consist of acute myocardial infarction (MI)
associated with electrocardiographic ST segment elevation
(STEMI) and unstable angina/non-ST segment elevation MI
(UA/NSTEMI).
• The former is most commonly caused by acute total coronary
occlusion, and urgent reperfusion is the mainstay of therapy,
• UA/NSTEMI is usually associated with severe coronary
obstruction but not total occlusion of the culprit coronary
artery.
• If the myocardial ischemia that results from the coronary
obstruction is long in duration and/or great in severity,
myocardial necrosis occurs, and the patient is classified as
having a non-Q-wave MI or, now more aptly termed, NSTEMI
Definizione clinica
• Unstable angina is defined as angina pectoris (or
equivalent type of ischemic discomfort) with at least one
of three features:
– (1) it occurs at rest (or with minimal exertion) usually lasting
more than 20 minutes (if not interrupted by nitroglycerin);
– (2) it is severe and described as frank pain and of new onset
(i.e., within 1 month); and
– (3) it occurs with a crescendo pattern (i.e., more severe,
prolonged, or frequent than previously).
• Some patients with this pattern of ischemic discomfort,
especially those with prolonged rest pain, develop
evidence of myocardial necrosis on the basis of the
release of cardiac markers and thus have a diagnosis of
NSTEMI.
BRAUNWALD CLINICAL CLASSIFICATION OF UNSTABLE ANGINA
CLASS
DEFINITION
DEATH OR
MYOCARDIAL
INFARCTION TO 1
YEAR*
Severity
Class I
New onset of severe angina or accelerated angina;
no rest pain
7.3%
Class II
Angina at rest within past month but not within
preceding 48 hr (angina at rest, subacute)
10.3%
Class III
Angina at rest within 48 hr (angina at rest, subacute)
10.8%†
Clinical Circumstances
A (secondary
angina)
Develops in the presence of extracardiac condition
that intensifies myocardial ischemia
14.1%
B (primary
angina)
Develops in the absence of extracardiac condition
8.5%
C (postinfarction
angina)
Develops within 2 weeks after acute myocardial
infarction
18.5%‡
Meccanismi eziopatogenetici
Possono agire isolatamente o congiuntamente
• Complicanza di placca: trombosi non
occlusiva su placca significativa ma non
critica (es. stenosi 60%)
– Trombo piastrinico
– E’ il meccanismo di gran lunga più frequente
• Spasmo su stenosi lieve, o in assenza di
stenosi (Prinzmetal)
– Più raro, ma spesso presente anche dopo un
trombo piastrinico (trombossano)
Meccanismi eziopatogenetici
Possono agire isolatamente o congiuntamente
• Ostruzione meccanica progressiva
(crescita di placca)
– Meccanismo tipico della restenosi dopo
angioplastica o intrastent
• Infiammazione o infezione
• Aumento della richiesta di flusso da causa
extracardiaca
– Tireotossicosi
– Anemia
Schematic representation of the causes of unstable angina. Each of the five bars
represents one of the etiologic mechanisms, and the red portion of the bar represents
the extent to which the mechanism is operative. A, Most common form of unstable
angina in which atherosclerotic plaque causes moderate (60 percent diameter)
obstruction and acute thrombus overlying plaque causes very severe (90 percent
diameter) narrowing. B, Mild coronary obstruction, adjacent to which there is intense
(90 percent diameter) vasoconstriction.
PLAQUE RUPTURE, FISSURE, OR
EROSION.
• Rupture or erosion of an atherosclerotic plaque with superimposed
nonocclusive thrombus is by far the most common cause of
UA/NSTEMI.
• The type of plaque that ruptures, the so-called vulnerable plaques,
are usually lesions with less than 50 percent
• Plaque rupture can be precipitated by multiple factors, including
– high plaque lipid content,
– local inflammation causing breakdown of the thin shoulder of the
plaque,
– coronary artery constriction at the site of the plaque,
– local shear stress forces,
– platelet activation, and the status of the coagulation system (i.e., a
potentially prothrombotic state),
• all of which culminate in the formation of platelet-rich thrombi at the
site of the plaque rupture or erosion and the resultant acute
coronary syndrome
Platelets initiate
thrombosis at the
site of a ruptured
plaque: the first
step is platelet
adhesion (1) via
the glycoprotein
Ib receptor in
conjunction with
von Willebrand
factor. This is
followed by
platelet
activation (2),
which leads to a
shape change in
the platelet, degranulation of
the alpha and
dense granules, and expression of glycoprotein IIb/IIIa receptors on the platelet
surface with activation of the receptor, such that it can bind fibrinogen. The final
step is platelet aggregation (3), in which fibrinogen (or von Willebrand factor) binds
to the activated glycoprotein IIb/IIIa receptors of two platelets. Aspirin (ASA) and
clopidogrel act to decrease platelet activation, whereas the glycoprotein IIb/IIIa
inhibitors inhibit the final step of platelet aggregation.
Vasocostrizione
• Prinzmetal
– Vasocostrizione di coronaria epicardica,
focale, anche in assenza di lesione
aterosclerotica
• Vasocostrizione microcircolatoria
• Vasocostrizione in presenza di placca
– Serotonina, Trombossano A2
Quadro clinico
• Circa 80% dei pazienti (45% di sesso
femminile) hanno già precedenti di
cardiopatia ischemica
• Sintomatologia importante: senso di peso
ma spesso vero dolore
• Insorgenza a riposo o da sforzi lievi
• Spesso sintomi collaterali neurovegetativi
Diagnosi
• Sintomi e quadro clinico
• Elettrocardiogramma
– Sottoslivellamento ST
– Onde T
• Markers cardiospecifici (cTroponina I e T)
– Livello di rischio
– Livello di necrosi
INDICATORS OF INCREASED RISK IN UNSTABLE ANGINA
History
Advanced age (>65 years)
Diabetes mellitus
Post-myocardial infarction angina
Prior peripheral vascular disease
Prior cerebrovascular disease
Clinical Presentation
Braunwald Class II or III (acute or subacute rest pain)
Braunwald Class B (secondary unstable angina)
Heart failure/hypotension
Electrocardiogram
New/ST segment deviation
0.05 mV
New T wave inversion
0.3 mV
Left bundle branch block
Cardiac Markers
Increased troponin T or I or CK-MB
Increased C-reactive protein (CRP)
Angiogram Thrombus
Stratificazione del rischio
nelle sindromi coronariche acute
Trattamento
• Stabilizzare (“passivating”) la placca
– Aspirina, Clopidogrel, UFH o LMWH
• Correggere l’ischemia
– Nitrati, beta-bloccanti, calcioantagonisti
– Rivascolarizzazione
• Angioplastica
• Bypass
• Prevenzione a lungo termine della
progressione della malattia
Pooled data from CAPTURE, PRISM-PLUS, and PURSUIT trials of unstable
angina, showing benefit of glycoprotein IIb/IIIa inhibition during medical therapy
only (left panel), during, and immediately after percutaneous coronary intervention
(PCI, right panel).
Meccanismi favorevoli degli inibitori
della GP IIb-IIIa
• Greater resolution of thrombus and
improved coronary flow compared with
aspirin and heparin
• Reduced size of an evolving NSTEMI
• Greater benefit of treatment when
administered earlier relative to the onset of
pain
• Warning: No thrombolytics!
Infarto miocardico acuto
Diagnosi di dimissioni ospedaliere nel triennio 1996 - 1998
1996
Numero
N° ricoveri per infarto
miocardico
Degenza media IMA
N° ricoveri per angina
pectoris
Degenza media AP
77.033
1997
Tassi per
10000
abitanti
134,21
11,62
75.966
Numero
80.920
1998
Tassi per
10000
abitanti
140,7
10,93
132,35
7,68
75.509
Numero
88.773
Tassi per
10000
abitanti
154,15
10,39
131,29
7,19
79.236
137,59
6,46
N°cateterismi cardiaci
61.378
106,94
72.188
125,52
82.140
142,63
N° By-pass
19.327
33,67
23.318
40,54
25.927
45,02
N° PTCA
14.415
25,11
20.250
35,21
28.104
48,8
IMA = infarto miocardico acuto; AP = angina pectoris
Fonte ISTISAN
Sopravvivenza post-IMA
SOPRAVVIVENZA
100 !
Angina stabile
!
80
+ Direct PTCA, statine
!
60
!
40
!
Bypass, PTCA, TL, ACE-I
Bypass
20
!
0
0
2
4
6
FOLLOW-UP (ANNI)
8
10
12
Infarto miocardico acuto
• Il 50% della mortalità avviene in fase
preospedaliera
• Mortalità ospedaliera
–
–
–
–
Epoca pre-UCIC: 25%
UCIC: 15%
Trombolisi: 5-8%
PTCA primaria: < 5% (studi randomizzati)
Patologia
•
•
•
•
Complicanza di placca
Formazione di trombo di piastrine e poi
Formazione di trombo di fibrina
Il trombo è occlusivo
Schematic representation of
the progression of myocardial
necrosis after coronary artery
occlusion. Necrosis begins in
a small zone of the
myocardium beneath the
endocardial surface in the
center of the ischemic zone.
This entire region of
myocardium (dashed outline)
depends on the occluded
vessel for perfusion and is the
area at risk. Note that a very
narrow zone of myocardium
immediately beneath the
endocardium is spared from
necrosis because it can be
oxygenated by diffusion from
the ventricle.
Temporal sequence of early biochemical, ultrastructural, histochemical, and histological
findings after onset of MI. At the top of the figure are schematically shown the time frames
for early and late reperfusion of the myocardium supplied by an occluded coronary artery.
For approximately one-half hour after the onset of even the most severe ischemia,
myocardial injury is potentially reversible; after that there is progressive loss of viability
that is complete by 6 to 12 hours. The benefits of reperfusion (both early and late) are
greatest when it is achieved early, with progressively smaller benefits occurring as
reperfusion is delayed.
Fisiopatologia
Fisiopatologia
• Funzione sistolica
• Funzione diastolica
• Aritmie
– Precoci
– Tardive
• Complicanze
Disfunzione ventricolare
• Nella zona infartuata
• A distanza
– Altre lesioni ischemizzanti
– Circolo collaterale
• Disfunzione sistolica
– Ipocinesia
– Acinesia
– Discinesia
• Disfunzione diastolica
– Ischemia, Edema, Fibrosi
Infarto miocardico acuto
Funzione ventricolare
0,70
0,65
0,60
0,55
0,50
0,45
0,40
Frazione di Eiezione
0,35
0,30
0,25
0,20
-10
0
10
20
30
INFARCT SIZE (%)
40
50
60
100
90
80
P <<0,001
70
P = 0,5
60
VOLUME (ml/m2)
LEFT VEN
50
40
30
0
10
20
30
40
INFARCT SIZE (% )
50
60
72-hrs
6-months
Infarto miocardico
Funzione ventricolare in fase acuta e a 6 mesi
0,8
0,7
0,6
0,5
0,4
Frazione di Eiezione
0,3
0,2
0,1
-10
0
10
20
30
INFARCT SIZE (%)
40
50
60
Infarto acuto
Infarto a 6 mesi
Aritmie
• Ipercinetiche precoci: da focus ectopico
– Extrasistoli e tachicardia ventricolare
– Fibrillazione ventricolare (morte improvvisa!)
• Ipercinetiche tardive
– Come sopra, ma da rientro
• Ipocinetiche
– Blocco atrioventricolare, anche completo,
particolarmente nell’infarto inferiore (coronaria
destra)
Objective documentation of the circadian pattern in the onset of myocardial
infarction (MI).
Dolore nell’infarto
•
•
•
•
Insorgenza brusca o graduale, non da sforzo
Durata almeno 20’-30’
Insensibile alla NTG
Accompagnato da fenomeni neurovegetativi
(nausea, vomito, diarrea)
• Esprime ischemia continuata: finché c’è dolore,
c’è miocardio a rischio!
• Scompare quasi subito col ripristino del flusso
coronarico
Presentazioni atipiche
• “De novo” o peggioramento di insufficienza cardiaca
congestizia
• Semplice angina senza particolare gravità
• Localizzazione anomala del dolore (solo dorsale,
mandibola)
• Sintomi neurologici centrali (ictus da brusca riduzione del
flusso cerebrale)
• Ansia e agitazione inspiegabile
• Psicosi acuta
• Sincope; Astenia invincibile
• Indigestione acuta
• Embolizzazione periferica
Obiettività clinica
• Il paziente è sofferente, ansioso, spesso sudato
e pallido
• Pressione arteriosa indifferente: spesso
ipotensione, naturalmente sempre presente nei
pazienti in shock
• All’ascoltazione possibili 3. e 4. tono
• Possibili sfregamenti pericardici a partire dalla
terza giornata
• Ascoltazione toracica: possibili rantoli in
presenza di scompenso cardiaco
Hyperacute phase of extensive anterior-lateral myocardial infarction. Marked ST
elevation melding with prominent T waves is present across the precordium, as well as
in leads I and aVl. ST depression, consistent with a reciprocal change, is seen in leads
III and aVf. Q waves are present in leads V3 through V6. Marked ST elevations with tall
T waves caused by severe ischemia are sometimes referred to as a monophasic
current-of-injury pattern. A paradoxical increase in R wave amplitude (V2 and V3 ) may
accompany this pattern. This tracing also shows left axis deviation with small or absent
inferior R waves, which raises the possibility of a prior inferior infarct.
Sequence of depolarization and repolarization changes with (A) acute anterior-lateral
and (B) acute inferior wall Q wave infarctions. With anterior-lateral infarcts, ST
elevation in leads I, aVl, and the precordial leads may be accompanied by reciprocal
ST depression in leads II, III, and aVf. Conversely, acute inferior (or posterior) infarcts
may be associated with reciprocal ST depression in leads V1 to V3.
Variability of electrocardiogram (ECG) patterns with acute myocardial ischemia. The
ECG may also be normal or nonspecifically abnormal. Furthermore, these
categorizations are not mutually exclusive. For example, a non-Q-wave infarct can
evolve into a Q wave infarct, ST elevation can be followed by a non-Q-wave infarct,
or ST depression and T wave inversion can be followed by a Q wave infarct.
Plot of the appearance of cardiac markers in blood versus time after onset of
symptoms. Peak A, early release of myoglobin or CK-MB isoforms after AMI; peak
B, cardiac troponin after AMI; peak C, CK-MB after AMI; peak D, cardiac troponin
after unstable angina. Data are plotted on a relative scale, where 1.0 is set at the
AMI cutoff concentration
Markers di danno miocardico
• Oggi si usano le troponine (cTnI e cTnT),
estremamente specifiche (la concentrazione
normale è zero)
• Essenziale effettuare misurazioni seriate (6-12
ore) almeno fino al picco, poi più distanziate
• Altri markers sono le CPK, meglio gli isoenzimi
(BB, MM, MB)
• Concomitanti alterazioni di AST e ALT, LDH
• CPK e Tn sono usate per stimare le dimensioni
dell’area necrotica
Trattamento
• Il trattamento inizia nella fase preospedaliera
– Rapido riconoscimento dei sintomi, ECG a distanza
• Limitare l’area infartuale
– Riperfondere al più presto
• Trombolisi preospedaliera
– Farmaci antiischemici
• Proteggere dalle aritmie potenzialmente letali
– Ricovero in UCIC
• Prevenire il rimodellamento
• Prevenire la progressione della malattia
Riperfusione miocardica
• Va eseguita al più presto, preferibilmente entro
tre ore dall’inizio dei sintomi; di scarsa utilità
dopo 6 ore
– Trombolisi controindicata dopo 12 ore
• Oggi si tende ad ottenerla mediante
angioplastica con stent (angioplastica primaria)
• Trombolisi possibile se il tempo necessario per
effettuare un’angioplastica è superiore a 60’-90’
– Dipende anche dal tempo già trascorso e dalla gravità
della presentazione clinica (shock)
Relationship between coronary blood flow and mortality in AMI
Time-Dependent Benefit of Reperfusion Therapy
100
Reimer/Jennings 1977
Bergmann 1982
GISSI-I 1986
% Benefit
80
60
40
20
0
0
2
4
6
8
Reperfusion Time (hours)
Adapted from Tiefenbrunn AJ, Sobel BE. Circulation.
1992;85:2311-2315.
10
12
Trattamento
•
•
•
•
Nitroderivati in infusione
Acido acetilsalicilico
Eparina
Betabloccanti
– Evitare i calcioantagonisti
• Possibilmente inserire al più presto
– Ace-Inibitori
– Statine
• Trattamento del dolore (anche oppioidi)
• Trattamento dell’insufficienza ventricolare
sinistra
Prevenzione del rimodellamento
• Limitare l’estensione della necrosi
– Rivascolarizzazione precoce!
• Trattamento dell’ischemia residua
• Pervietà dell’IRA (?)
• Trattamento medico
–
–
–
–
ACE-inibitori
Bloccanti del recettore dell’angiotensina II
Beta-bloccanti
Nitrati
Complicanze
• Shock cardiogeno
– Mortalità 80%
• Rottura di cuore
– Mortalità 100%
• Insufficienza mitralica acuta
• Rottura del setto interventricolare
• Sindrome di Dressler (a distanza)
– Non confondere con angina precoce
postinfartuale
Cause di morte per infarto
miocardico acuto
• Shock cardiogeno
• Rottura di cuore
• Aritmie
– Oggi raro perché i pazienti sono ricoverati in
UCIC
• Dopo rivascolarizzazione efficace non si
verifica rottura di cuore
Dimissione
• Oggi circa in decima giornata
• Valutazione del rischio complessivo
• Valutazione di:
– Funzione ventricolare
– Aritmie
– Ischemia residua
• Angina precoce postinfartuale
TIMI Risk Score for STEMI for predicting 30-day mortality. STE = ST elevation;
LBBB = left bundle branch block; h/o = history of; HTN = hypertension.
Impact of left ventricular function on survival after myocardial infarction. The
curvilinear relationship between left ventricular ejection fraction (LVEF) for patients
treated in the thrombolytic era is shown.