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What is ischaemic heart disease (IHD)?

IHD is a broad term encompassing several closely related syndromes caused by myocardial ischaemia - an imbalance between cardiac blood supply (perfusion) and myocardial oxygen and nutritional requirements.

Cardiac myocytes generate energy almost exclusively through mitochondrial oxidative phosphorylation, cardiac function is therefore strictly dependent upon the continuous flow of oxygenated blood through the coronary arteries.


What causes IHD? What else can cause cardiac pain?

In more than 90% of cases, IHD is a consequence of reduced coronary blood flow secondary to obstructive atherosclerotic vascular disease. Thus, unless otherwise specified, IHD is usually synonymous with coronary artery disease (CAD).

Less commonly, IHD can also results from
- aortic dissection, hypotension and shock (diminished blood volume)
- paroxysmal tachycardias (increased demand)
- severe anaemia (diminished oxygen carrying capacity), cardiomyopathy, coronary artery embolism (rare) and vasculitis
- pneumonia or CHF (diminished oxygenation)


What are the clinical presentations of IHD?

The manifestations of IHD are a direct consequence of the insufficient blood supply to the heart. The clinical presentation may include one or more of the following cardiac syndromes:

1) Angina pectoris - ischaemia induces pain but is insufficient to cause myocyte death. Angina can be stable (occurring on exertion), unstable (angina of increasing frequency or occurring at rest), Prinzmetal (chest pain caused by coronary artery spasm) or Decubitus (precipitated by lying flat)

2) Acute myocardial infarction - the severity or duration of ischaemia is sufficient to cause cardiomyocyte death and necrosis

3) Chronic IHD with CHF - progressive cardiac decompensation after acute MI or secondary to accumulated small ischemic insults

4) Sudden cardiac death - this can occur as a consequence of tissue damage from MI, but most commonly results from a lethal arrhythmia without myocardial necrosis


What would suggest a non cardiac cause of chest pain?

This would be favoured by pain that is continuous for several days, precipitated by changes in posture or deep breathing, the ability to continue normal activities and lack of relief by rest.

The more common alternatives in the differential diagnosis are oesophageal pain and musculoskeletal pain.


What is the pathogenesis of IHD? How does inflammation, thrombus formation and vasoconstriction play a role?

IHD is primarily a consequence of inadequate coronary perfusion relative to myocardial demand. This imbalance occurs as a consequence of the combination of a pre-existing ("fixed") atherosclerotic occlusion of coronary arteries, and new, superimposed thrombosis and/or vasospasm.

The following factors are important in the development of coronary atherosclerosis:
i) Inflammation - atherosclerosis begins with the interaction of damaged endothelial cells and circulating leucocytes, resulting in T cell and macrophage recruitment and activation. These cells drive subsequent smooth muscle cell accumulation and proliferation

ii)Thrombosis associated with a disrupted plaque - often triggers the acute coronary syndrome. Partial occlusion by a newly formed thrmbus on a disrupted ahterosclerotic plaque can wax and wane with time leading to unstable angina or sudden death. But, even partial luminal occlusion by thrombus can compromise blood flow sufficiently to case a small infarction of the innermost zone of the myocardium (subendocardial infarct). Organizing thrombi produce potent activators of smooth muscle proliferation, which can contribute to the growth of atherosclerotic plaques

iii) Vasoconstriction - directly compromises lumen diameter and by increasing local mechanical shear forces, vessel spasm can cause plaque disruption. Vasoconstriction in atherosclerotic plaques can be stimulated by (1) circulating adrenergic agonists, (2) locally released platelet contents, (3) imbalance between endothelial cell -relaxing factors (e.g. NO) and contracting factors (e.g. endothelin) and (4) mediators released from perivascular inflammatory cells


What is meant by the term "critical stenosis"?

Fixed obstructions that occlude less than 70% of a coronary vessel lumen typically are asymptomatic, even with exertion. In comparison, lesions that occlude more than 75% of a vessel lumen - resulting in the so called critical stenosis - generally cause symptoms in the setting of increased demand. A fixed stenosis that occludes 90% of more of a vascular lumen can lead to inadequate coronary blood flow with symptoms even at rest - one of the forms of unstable angina.


What is the cause of the majority of acute coronary syndromes?

In most cases, unstable angina, infarction and sudden cardiac death occur because of abrupt plaque change followed by thrombosis. The initiating event typically is sudden disruption of a fixed partially occlusive plaque. More than one mechanism of injury may be involved: rupture, fissuring or ulceration of plaques can expose highly thrombogenic constituents or sub endothlial basement membrane leading to thrombosis. In addition, haemorrhage into the core of plaques can expand plaque volume, which increases luminal occlusion.


What intrinsic factors affect plaque vulnerability?

Factors that trigger acute plaque change are believed to act by increasing the lesions susceptibility to disruption by mechanical stress. Both intrinsic aspects of plaque composition and structure, and extrinsic factors, such as blood pressure and platelet reactivity may contribute as follows:

- plaques that contain large atheromatous cores, or have thing overlying fibrous caps are more likely to rupture and are therefore termed "vulnerable". Fissures frequently occur at the junction of the fibrous cap and the adjacent normal plaque free arterial segment, where the mechanical stresses are highest and the fibrous cap is thinnest.
- plaques with a lack of smooth muscle cells, or large numbers of inflammatory cells are more vulnerable to rupture (due to the lack of collagen produced by SM cells)


How do extrinsic factors affect plaque vulnerability?

Adrenergic stimulation can put physical stress on the plaque by causing hypertension or local vasospasm. The surge in adrenergic stimulation associated with awakening and rising may underlie the observation that the incidence of acute MI is highest between 6am and 12pm.


What happens to plaques that are disrupted and heal?

Plaque disruption and non occlusive thrombosis are common, repetitive and often clinically silent complications of atheromas. The healing of these subclinical plaques and overlying thrombosis is an important mechanism by which atherosclerotic lesions progressively enlarge and underlies chronic ischaemic heart disease by forming a severe, fixed, stable obstruction.


What is the pathogenesis of stable angina?

Stable angina occurs when coronary blood flow is impaired by a fixed atheroma of the coronary arteries. During exertion, an imbalance between myocardial oxygen supply and demand causes transient myocardial ischaemia.

Coronary atheroma is by far the most common cause of angina, however, the symptom may also be a feature of other forms of heart disease such as aortic valve disease, HOCUM, and coronary vasospasm.


What are the clinical features of stable angina?

The history is by far the most important factor in making the diagnosis of stable angina.

The condition is characterised by central chest pain, breathlessness on exertion and is promptly relieved by rest.

Physical examination is frequently negative, but may reveal evidence of:
- aortic stenosis (an occasional cause of angina)
- CHD risk factors (e.g. hypertension, diabetes)
- LV dysfunction (e.g. cardiomegaly)
- other arterial disease (e.g. bruits, peripheral vascular disease)
- conditions that exacerbate angina (e.g. anaemia, thyrotoxicosis)
- retinopathy (diabetic or hypertensive)


How should stable angina be investigated?

1) Resting ECG
2) Exercise ECG
3) Myocardial perfusion scanning
4) Stress echo
5) Coronary angiography


What does a resting ECG show in stable angina?

This may show signs of previous MI but is often normal, even in patients with left main or severe three vessel coronary artery disease. The most convincing ECG evidence of myocardial ischaemia is obtained by demonstrating reversible ST segment depression or elevation with or without T wave inversion during symptoms.


What is involved and when is an exercise ECG performed for stable angina?

The patients ECG and BP are monitored during exercise using a standard treadmill or bicycle protocol. Planar, or down sloping ST segment depression of >1mm is indicative of ischaemia. Up sloping ST segment depression is less specific.

Exercise testing is also a useful means of assessing the severity of coronary disease and identifying high risk individuals. However, false negatives do occur and the predictive accuracy of exercise testing is lower in women than men.


What is a myocardial perfusion scan?

This is particularly helpful in patients who are unable to exercise test or who have equivocal or uninterpretable exercise tests. Scintiscans of the myocardium are obtained at rest and during stress (e.g. exercise or pharmacological - e.g. dobutamine) after IV administration of a radio-isotope that is taken up by viable perfused myocardium. A perfusion defect present during stress but not at rest indicates reversible myocardial ischaemia; a persistent defect suggests a previous MI.


When are stress echoes performed?

These are an alternative to myocardial perfusion scans but have a similar predictive accuracy. Ischaemic segments of myocardium exhibit reversible defects in contractility (on echo) during exercise or pharmacological stress. Areas of infarction do not contract at rest or during stress. The technique is particularly useful for identifying areas of "hibernating" myocardium in patients with heart failure and CAD being considered for revascularisation.


List risk factors associated with IHD

1) Age and sex - age is the most powerful independent risk factor for atherosclerosis. Pre-menopausal women have lower rates of disease than men but thereafter risk is similar. HRT has no role in prevention of atherosclerosis however.

2) FHx - a "positive" family history is present when clinical problems occur in first degree relatives aged <50 years (males) or <55 years (females). Increased risk reflects a combination of genetic and environmental risk factors.

3) Hypertension - the incidence of atherosclerosis increases as BP rises

4) Hypercholesterolaemia - risk rises with plasma cholesterol concentration. Lowering low density lipoprotein (LDL) and total cholesterol reduces the risk of cardiovascular events (death, MI, stroke)

5) Diabetes - this is the most potent risk factor for all forms of atherosclerosis and is often associated with diffuse disease. Insulin resistance (normal glucose homeostasis with high levels of insulin) is also a risk factor for CAD

6) Others - obesity, smoking, alcohol, diet


What are the aspects of stable angina management?

- identification and control of risk factors
- symptom control
- identification of high risk patients for treatment and to improve life expectancy


How should risk factors be managed for stable angina?

The most important lifestyle advice is smoking cessation but other steps include regular exercise and aiming for ideal BMI. All patients with CAD should receive statin therapy, irrespective of serum cholesterol. BP should be treated to a target of <140/85 mmHg, although ACEi (unless contraindicated) are of benefit in all patients with vascular disease. Aspirin reduces the risk of adverse events such as MI and should be prescribed indefinitely for all patients with CAD. Clopidogrel is an equally effective alternative in patients who cannot tolerate aspirin.


What drugs are first line for relief of symptoms in stable angina? What is their rationale for use in angina?

The basic aim of drug treatment in angina is to reduce the work of the heart and hence its oxygen demand. The nitrates (e.g. GTN, isosorbide mononitrate, isosorbide dinitrate) are first line drugs. Their main effect is to cause peripheral vasodilatation, especially in the veins, by an action on vascular smooth muscle that involves the formation of NO and an increase in intracellular cGMP. The resulting pooling of blood in the venous capacitance vessels (due to increased venous compliance) reduces venous return and the end diastolic volume is decreased. Reduction in the distension of the heart wall decreases oxygen demand and pain quickly subsides.

GTN is given sublingually to avoid first pass metabolism and is used to treat acute angina attacks. If this is required more than twice per week then combined therapy with a beta blocker or calcium channel blocker may be required.


What are the short and long acting nitrates?

The main short acting nitrate in clinical use is GTN. It is given by sublingual spray and works for about 30mins. It is more useful in preventing attacks than in stopping them once they have started. Patches containing GTN (transdermal patches) have a long duration of action (up to 24h).

Long acting nitrates are more stable and may be effective for several hours depending on the drug and preparation used. Isosorbide dinitrate is widely used, but it is rapidly metabolised by the liver. The use of isosorbide mononitrate, which is the main active metabolite of the dinitrate, avoids the variable absorption and unpredictable first pass metabolism of the nitrate.


What are the adverse effects of nitrates?

The arterial dilatation produced by nitrates causes headache, which frequently limit the dose. More serious side effects are hypotension and fainting. Reflex tacchycardia often occurs, but this is prevented by combined therapy with beta blockers. Prolonged high dosage may cause methaemoglobinaemia as a result of oxidation of haemaglobin.


What is the mechanism of nitrates?

Initial metabolism of these drugs releases NO2-, a process that requires tissue thiols. Within the cell, NO2- is converted into nitric oxide, which then activates guanylyl cyclase, causing an increase in the intracellular concentration of cGMP in the vascular smooth muscle cells. cGMP activates protein kinase G (PKG) an enzyme that causes the vascular smooth muscle to relax by several mechanisms. These include: (i) activation of Ca pumps that sequester Ca++ into the smooth endoplasmic reticulum (SERCA) and extrude Ca++ into the extracellular space (PMCA); and (ii) activation of K+ channels causing membrane hyperpolarization that inhibits Ca++ influx by switching off voltage dependent Ca++ channels. The fall in intracellular Ca++ decreases MLCK activity and relaxation occurs as light chain phosphorylation is reduced by MLC phosphatase, the activity of which is increased by PKG.


What is the rationale for using beta adrenoceptor antagonist in angina?

Beta blockers depress myocardial contractility and reduce the heart rate. In addition to these effects, which reduce the oxygen demand, beta blockers may increase the perfusion of the ischaemic area because the increase in heart rate increases the duration of diastole and hence the time available for coronary blood flow. If necessary, a long acting nitrate is added.

Beta blockers are the standard drug used in angina, but they have many side effects and contraindications. If beta blockers cannot be used, e.g. in patients with asthma, then a calcium channel blocker can be used as an adjunct to short acting nitrates.


Why is the choice of beta blocker important in angina?

Beta blockers are used for the prophylaxis of angina. The choice of drug may be important, intrinsic activity may be a disadvtange in angina and the cardioselective beta blockers such as atenolol and metoprolol are probably the drugs of choice.


How to calcium channel blockers work in angina?

These drugs are widely used in angina and have fewer side effects than beta blockers. CCBs inhibit L-type voltage sensitive Ca++ channels in arterial smooth muscle causing relaxation and vasodilatation. Preload is not significantly affected. Calcium channels in the myocardium and conducting tissue are also affected by CCBs, which produces a negative inotropic effect by reducing Ca++ influx during the plataeu phase of the action potential. However, the dihydropyridines (e.g. nifedipine, amlodipine) have relatively little effect on the heart because they have a much higher affinity for channels in the inactivated state. Such channels are more frequently found in vascular smooth muscle because it is relatively more depolarised compared to cardiac myocytes. Furthermore, at clinical doses, vasodilatation results in a reflex increase in sympathetic tone that causes a mild tacchycardia and counteracts the negative inotropic effect. Amlodipine, which has a long duration of action, produces less tachycardia than nifedipine.


How do the non-dihydropyridine CCBs affect cardiac function?

The non-dihydropyridines include diltiazam and verapamil. Verapamil, and to a lesser extent diltiazam, depress the sinus node, causing a mild resting bradycardia. Verapamil binds preferentially to open channels and is less affected by the membrane potential. Conduction in the AVN is slowed and, because the effect of verapamil (unlike nifedipine) is frequency dependent, it effectively slows the ventricular rate in atrial arrhythmias.

The negative inotropic effects of verapamil and diltiazam are partially offset by the reflex increase in adrenergic tone and the decrease in afterload. Diltiazam has actions intermediate to those of verapamil and nifedipine and is popular in the treatment of angina because it does not cause tacchycardia.


What is involved in PCI and when is it used for stable angina?

PCI is performed by passing a fine guidewire across a coronary stenosis under radiographic control and using it to position a balloon which is then inflated to dilate the stenosis. A coronary stent is a piece of coated metallic "scaffholding" that can be deployed on a balloon and used to maximise and maintain dilatation of a stenosed vessel.

PCI is an effective symptomatic treatment for angina but has not been shown to improve survival in patients with stable angina. It is mainly used to treat single or two vessel disease. CABG surgery is usually the preferred option in patients with three vessel of left main disease.


What are the complications of PCI?

The main acute complication is vessel occlusion by thrombus or dissection, which may lead to myocardial damage (2-5%) requiring stenting or emergency CABG. The overall mortality risk is <0.5%. The main long term complication is restenosis. The routine use of stents in appropriate vessels reduces both acute complications and the incidence of restenosis. Drug eluting stents can reduce the risk even further at the cost of a small risk of late stent thrombosis. In combination with aspirin and heparin, adjunctive therapy with potent platelet inhibitors such as clopidogrel or glycoprotein IIb/ IIIa receptor antagonists, improves the outcome of PCI with lower short and long term rates of death and MI.


Which vessels are used for a CABG?

The internal mammary arteries, radial arteries or reversed segments of saphenous veins can be used to bypass coronary artery stenosis, usually under cardiopulmonary bypass.


What are the complications of CABG?

The operative mortality is approximately 1.5% but higher in elderly patients and those with poor LV function or significant co-morbidity (e.g. renal failure). There is a 1-5% risk of post operative stroke.


What is the prognosis following a CABG?

Approximately 90% of patients are angina free 1 year after surgery, but <60% of patients are asymptomatic >5 years after CABG.

Arterial grafts have a much better long term patency rates than veins. Treatment with aspirin or clopidogrel improves graft patency while intensive lipid lowering therapy slows progression of disease in the native coronary vessels and grafts. Persistant smokers are twice as likely to die in the 10 years following surgery compared with those who give up smoking at surgery.

CABG improves survival in patients with left main coronary stenosis and those with symptomatic three vessel coronary disease. The benefit is greatest in those with impaired LV function or positive stress testing prior to surgery.


What are the acute coronary syndromes?

This term encompasses unstable angina and myocardial infarction. Unstable angina refers to new onset or rapidly worsening (crescendo) angina, and angina on minimal exertion or at rest without myocardial damage. In MI there are symptoms at rest and myocardial necrosis occurs, leading to partial thickness, non ST segment elevation MI (NSTEMI) or full thickness ST elevation MI (STEMI).

Acute coronary syndrome may present de novo or against a background of chronic stable angina. The underlying pathophysiology is usually a fissured atheromatous plaque with adherent thrombus formation.


Why is unstable angina sometimes referred to as pre-infarction angina?

Unstable angina is associated with plaque disruption and superimposed partial thrombosis, distal embolisation of the thrombus and/or vasopasm. Unstable angina is the harbinger of more serious, potentially irreversible ischaemia (due to complete luminal occlusion by thrombus) and is therefore sometimes call pre-infarction angina.


Why is the subendocardial layer of the myocardium more susceptible to ischaemia?

Even though there is a well developed subendocardial plexus of blood vessels, flow in this part of the myocardium is restricted to diastole. Blood vessels are collapsable tubes and are susceptible to compression when tension within the myocardial wall increases. This tension is greatest when the ventricles are dilated, especially in the subendocardial layer. In the area at risk for ischaemia/ infarction (i.e. the perfusion area of the occluded artery) myocyte necrosis progresses from the endocardium to the epicardium as a "wavefront", with a defined time course. 40% of the myocardium can be salvaged if reperfusion takes place within 3 hours.


What is myocardial infarction?

Commonly called a "heart attack", a myocardial infarction is an area of necrosis of heart muscle resulting from a sudden absolute or relative reduction in the coronary blood supply. The commonest precipitating cause is thrombosis superimposed on, or haemorrhage within, an atheromatous plaque in an epicardial coronary artery.


What is the pathogenesis of myocardial infarction?

The vast majority of MIs are caused by acute coronary artery thrombosis. In most instances, disruption of preexisting atherosclerotic plaques serves as the precipitating cause of thrombus generation, vascular occlusion and subsequent transmural infarction of the downstream myocardium.

In 10% of MIs, however, transmural infarction occurs in the absence of occlusive atherosclerotic vascular disease. These infarcts are probably due to coronary artery vasospasm or embolization from mural thrombi (e.g. in AF) or valve vegetations.

Occassionally, especially with infarcts limited to the innermost (subendocardial) myocardium, thrombi or emboli may be absent. In such cases, severe diffuse coronary atherosclerosis leads to marginal perfusion of the heart. In this case, a prolonged period of increased demand (e.g. due to tachycardia or hypertension) can lead to ischaemic necrosis of the myocardium most distal to the epicardial vessels.

Finally, ischaemia without detectable atherosclerosis or thromboembolic disease can be caused by disorders of small intramyocardial arterioles including vasculitis, amyloid deposition or stasis as in sickle cell disease.


What is the series of events happening after coronary artery occlusion in MI?

In a typical MI, the following events occur:
- an atheromatous plaque is suddenly disrupted by intraplaque haemorrhage or mechanical forces, exposing sub endothelial collagen and necrotic plaque contents to the blood

- platelets adhere, aggregate and are activated, releasing thromboxane A2, ADP, and serotonin - causing further platelet aggregation and vasospasm

- activation of coagulation by exposure of tissue factor and other mechanisms adds to the growing thrombus

- within minutes, the thrombus can evolve to completely occlude the coronary artery lumen


How does the myocardium respond to ischaemia?

Loss of myocardial blood supply leads to biochemical changes. Within minutes of vascular occlusion, aerobic glycolysis stops leading to a drop in ATP and accumulation of lactic acid. The functional consequence of this is a rapid loss of contractility, which occurs within a minute or so of the onset of ischaemia. Ultrastructural changes (e.g. mitochondrial swelling, myofibril relaxation) are also present. These early changes are potentially REVERSIBLE. Only severe ischaemia lasting at least 20-40 minutes causes irreversible damage and myocyte death leading to coagulation necrosis. With longer periods of ischaemia, vessel injury occurs leading to microvascular thrombosis.


What is meant by the term "stunned myocardium"?

If myocardial blood supply is restored before irreversible injury occurs, cell viability can be preserved. This is the rationale behind early diagnosis and intervention by thrombolysis or angioplasty (PCI). But, despite timely reperfusion myocardial dysfunction lasts several days. This defect is caused by persistant problems with myocardial biochemistry that result in a non-contractile state (stunned myocardium). Such stunning can be severe enough to produce transient but reversible cardiac failure.


What is the most common cause of death following an MI?

Fatal arrhythmias are the most common complication of MI. Myocardial ischaemia contributes to ischaemia by disrupting the blood supply of the conducting system. Although massive myocardial damage can cause a fatal mechanical failure, sudden cardiac death in the setting of myocardial ischaemia is most often (in 80-90%) of cases due to VF arrest.


Describe the pattern of progression of myocardial necrosis after coronary artery occlusion

Irreversible injury of ischaemic mycocytes first occurs in the subendocardial zone. This region is especially vulnerable to ischaemia because it is the last area to receive blood delivered by the epicardial vessels, and also because it is exposed to relatively high intramural pressures which act to impede the inflow of blood. With more prolonged ischaemia, a wavefront of cell death moves through other regions of the myocardium with the infarct usually achieving its full extent within 3 to 6 hours. In the absence of intervention, the infarct can involve the entire wall thickness (transmural infarct).


Where does occlusion of the left anterior descending artery affect?

Acute occlusion of the proximal LAD artery is the cause of 40-50% of MIs and typically results in infarction of the anterior wall of the left ventricle, the anterior two thirds of the ventricular septum and most of the heart apex. More distal occlusion of the LAD may only affect the apex.


What territory does the RCA supply?

The coronary artery - either RCA or LCX - that perfuses the posterior third of the septum is called "dominant" (even though the LAD and LCX collectively perfuse the majority of the left ventricular myocardium). In a right dominant circulation (80% of people) the RCA supplies the entire right ventricular free wall, the posterobasal wall of the left ventricle and the posterior third of the ventricular septum. The LCX generally perfuses only the lateral wall of the left ventricle. Thus, RCA occlusions can potentially lead to left ventricular damage.


What causes a transmural infarction?

Myocardial infarcts caused by occlusion of an epicardial vessel (in the absence of any therapeutic intervention) are typically transmural. This means that the necrosis involves the full thickness of the ventricular wall in the distribution of the affected coronary artery. This pattern of infarction is usually associated with a combination of chronic coronary atherosclerosis, acute plaque change and superimposed thombosis and produces ST elevation MI on ECG.

Nearly all transmural infarcts (involving 50% or more of the ventricle thickness) affect at least a portion of the left ventricle and/or interventricular septum. Even in transmural infarcts, a narrow rim of viable subendocardial myocardium is preserved by diffusion of oxygen and nutrients from the ventricular lumen.


What are subendocardial infarcts?

The subendocardial zone is normally the least perfused region of the myocardium, so this area is most vulnerable to a reduction in coronary blood flow. A subendocardial infarct - typically involving roughly the inner third of the ventricular wall - can occur as a result of a plaque disruption followed by a coronary thrombus that becomes lysed (therapeutically or spontaneously) before myocardial necrosis extends across the full thickness of the wall.

Subendocardial infarcts can also result from prolonged severe reduction in systemic blood pressure, as in shock superimposed on chronic, otherwise, non critical, coronary stenosis. In subendocardial infarcts that occur due to hypotension, myocardial damage is usually circumferential, rather than being limited to the distribution of a single coronary artery.


What causes multifocal microinfarcts?

This pattern is seen when there is pathology involving only smaller intramural vessels. This may occur in the setting of microembolization, vasculitis, or vascular spasm, for example due to endogenous catechols, or drugs (cocaine). Elevated catechols also increase heart rate and myocardial contractility, exacerbating ischaemia caused by vasospasm.

The outcome of such vasospasm can be sudden cardiac death (usually caused by a fatal arrhythmia) or an ischaemic dilated cardiomyopathy - so called "takotsubo cardiomyopathy" (broken heart syndrome).


What determines the gross and microscopic appearance of an MI?

The micro and macroscopic appearance of an MI depends on the age of the injury. Areas of damage progress through highly characteristic sequence of morphological changes, from coagulative necrosis to acute and then chronic inflammation, to fibrosis. Myocardial necrosis causes scar formation WITHOUT any significant regeneration.


At what time point do MI's become grossly recognisable?

Recognition of very recent MI can be challenging, especially when death occurs within a few hours. Myocardial infarcts less than 12 hours old usually are not grossly apparent. However, infarcts more than 3 hours old can be visualised by exposing myocardium to vital stains, such as triphenyl tetrazolium chloride, a substrate for lactate dehydrogenase. Because this enzyme is depleted in areas of ischaemic necrosis (it leaks out of the damaged cells), the infarcted area is unstained (pale), while old scars appear white and glistening.

By 12-24 hours after MI, an infarct usually can be grossly identified by a red blue discolouration caused by stagnated, trapped blood.


Outline the macroscopic changes infarcts undergo following MI

Up to 18 hours - no visible changes

24-48 hours - dark mottling, with some pale, oedematous muscle. Haemorrhagic appearance if reperfusion therapy given

3-4 days - yellow rubbery centre with haemorraghic border (even if no reperfusion therapy)

1-3 weeks - infarcted area paler and thinner than unaffected ventricle

3-6 weeks - silvery scar becoming tough and white


How do the microscopic features of an infarct change with time?

Unlike gross features, microscopic features can be detected fairly soon after infarction. Typical features of coagulative necrosis become detectable within 4 to 12 hours of infarction. "Wavy fibres" also can be present at the edges of an infarct; these reflect stretching and buckling of noncontractile dead fibres. Sublethal ischaemia can also induce intracellular myocyte vacuolization; such myocytes are viable but unable to contract.

Necrotic myocardium causes acute inflammation most prominant 1 to 3 days after MI, followed by a wave of macrophages that remove necrotic myocyctes and neutrophil fragments (most prnounched 5 to 10 days after).

The infarcted zone is replaced by granulation tissue after 1-2 weeks which forms the scaffholding upon which dense collagenous scar forms. Fibrosis occurs after 3-6 weeks.

Healing requires the migration of inflammatory cells and ingrowth of new vessels from the infarct margins. Thus, an MI heals from its borders toward the centre and a large infarct may not heal as fast or as completely as a small one. Once healed estimation of age is impossible.


What blood markers change in MI?

Extensive necrosis of cardiac muscle is associated with release of cardiac enzymes and proteins into the circulation. These molecules include myoglobin, cardiac troponins T and I, creatin kinase (CK) (specifically the myocardial isoform CK-MB) and lactate dehydrogenase. Troponins and CK-MB have high specificity and sensitivity for myocardial damage. Patients may also show a transient leucocytosis in the first 1-3 days but the value rarely exceeds 15.

In unstable angina there is no detectable rise in cardiac biomarkers or enzymes, and the initial diagnosis is made from the clinical history and ECG only.


How soon after infarction does CK-MB rise?

CK-MB remains a valuable marker of myocardial injury, but total CK activity is not since various isoforms of CK are also found in brain, myocardium and skeletal muscle. However, CK-MB isoform - principally derived from myocardium, but found in low levels in skeletal muscle - is the more specific indicator of heart damage.

- activity rises within 2-4 hours
- peaks at 24-48 hours
- returns to normal within approximately 72 hours


How does the troponin profile change after MI?

TnI and TnT normally are not found in the circulation, however, after acute MI both are detectable within 2 to 4 hours with levels peaking at 48 hours and remaining elevated for 7 to 10 days. Although cardiac troponin and CK-MB are equally sensitive markers of the early stages of an MI, persistence of elevated troponin levels for approximately 10 days allows the diagnosis of an acute MI long after CK-MB levels have returned to normal.


What are the clinical features of the acute coronary syndromes?

Pain: like that of angina but more severe and prolonged


Vomiting: due to vagal stimulation, particularly in inferior MI

Syncope or sudden death due to arrhythmia

MI may occasionally be painless in diabetics or elderly patients


How should the acute coronary syndromes be investigated?

The ECG is THE most important investigation in the assessment of acute chest pain. It shows a characteristic series of changes.

The earliest change is usually ST segment elevation, followed by diminuation in the size of the R waves and development of a Q wave (indicating full thickness infarction). Subsequently, the T wave becomes inverted and this change persists after the ST segment has returned to normal. ECG changes are best seen in leads the "face" the infarcted area.


What leads suggest an anterior infarction?

Changes in V1 to V4 indicate occlusion of the LAD.


In what ECG leads does an anteriolateral infarction affect?

Occlusion of the LCX causes ECG changes in leads V4 to V6, lead I and lead aVL.


Which leads best show an inferior infarction?

Inferior infarction (usually caused by obstruction of the proximal right coronary artery) produces changes in leads II, III and aVF.


What vessel occlusion causes a posterior infarction?

The posterior third of the interventricular septum and the posterior left ventricle are perfused by the posterior descending artery. This can arise from either the RCA (in 90% of individuals) or the LCX. Obstruction of the distal RCA to include the posterior descending artery causes a posterior infarct.

Infarction of the posterior wall of the left ventricle does not cause ST elevation or Q waves in the standard leads, but can be diagnosed by the presence of reciprocal changes (ST depress and tall R waves in leads V1-V4). Occassionally, new onset LBBB is the only ECG change.


What are the ECG changes associated with NSTEMI?

In patients with NSTEMI or unstable angina, the ECG may show ST/T wave changes, including ST depression, transient ST elevation and T wave inversion. These conditions carry a high risk of progression to STEMI or death.


When is echo used in the context of an MI?

This is useful for assessing LV and RV function and for detecting important complications, such as mural thrombus, cardiac rupture, VSD, mitral regurgitation and pericardial effusion.


What is the GRACE score and what is it used for?

Risk stratification using the GRACE score, guides the use of more complex pharmacological and interventional treatment. Clinical features include:
- heart failure score (Kilip class)
- systolic BP
- HR
- age (years)
- serum creatinine
- ST segment deviation
- elevated cardiac enzymes

The points are added up and predict in hospital death:
- 0.2% for points <60
- 52% for points total >240

Additional markers of an adverse prognosis include:
recurrent ischaemia, extensive ECG changes, elevated troponin, arrhythmias, haemodynamic complications during ischaemic episodes


Outline the immediate management of patients with unstable angina or NSTEMI

Assess the patient clinically, using ECG and troponin levels and get peripheral access.

In unstable angina and NSTEMI there is no ST segment elevation so that management is BROMANCE:
- beta blocker - e.g. atenolol 5mg IV unless contraindicated, e.g. asthma
- repeat ECG (and place the patient on cardiac monitoring)
- oxygen
- morphine (plus anti-emetic - e.g. metaclopramide IV)
- aspirin 300 mg
- nitrates (sub lingual GTN or nitrate infusion if chest pain worsening)
- clopidogrel 600 mg (or second antiplatelet - e.g. ticagralor 180 mg PO)
- enoxaparin or other low molecular weight heparin (e.g. fondaparinux)

Next calculate the patients GRACE score, if they are a low risk (<1%) and do not have recurrent symptoms then admit them to CCU for maintenance therapy with aspirin, ticagrelor, fondapurinux/ LMWH, statin, beta blocker (e.g. metoprolol) and an ACEi.

If the patient is at medium or high risk (5-9%)(esp diabetes or high trop) OR they have recurrent symptoms, consider them for coronary angiography + GP IIb/IIIa receptor antagonist IV - e.g. tirofiban and abciximab. After which, admit them for maintenance therapy.


How should patients with STEMI be managed?

All ACS patients should be initially treated with MONA - morphine, oxygen, nitrates, aspirin. Beta blockers - e.g. atenolol 5mg IV is also given unless contraindicated.

Clinical assessment showing ST segment elevation should prompt consideration for primary PCI. If:
- it is available
- <120 mins away
- >120 mins but the patient is ineligible for thrombolysis

If yes to the above:
- give IV GP IIb/IIIa receptor antagonist + emergency PCI
- admit for maintenance therapy

If no the above and the patient is eligible for thrombolysis:
- thrombolysis IV
- if there is no failed reperfusion then consider angiography and GP IIb/IIIa receptor antagonists and admit
- if there is failed reperfusion give GP IIb/IIIa antagonists and emergency PCI

If the patient is ineligible for thrombolysis treat as for NSTEMI or unstable angina.


What antithrombotic therapy is used to treat ACS?

Antithrombotic therapy includes antiplatelet and anticoagulant drugs. Antiplatelet therapy with oral aspirin (300mg initially, then 75mg daily) improves survival. In combination with aspirin, the early use of a 2nd antiplatelet, clopidogrel, (600mg then 150mg daily for a week, then 75mg daily) confers a further reduction in mortality. However, in acute coronary syndrome, ticagrelor (180 mg, then 90 mg twice daily) is more effective.

Anticoagulation reduces thromboembolic complications and reinfarction. The pentapolysaccharide fondapurinux (2.5 mg SC daily) has the best safety and efficacy profile, but unfractionated or low molecular weight heparin is also useful. Anticoagulation should be continued for 8 days or until hospital discharge.


Should reperfusion therapy be given in NSTEMI?

Immediate reperfusion therapy has no demonstrable benefit and thrombolytic therapy may be dangerous in these patients. Selected medium (5%) and high risk (>9%) patients may benefit from in hospital coronary angiography and revascularisation but this does not need to be within 12 hours.


What is the gold standard treatment of choice for STEMI?

Primary percutaneous coronary intervention (PCI) is the treatment of choice for STEMI. Outcomes are best when used in combination with glycoprotein IIb/IIIa receptor antagonists and intracoronary stent implantation. Compared to thrombolytic therapy, it is associated with a greater reduction in the risk of death, recurrent MI or stroke. But the use of primary PCI has been limited by availability, so IV thrombolytic therapy remains first line treatment in many hospitals. When primary PCI cannot be achieved within 2 hours, thrombolytic therapy should be administered.


In what patients is thrombolysis offered?

Thrombolysis is provided to patients with STEMI who are unable or ineligible to receive primary PCI within 2 hours.

It helps to restore coronary patency, preserves LV function and reduces the mortality of MI by 25-50%. Successful thrombolysis leads to reperfusion with relief of pain and resolution of acute ST elevation. It is indicated only in patients presenting within 12 hours of onset of symtpoms, and with ECG changes of LBBB or ST segment elevation of >1mm in the limb leads or 2mm in the chest leads. The benefit is greatest when treatment is given within the first few hours.


What agents are used for thrombolysis?

Alteplase (human tissue plasminogen activator, tPA) 15 mg bolus then 0.75 mg/kg up to 50 mg over 30 mins, then 0.5 mg/kg up to 35 mg over 60 mins is associated with better survival rates than other agents such as streptokinase, but carries a slightly higher risk of intracerebral bleeding. Newer generation analogies of tPA, such as tenecteplase and reteplase have equivalent efficacy to alteplase but have a longer plasma half life and can be given by bolus administration. The major hazard of thrombolytic therapy is bleeding, particularly cerebral haemorrhage.


When are patients with MI most likely to experience an arrhythmia?

MI's lead to cardiac irritability and conduction disturbances that can cause sudden death. Pump failure and excessive sympathetic stimulation may also play a role. Approximately 90% of patients develop some form of arrhythmia with the incidence being higher in STEMIs than NSTEMIs. MI associated arrhythmias include heart block of variable degree (including asystole), bradycardia, SVT, ventricular premature contractions or VT and VF. The risk of serious arrhythmias (e.g. VF) is greatest in the first few hours - days following infarction. AV block complicating inferior infarction is usually temporary and often resolves following re perfusion. AV block complication anterior infarction carries a risk of asystole and prophylactic temporary pacemaker should be inserted.

Pain relief, rest and correction of hypokalaemia are important preventative measures.


How should patients who have experienced an infarct but have persistent ischaemia be treated?

Persistant chest pain following infarction is due to progressive myocardial necrosis (extension of the infarct) and usually occurs 12 hours to a few days following the original infarct. Angina can be immediate or delayed (weeks) and is caused by ischaemia to non infarcted cardiac muscle.

Patients with recurrent angina following acute coronary syndrome are at high risk and should be considered for coronary angiography and urgent revascularisation. Angiography is also indicated in all those who have had successful thrombolysis to treat residual stenosis.


How often does severe pump failure occur following MI?

In general, MIs affect ventricular pump function in proportion to the volume of damage. In most cases, there is some degree of left ventricular failure manifested as hypotension, pulmonary congestion and pulmonary oedema. Severe pump failure (cardiogenic shock) occurs in roughly 10% of patients with transmural infarcts and indicates a bad prognosis. They are typically associated with infarcts that damage more than 40% of the myocardium.

Pump failure can also be caused by papillary muscle dysfunction. Although papillary muscles rarely rupture following an MI they are frequently dysfunctional and can be poorly contractile due to the ischaemia leading to post infarct mitral regurgitation. Much later, papillary muscle fibrosis and shortening or global ventricular dilation also can cause mitral valve insufficiency.


What are the clinical features of papillary muscle rupture?

This may cause acute pulmonary oedema and shock, with a pansystolic murmur audible on auscultation due to sudden onset of severe mitral regurgitation. There may also be a right ventricular heave or palpable thrill. Emergency mitral valve replacement may be necessary.

Papillary muscle rupture causing mitral incompetence occurs in the first few days following infarction but can also be a late feature.


How commonly is the right ventricle involved in infarction?

Isolated right ventricular infarction occurs in only 1% to 3% of MIs. But the right ventricle frequently is injured in association with septal or left ventricular infarction. In either case, right sided heart failure is a common outcome, leading to venous circulation pooling and systemic hypotension.


Myocardial rupture is a rare complication of MI. How often does it complicate infarction and when is it likely to occur?

Cardiac or ventricular rupture complicates only 1% to 5% of MIs but is frequently fatal when it occurs. Left ventricular free wall rupture is most common, usually resulting in rapidly fatal haemopericardium and cardiac tamponade.

Ventricular septal rupture creates a VSD with left to right shunting and papillary muscle rupture leads to severe mitral regurgitation.

Rupture occurs most commonly within 3 to 7 days after infarction - the time in the healing process when lysis of myocardial connective tissue is maximal and when much of the infarct has been converted to soft granulation tissue. RIsk factors for free wall rupture include age over 60 years, anterior or lateral wall infarctions, female gener, lck of left ventricular hypertrophy and first MI (as scarring associated with prior MIs tends to limit the risk of myocardial tearing).


What are the clinical features of interventricular septum rupture?

This usually presents with sudden haemodynamic deterioration accompanied by a new load pansystolic murmur. It may be difficult to distinguish from acute mitral regurgitation but tends to cause right heart failure rather than pulmonary oedema. Doppler echocardiography will confirm the diagnosis. Without prompt surgery the condition is usually fatal.


When do mural thrombi tend to develop as a complication of MI?

Mural thrombi usually develop 1 week or more following MI. With any infarct, the combination of attenuated myocardial contractility (causing stasis) and endocardial damage (causing a thrombogenic surface) can foster mural thrombosis, eventually leading to left sided thromboembolism. However, this is much reduced by modern thrombolytic and anticoagulant therapies.


When does pericarditis typically occur following MI?

Pericarditis is particularly common on the second and third days following infarction. A distinct new pain develops, which is often positions or exacerbated by inspiration and pericardial friction rub is present. Opiate analgesics are preferred over NSAIDs as the latter may increase the risk of aneurysm formation and myocardial rupture. Dressler's syndrome is an autoimmune disorder that occurs weeks to months after the infarct and is characterised by persistent fever, pericarditis and pleurisy. Severe symptoms may require treatment with an NSAID or corticosteroids.

Transmural MIs can elicit fibrinohaemorrhagic pericarditis; this is an epicardial manifestation of the underlying myocardial inflammation. Extensive infarcts or severe pericardial inflammation occasionally leads to large effusions or can organize to form dense adhesions that eventually manifest as a constrictive lesion.


When can a ventricular aneurysm develop following MI?

This is a late complication, and aneurysms of the ventricular wall most commonly result from a large transmural anteroseptal infarct that heals with the formation of thin scar tissue. Complications of ventricular aneurysms include mural thrombus, arrhthymias and heart failure but rupture of the fibrotic wall does not occur.


How are scoring systems used in the late management of patients following MI?

Scores (e.g. GRACE score) predict early mortality and are used to select patients for intensive therapy. Prognosis of survivors of acute coronary syndrome is related to:
1) Myocardial damage - assessed by echo early in recovery

2) Ischaemia - patients with early ischaemia need urgent coronary angiography and revascularisation. Others should undergo exercise tolerance test 4wks after the infarct; coronary angiography is required for those with a strongly positive test

3) Ventricular arrhythmias - if these occur during recovery from ACS they may indicate poor ventricular function and risk of sudden death. Although empiric anti-arrhythmic treatment is of no value, selected patients may benefit from specific anti-arrhtyhmic therapy (eg. ICDs)


What lifestyle and risk factors should be modified following an MI?

Smoking - giving up is one of the most effective things a patient can do after an ACS, as cessation halves mortality at 5 years

Hyperlipidaemia - lowering serum cholesterol with statins following ACS reduces risk of death, reinfarction, stroke and the need for revascularisation. Lipids should be measured within 24 hrs of presentation because cholesterol often falls in the 3 months following infarction. Irrespective of serum cholesterol, all patients should receives statins following ACS, but those with LDL cholesterol >3.2 mmol/L benefit from more intensive therapy - e.g. atorvastatin 80 mg daily

Others - maintain idea weight, eating Mediterranean diet, taking regular exercise, controlling diabetes and HTN


When can patients be discharged following an MI?

If there are no complications, the patient can return home in 5 days and gradually increase activity, with the aim of returning to work in 4-6 weeks. The majority of patients may resume driving after 4-6 weeks. Formal rehabilitation programmes, based on graded exercise protocols with individual and group counselling, are often very successful.


What secondary prevention should patients be placed on following MI?

Low dose aspirin therapy reduces the risk of further infarction and other vascular events by 25% and should be continued indefinitely.
Clopidogrel should be given in addition to aspirin for at least 3 months and is a suitable alternative in aspirin intolerant patients.

Long term beta blocker therapy reduces mortality by 25% in survivors of acute MI and should be prescribed unless there are specific contraindications.

ACEi can prevent the onset of heart failure, improve survival and reduce hospitalisation, and should be considered in all patients with acute coronary syndrome.

Patients with acute MI complicated by heart failure and LV dysfunction, and either pulmonary oedema or diabetes, further benefit from additional mineralocorticoid receptor antagonism (e.g. eplerenone 25-50mg daily). ICDs reduce the incidence of sudden cardiac death in patients with severe LV impairment.


What is the prognosis for patients with ACS?

Of those who survive the acute incidence, >80% live for a further year, this decreases to 50% survival for 10 years. Early death is usually due to an arrhythmia but, later on, the outcome is determined by the extent of myocardial damage. Unfavourable features include poor LV function, AV block and persistent ventricular arrhythmias. The prognosis is worse for anterior than for inferior infarcts.

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