Coronary Artery Disease

Coronary Artery Disease (CAD)

Introduction

• Coronary artery disease (CAD), also known as ischaemic heart disease, is a major cause of disease and death in the Western world.
• It results from damage to heart cells due to inadequate blood flow (ischaemia) and reduced oxygen delivery (hypoxia).
• Heart cells are vulnerable to ischaemic damage because they lack regenerative ability, leading to the replacement of functional muscle with non-contractile scar tissue.
• Repeated stressors can lead to continued deterioration and heart failure.
• The primary cause of coronary ischaemia is atherosclerosis, which is potentially reversible.
• Angina occurs when cells experience a temporary ischaemic state.
• Myocardial infarction occurs when cells experience anoxia and die.

Epidemiology

• CAD is the leading cause of death in Australia.
• Cardiovascular disease (CVD), including CAD and stroke, costs the Australian federal government 7.7 billion each year, including 1.65 billion for drugs.
• CVD affects 4.2 million Australians.
• The burden of CVD increases with the aging population and rising obesity rates.
• Women are 2.9 times more likely to die of CVD than breast cancer.
• Aboriginal and Torres Strait Islander peoples are 14 times more likely to die from CAD than non-Indigenous Australians.

Vascular Changes in Aging

• 74\% of all deaths from coronary disease occur in individuals aged 75 and older.
• Male deaths from CAD between ages 45 and 74 are almost three times those of females.
• After age 75, 87\% of females die from CAD compared to 64\% of males.

The Role of Endothelial Cells

• The endothelium is the single-cell layer lining blood vessel walls and plays a key role in cardiovascular function.
• Endothelial cells are involved in:
  • Manipulation of vascular tone (vasodilation and vasoconstriction).
  • Control of vascular permeability.
  • Mediation of inflammation.
  • Angiogenesis (new blood vessel production).
  • Hemostasis (blood clotting).
• Vascular tone reflects the balance between central control exerted by the brain stem and local responses to metabolic activity.
• Systemic vasoconstriction is controlled centrally by noradrenaline binding to alpha-adrenergic receptors.
• Local vasoconstriction is mediated by local oxygen availability and endothelin-1.

Vasodilation

• Nitric oxide (NO) is a potent vasodilator produced by endothelial cells.
• NO diffuses to smooth muscle cells, activating guanylate cyclase, which produces cyclic guanosine monophosphate (cGMP).
• cGMP closes voltage-gated calcium channels, reducing smooth muscle contraction and causing vasodilation.
• Adenosine, a building block of ATP, increases with metabolic rate.
• Adenosine activates adenosine A2 receptors on smooth muscle cells, increasing cyclic adenosine monophosphate (cAMP).
• cAMP closes voltage-gated calcium channels, leading to vasodilation.
• Prostaglandins, specifically prostacyclin produced by endothelial cells, oppose thromboxane A2, preventing platelet aggregation.
• Endothelial cells release plasmin to dissolve thrombi.

Oxygen as a Vasoconstrictor

• Oxygen acts as a vasoconstrictor in the vascular beds of the body (except in the lungs).
• High levels of oxygen can lead to cellular damage via free radicals, also known as reactive oxygen species (ROS).
• The body manages free radicals with antioxidants like vitamin E (alpha-tocopherol) and tight regulation of oxygen availability.
• Antioxidants act as sponges to mop up free radicals produced by normal metabolic processes and dietary intake.

Aetiology and Pathophysiology of Coronary Artery Disease

• Coronary artery disease is primarily caused by atherosclerosis, with other causes including coronary artery spasm and emboli.
• Atherosclerosis refers to the fatty material that fills and stiffens the arteries, often complicated by thrombi.
• Increased shear stress causes the release of nitric oxide (NO) to promote vasodilation, while reduced shear stress results in the release of endothelin (ET) to promote vasoconstriction.
• Aging endothelium reduces vasodilating molecules and increases vasoconstricting molecules, causing the vessel wall to become stiffer.
• Other vascular changes of senescence include increased oxidative stress, a pro-inflammatory state, reduced anti-inflammatory molecules, DNA damage, and telomere erosion, leading to intimal wall thickening and luminal narrowing.

Lipids and Lipid Transport

• Lipids are transported throughout the circulatory system by lipoproteins due to their insolubility in blood.
• Triglycerides and cholesterol are two important types of lipids carried by lipoproteins.
• Triglycerides are a critical energy source, and cholesterol is necessary for cell membranes, steroids, and bile acid production.
• Apoplipoproteins are interwoven around and through the lipoprotein structure, functioning in assembly, structural integrity, receptor binding, and enzyme coactivation.
• High-density lipoprotein (HDL) retrieves cholesterol from arterial walls for delivery to the liver and is known as ‘good’ cholesterol. Serum apolipoprotein A1 (apoA1) measures HDL.
• Low-density lipoprotein (LDL) deposits cholesterol to arterial walls and is known as ‘bad’ cholesterol. Serum apolipoprotein B (apoB) measures LDL.
• Very-low-density lipoprotein (VLDL) carries triglycerides to cells for energy. Most VLDLs become intermediate-density lipoproteins (IDLs) and then LDLs.
• Chylomicrons transport dietary triglycerides and cholesterol from the intestinal epithelial cells to the liver, skeletal muscle, and adipose tissue via the intestinal lymphatic system and blood.
• VLDLs, LDLs, IDLs, and chylomicrons are collectively known as non-HDL cholesterol.
• Cells require cholesterol and fat for cell membranes, steroid hormones, and metabolic functions.
• Lipoproteins with more protein are more easily transported into cells due to cell-receptor recognition.
• Lipoproteins with less protein are less likely to be taken up by cells and are more likely to be found freely circulating in the bloodstream, contributing to atherosclerotic plaque development.
• Recommended serum levels:
  • LDL cholesterol: < 2.0 mmol/L
  • HDL cholesterol: > 1.0 mmol/L
  • Triglycerides: < 2 mmol/L

The Development of an Atherosclerotic Plaque

• Atherosclerotic plaques damage the blood vessel wall, reduce blood flow, and change the architecture of the blood vessel, making it twisted and tortured.
• Plaque formation requires:
  • Damage to the endothelial cells lining the wall.
  • Retention of LDL and VLDL in the blood vessel wall.
• Cholesterol moves passively into the blood vessel wall, and micro-tears form due to hypertension and turbulence of blood flow.
• Hypertension increases blood pressure against the vessel wall, and turbulence occurs at vessel curves or bifurcations, both leading to endothelial cell damage.
• These events lead to a focal zone for atherosclerotic plaque development, initiating recruitment of leukocytes and inflammation.
• Increased fat and cholesterol entry into the vessel wall leads to formation of micro-aggregates.
• A small proportion of LDL is converted to oxidized LDL (Ox-LDL), attracting circulating monocytes (macrophages), local macrophages, T lymphocytes, and smooth muscle cells.
• Macrophages increase LDL oxidation to remove LDL, but Ox-LDL is cytotoxic at elevated levels, leading to macrophage and smooth muscle cell death and deposition of cellular contents in the focal zone.
• A necrotic core develops, leading to fibrin infiltration and a fibrous cap formation, contributing to vessel wall stiffening.
• Calcium is deposited, further contributing to the hardening of the blood vessel wall.

Plaque Rupture and Thrombus Formation

• The growing plaque with its stiff cap is prone to rupture due to:
  • Pulsing and flexing of arteries.
  • Increased presence of cholesterol crystals.
• Once the cap splits, the necrotic material traps platelets, forming aggregates and releasing pro-thrombotic factors, leading to thrombus formation.
• Damage to endothelial cells reduces or eliminates the release of thrombolytic factors, favoring thrombi formation.
• Availability of nitric oxide (NO) is reduced, decreasing blood vessel diameter due to unopposed vasoconstriction.

Relationship Between Atherosclerosis and Coronary Artery Disease

• The combination of atherosclerotic plaque, unopposed vasoconstriction, and thrombus leads to an imbalance between blood supply and demand in the heart.
• Baroreceptors and chemoreceptors increase demand on the heart, increasing sympathetic outflow to increase heart rate and contraction force.
• Inadequate oxygen leads heart cells to anaerobic metabolism, releasing lactate, adenosine, bradykinins, serotonin, histamines, and ROS.
• Adenosine is responsible for much of the pain signaling as a result of myocardial ischaemia which stimulates chemosensitive receptors of unmyelinated nerve fibres.
• Impulses travel along nociceptors to sympathetic ganglia between the seventh cervical and fourth thoracic portions of the spinal cord, resulting in poorly localized pain signals.
• 'Silent' angina is more likely in women and individuals with peripheral vascular disease due to nerve damage.

Risk Factors for Atherosclerosis

• Risk factors are divided into major modifiable and non-modifiable risk factors.

Major Modifiable Risk Factors

• Hyperlipidaemia: Elevated LDL levels promote atherosclerosis, while low HDL levels reduce reverse cholesterol transport.
• Hypertension: Leads to increased vascular inflammation. Angiotensin II causes macrophages, smooth muscle cells, and endothelial cells to produce pro-inflammatory cytokines, superoxide anions, and pro-thrombotic factors, which ultimately result in further endothelial damage.
• Cigarette smoking: Promotes vasoconstriction, increases oxidative stress, and increases platelet aggregation. It also disrupts lipid metabolism, resulting in decreased HDLs and increased LDLs.
• Insulin resistance: Contributes to significant metabolic and cardiovascular derangement as it stimulates endothelial production of the critical vasodilator NO, which is also important in limiting vascular smooth muscle cell (VSMC) growth and migration.
• Diabetes mellitus: Causes the formation of advanced glycation end products (AGE). Diabetes is pro-atherogenic through AGE production, resulting in increased oxidative stress and reactive oxygen radicals, and the release of pro-inflammatory cytokines.
• Lack of physical activity and obesity: Obesity is considered pro-atherogenic because of its influence on endothelial dysfunction. An individual with a body mass index (BMI) of more than 30 kg/m^2 has a more than four times greater likelihood of developing cardiovascular disease than an individual with a BMI of 25 kg/m^2 or less.
• Unhealthy diet: Foods high in saturated fats increase the atheroma burden. Consistently consuming an unhealthy diet can also lead to obesity, diabetes mellitus and hypertension, further increasing atherosclerotic risk.
• Obstructive sleep apnoea (OSA): Contributes to an atherogenic risk independently, experiencing intermittent cessation of breathing and resulting hypoxia.
• Excess alcohol intake: Excessive alcohol intake (> 40 g/day) is associated with pro-inflammatory effects, endothelial dysfunction from reduced NO, increased lipid peroxidation and oxidative stress, and increased monocyte adhesion to the endothelium.
• Hyperhomocysteinaemia: High levels of homocysteine can be found in the blood and is known to be atherogenic through various mechanisms, such as its ability to cause a reduction of NO, increase reactive oxygen species and lipid peroxidation, and also increase platelet aggregation.

Non-Modifiable Risk Factors

• Age, male gender and a positive family history of early heart disease.

Inflammation and the Gut Microbiota

• Both innate and specific immune systems contribute to chronic inflammation.
• The non-specific (innate) immune system initiates, exaggerates and sustains numerous cellular mechanisms, contributing to a state of atherogenesis.
• The adaptive immune system also contributes to the atherogenic process, with T cells that transmigrate to the intima and, in response to antigens, initiate the production of even more pro-inflammatory mediators.
• Data are suggesting that the composition of a person’s intestinal microorganisms (gut microbiota or microbiome) can significantly influence their propensity to develop atherosclerosis.
• Some bacterial species are more likely to have a systemic anti-inflammatory effect, while other species appear to induce a systemic pro-inflammatory effect that can augment the development of atherosclerosis.

Metabolic Syndrome

• Metabolic syndrome is a cluster of disorders such as abdominal obesity, insulin resistance/diabetes, abnormal glucose tolerance, hypercholesterolaemia and hypertension.

Acute Coronary Syndrome

• Acute coronary syndrome is a collective term for conditions that result in an alteration to blood flow to a part of the myocardium.
• This condition may be potentially reversible, such as with unstable angina pectoris (UAP), or result in irreversible cell death, such as in myocardial infarction (MI).
• Myocardial infarction can be further divided into:
  • Non-ST elevation myocardial infarction (NSTEMI, also known as non-ST elevation acute coronary syndrome [NSTEACS]), where a partial or transiently obstructive thrombus in the coronary artery results in ischaemia and necrosis.
  • ST elevation myocardial infarction (STEMI, also known as ST elevation acute coronary syndrome [STEACS]), where complete obstruction by a thrombus in the coronary artery results in ischaemia and necrosis.

Angina Pectoris

• Angina pectoris was first defined in 1744 as a disease marked by attacks of chest pain due to insufficient oxygenation of the heart. The three forms of angina are: stable, unstable and variant.

Stable Angina

• Stable angina is the result of atherosclerotic plaque and inappropriate vasoconstriction within one or more blood vessels.
• Hallmark of stable angina: blood flow is adequate at rest but compromised when the person exerts themselves, causing pain (for usually five minutes or less), which is relieved by rest. May also be referred to as exertional angina.

Unstable Angina

• Marked by an atherosclerotic plaque and an associated thrombus, resulting in a greater degree of vascular obstruction. The person has compromised blood flow at rest, leading most often to marked chest pain without exertion.

Variant (Prinzmetal) Angina

• Rare form of angina marked by unexplained vasospasms rather than atherosclerotic plaque formation, occurring in conjunction with ST elevation on the electrocardiograph (ECG) trace.

Myocardial Infarction

• A myocardial infarction (MI; colloquially known as a heart attack), results in significantly reduced blood flow such that myocardial cells die.

Classification of MI by Type

• Type 1: Spontaneous—Most common type of MI; when impeded coronary artery perfusion resulting in necrosis is caused by the rupture, ulceration or erosion of an atherosclerotic plaque.
• Type 2: Secondary to an ischaemic imbalance—When impeded coronary artery perfusion resulting in necrosis occurs because of an imbalance between oxygen supply and oxygen demand (unrelated to a plaque).
• Type 3: Resulting in death when biomarker values are unavailable—When there is impeded coronary artery perfusion resulting in cardiac death.
• Type 4A: Related to percutaneous coronary intervention (PCI)—When impeded coronary artery perfusion resulting in necrosis occurs from the iatrogenic effects of an angiogram, angioplasty or stent insertion.
• Type 4B: Related to percutaneous stent thrombosis—When impeded coronary artery perfusion resulting in necrosis occurs from the development of a clot on a previously inserted stent.
• Type 5: Related to coronary artery bypass grafting—When impeded coronary artery perfusion resulting in necrosis occurs as a result of coronary artery bypass grafting.

MI Evolution and Ventricular Remodelling

• Once the fibrous cap of the atherosclerotic lesion ruptures, a cascade of events can cause significant tissue damage, exposing subendothelial collagen, which causes platelet aggregation and activation.
• Hypoxia may rapidly turn to anoxia. In the absence of oxygen, cells switch to anaerobic respiration, resulting in the production of lactate and a shift to an increasingly acidic environment.
• Process
  • Sodium–hydrogen (Na1/H1) exchanger pumps out hydrogen in exchange for sodium, causing a marked increase in intracellular sodium.
  • Sodium–calcium (2Na1/Ca21) pump attempts to reduce intracellular sodium by exchanging it with calcium, resulting in too much intracellular calcium.
  • Na1/K1-ATPase pump fails due to ischaemia, adding to the sodium overload.
  • Cells die and necrosis sets in.
• Subendocardial layers begin to become necrotic within a half an hour, and over the next 3–6 hours the necrosis grows outwards towards the epicardium.
• If blood flow is restored before this time, it is can be called a subendocardial MI; if the necrosis spans the myocardial wall, it is called a transmural MI.

Myocardial Reperfusion Injury

• Reperfusion interventions provide previously anoxic tissue with a sudden and immense flow of oxygen-rich blood.
• As the electron transport chain begins to work again, the mitochondria produce ROS and induce oxidative stress.
• Dysfunctional sarcoplasmic reticulum adds to the intracellular calcium overload, the cell membrane is damaged by lipid peroxidation, and the oxidative effects damage the DNA.
• The cumulative effects of this cellular chaos can lead to more myocardial necrosis, and induce dysrhythmia, systolic dysfunction and heart failure.
• Reperfusion injury is estimated to contribute to up to 50\% of the total myocardial damage.

Clinical Manifestations

• Common manifestations of acute coronary syndrome include an increase in the heart rate and the respiration rate, diaphoresis and sometimes nausea and vomiting.
• Chest pain may be felt, and a typical presentation may be reported as crushing central chest pain radiating into the person’s jaw or arm.
• Atypical symptoms, including syncope, fatigue, or epigastric, back or right-arm pain.
• Older adults and people with neuropathic diseases or diabetes may not report pain at all, also known as a silent MI.

Clinical Diagnosis and Management

• Diagnosis of a myocardial infarction relies primarily on the demonstration of cell death, by the measurement of cardiac markers.
• Intracellular proteins such as cardiac troponin I (cTnI) should not be found in the blood (signals myocardial cell damage).
• Once the primary issues are resolved, the focus shifts to risk elimination, such as addressing dyslipidaemias, hypertension, glycaemic control and any other modifiable risk factors that exist.
• If a person demonstrates an increased clotting risk, consideration should be given to the administration of a dual antiplatelet medication (one that contains both aspirin and a P2Y12 inhibitor) if possible.

Indigenous Health Fast Facts and Cultural Considerations

• Aboriginal and Torres Strait Islander peoples are 14 times more likely than non-Indigenous Australians to die from coronary artery disease.
• Aboriginal and Torres Strait Islander peoples are half as likely as non-Indigenous Australians to receive coronary angiography and revascularisation procedures.