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L22 CVS Patient Presentation Peripheral vascular disease

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aliasesL22 CVS Patient Presentation Peripheral vascular disease

11 min read

Overview

This lecture uses cardiovascular research examples to review the major types of cardiovascular disease (CAD, AAA, PAD, carotid disease) and to compare their risk factors. It covers the epidemiological burden of CVD, clinical risk assessment tools, the genetic architecture of CVD and AAA, Virchow’s Triad as a framework for vascular disease pathogenesis, and the ApoE-/- mouse model, which demonstrates the stepwise cellular pathogenesis of atherosclerosis from endothelial injury through fatty streak formation to a complicated, aneurysmal lesion.

Burden and Types of Cardiovascular Disease

  • Objectives: review the different types of CVD using research examples, and compare environmental and genetic risk factors.
  • All CVD accounted for 54% of deaths in European women in 2008, falling slightly to 51% in 2014.
  • Breakdown of causes of death in European women: coronary heart disease 22%, stroke 17%, other CVD 15%, other causes 18%, respiratory disease 6%, injuries/poisoning 5%, other cancer 9%, breast cancer 3%, lung cancer 2%, colorectal cancer 2%, stomach cancer 1%.
  • Coronary Artery Disease (CAD) arises from three mechanisms shown at different coronary artery locations: atherosclerosis with ulceration and thrombus (blood clot), plain atherosclerosis, and vessel spasm.

Aortic Aneurysm and Aortic Occlusive Disease

  • Abdominal Aortic Aneurysm (AAA): a dilation of the abdominal aorta, shown against a normal aorta for comparison.
  • AAA size is monitored by serial CT imaging, with the aneurysm’s diameter measured and tracked over time.

Slide flag: the aneurysm diameter measurements (6, 3 and 9.8) shown on the CT images are not labelled with units.

  • Case: a 66 year old man with a 2 month history of abdominal bloating and worsening constipation was found on examination to have a painless, pulsatile abdominal mass; CT angiography confirmed a large aortic aneurysm. This illustrates the classic, though nonspecific, presentation of AAA.
  • Infrarenal AAA: the aneurysmal dilation sits below the renal arteries, correlated on paired gross specimen and CT images using matched anatomical landmarks (proximal, mid and distal points).
  • AAA histopathology: the aortic wall at the site of the aneurysm shows disruption of its normal layered elastic lamina structure.
  • Aortic occlusive disease: narrowing of the aorta at its bifurcation, seen on angiography and CT; histologically this corresponds to occlusive atherosclerotic material (layered fibrous and calcified tissue) within the vessel wall.

Peripheral Arterial Disease

  • Peripheral Arterial Disease (PAD) affects the lower limb arterial tree, including the tibioperoneal trunk (TPT), anterior tibial artery (ATA), posterior tibial artery (PTA) and peroneal artery (PA), visualised by angiography.
  • Advanced PAD with critical limb ischaemia presents clinically with erythema of the foot and ankle, a discoloured area on the heel, and blackened, necrotic toes.

Slide flag: bilateral lower-limb angiogram images are shown with no accompanying text or labels indicating the specific teaching point.

Assessing Cardiovascular Risk

  • Standard CV risk tables stratify 5 year CVD risk (fatal and non-fatal) using: sex, age, blood pressure, smoking status, diabetes status, and TC:HDL ratio, producing colour-coded risk grids split by age band, diabetes status and smoking status, separately for men and women.
  • Risk level categories: Very High >30%, High 25 to 30%, Moderate 15 to 20% (women) / 10 to 15% (men), Mild 5 to 10% (women) / 2.5 to 5% (men), lowest <2.5%.
  • How to use the tables: identify the table matching the person’s sex, diabetic status, smoking history and age; within it, choose the cell nearest their age, blood pressure and TC:HDL ratio. If systolic and diastolic readings fall into different risk levels, the higher category applies. Values falling exactly on a threshold between cells are placed in the higher-risk cell.
  • “Modern” CVD risk equations (e.g. Predict) add further factors beyond the standard table: ethnicity, social deprivation, personal history of CVD (including atrial fibrillation and renal dysfunction), cardiovascular medications, family history of CVD, stress, inflammation, and adiposity (BMI, waist:hip ratio, waist circumference).

Genetics of Cardiovascular Disease and AAA

  • Twin studies suggest up to 70% of AAA risk is inherited, compared with about 50% for coronary artery disease.
  • Several monogenic disorders produce aneurysmal disease, for example Marfan Syndrome.
  • A genome-wide association study (GWAS) for AAA identified a chromosome 1 locus (SNP rs12133641 region) associated with disease risk.

Slide flag: this slide's title was partially obscured by an inset graphic; the title given here ("Abdominal Aortic Aneurysm Genome-Wide Association Study") reflects text extraction rather than a fully legible slide image.

  • Genetic risk markers are not fully independent of demographic or environmental risk factors, e.g. LDL, HDL, hypertension and smoking. Example: a genetic variant in a (nicotinic) acetylcholine receptor is associated with smoking quantity (Nature, 2008).
  • Growth in known genetic loci for CV-related traits: by 2018, roughly 1123 loci were known for cardiovascular disease overall, >300 for coronary artery disease, >120 for abdominal aortic aneurysm, and >50 for ischaemic stroke, a marked increase from the sparser picture mapped as of May 2014.

Atherosclerosis: Natural History

  • Atherosclerotic plaque develops progressively over decades: from an unaffected, near-normal thin vessel wall in the first decade of life, through fatty streak formation, to an advanced plaque with a necrotic lipid core and markedly thickened wall by the third to fourth decade.

Virchow’s Triad of Vascular Disease Pathogenesis

  • Proposed by Rudolf Virchow (1821 to 1905) in 1856, originally as a triad of thromboembolism, later reframed more broadly as a triad of vascular disease pathogenesis.
  • Three components:
    • Blood constituents: coagulability, dyslipidaemia.
    • Rheological factors: haemodynamics.
    • Vessel wall factors: endothelial injury, connective tissue fragility.

Experimental Model: ApoE-/- Mouse and the Stepwise Pathogenesis of Atherosclerosis

  • The apolipoprotein E knockout (ApoE-/-) mouse models cardiovascular disease: loss of ApoE causes dyslipidaemia with elevated LDL-cholesterol.
  • Compared with a control mouse aortic arch (labelled branch vessels: brachiocephalic, left common carotid, left subclavian), the ApoE-/- mouse aortic arch develops atherosclerotic lesions, but not uniformly at every branch point, raising the question of why lesions form at some vessel sites and not others.
  • Stepwise pathogenesis demonstrated in the ApoE-/- model:
    1. Internal elastic lamina (IEL) failure: disruption of the IEL with smooth muscle migration into the intima. Percentage of IEL disrupted rises with age (measured at 8, 18, 30, 50 weeks), significantly higher in ApoE-/- mice (rising from ~1% to ~15%) than in C57/Bl6 controls (rising from ~0% to ~6%).
    2. Monocyte adhesion: monocytes adhere to the endothelial surface, mediated by monocyte chemoattractant protein and by endothelial expression of intercellular adhesion molecule-1 (ICAM-1). Electron microscopy shows an adherent monocyte beginning to migrate through the endothelium.
    3. Monocyte transformation: adherent monocytes/macrophages transform into lipid-laden foam cells, forming an early fatty streak lesion.
    4. Lesion progression: the plaque extends from the intima into the media and adventitia (shown in the ApoE-/- common iliac artery), narrowing the vessel lumen.
    5. Complicated lesion / aneurysm: adding a cardiovascular risk factor such as hypertension produces a complicated, disorganised lesion with disrupted elastic lamina layers and focal aneurysmal dilation of the artery.

Carotid Artery Disease and Stenting

  • Carotid artery stenosis appears on angiography as a narrowed segment at the carotid bifurcation, corresponding histologically to a markedly narrowed/occluded lumen with plaque, versus a near-normal circular lumen.
  • Carotid artery stenting is shown as an intervention: angiograms before (narrowed vessel with stenosis) and after stent placement, using a vascular stent device.

Self-test

  1. What percentage of deaths in European women in 2014 were attributable to cardiovascular disease, and how did this compare with 2008?
  2. Describe the three mechanisms of coronary artery disease illustrated in the lecture.
  3. Describe the classic clinical presentation of abdominal aortic aneurysm illustrated by the case of the 66 year old man.
  4. What anatomical feature defines an “infrarenal” abdominal aortic aneurysm?
  5. Distinguish aortic occlusive disease from AAA in terms of the underlying vessel pathology shown.
  6. Name the four arteries of the lower limb arterial tree assessed for peripheral arterial disease.
  7. Describe the clinical signs of critical limb ischaemia seen in the PAD case photograph.
  8. List the six factors used to calculate 5 year CVD risk on the standard risk tables.
  9. Explain how to resolve a case where systolic and diastolic blood pressure readings fall into different risk categories on the risk table.
  10. List four of the additional risk factors used in “modern” CVD risk equations (e.g. Predict) beyond the standard risk table.
  11. Compare the proportion of AAA risk versus coronary artery disease risk attributable to genetics, according to twin studies.
  12. Give an example of a monogenic disorder associated with aneurysmal disease.
  13. Explain why genetic risk markers cannot be considered completely independent of environmental risk factors, using the smoking-related example given.
  14. Describe the change in the number of known genetic loci for cardiovascular disease, coronary artery disease, AAA and ischaemic stroke between the earlier GWAS era and 2018.
  15. Describe the stages of atherosclerotic plaque development from the first to the fourth decade of life.
  16. State the three components of Virchow’s triad of vascular disease pathogenesis.
  17. Describe, in order, the five steps of atherosclerotic lesion development demonstrated in the ApoE-/- mouse model.
  18. What happens to the lesion pathology when a cardiovascular risk factor such as hypertension is added in the ApoE-/- model?
  19. Describe how histology distinguishes a normal carotid artery lumen from a stenosed one.
  20. Using Virchow’s triad, classify each step of the ApoE-/- atherosclerosis pathway (IEL failure, monocyte adhesion, monocyte transformation, lesion progression, complicated lesion/aneurysm) by which triad component(s) it primarily reflects.

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