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Atherosclerosis and Ischemic Heart Disease

by B. Mahato

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What are the layers of an artery?

Starting from the innermost layer:

    • Intima: normally made up of single endothelial cell layer
    • Internal elastic lamina
    • Media: made up of smooth muscle cells
    • External elastic lamina
    • Adventitia

So artery can be thought of as having three main layers: intima, media, and adventitia. The intima and the media are separated by the internal elastic lamina. The media and the adventitia are separated by the external elastic lamina.

How is an atherosclerotic plaque formed?

  • The endothelial layer of the artery is damaged either due to hemodynamic stress or chemical irritants. This is the primary event in plaque formation.
  • Lipids enter the subintimal space (between endothelial layer and the internal elastic lamina). Lipids are modified, for example, by oxidation or glycation.
  • Leukocytes, including monocytes, are recruited to the site.
  • Monocytes are now macrophages, and they express scavenger receptors. Scavenger receptors enable the uptake of the modified lipids. Macrophages have now become foam cells.
  • Smooth cells migrate to the site from the media. They proliferate and produce extracellular matrix. There is intimal thickening and the plaque gains a fibrous cap.
What determines the integrity of the fibrous cap?

The balance between synthesis and degradation of collagen and elastin. Smooth muscle cells synthesize these fibrous cap constituents, whereas foam cells destroy them by secreting matrix metalloproteinases (MMP) and other enzymes. PDGF and TGF-beta stimulate smooth muscle cells, and IL-1, TNF-alpha, and MCP-1 (monocyte chemoattractant protein-1) stimulate foam cells. T-lymphocytes stimulate the degradation process. They produce INF-gamma that inhibit smooth muscle cells, and the same time they produce CD40L that stimulate foam cells.

What are the structural differences between stable and unstable/vulnerable plaques?

A stable plaque has thick fibrous cap. It also contains very little lipid, and the lumen of the artery is more or less preserved. An unstable plaque, on the other hand, has thin fibrous cap, contains a lot of lipid, and the lumen is narrowed. It also contains a higher number of inflammatory cells. Vulnerable plaques can rupture and lead to thrombus formation with partial or complete occlusion of the artery.

What is an ischemic heart disease?

It is a condition of imbalance between myocardial oxygen supply and demand.

What factors determine the supply of myocardial oxygen?

  • blood oxygen content
    • amount of RBCs/hemoglobin
    • health of the lung (e.g. V/Q ratio)
  • coronary blood flow (Q = P/R)
    • coronary perfusion pressure = diastolic pressure
    • vascular resistance (R). Combining Q=P/R with Poiseuille’s equation Q=(P*pi*r^4)/(8*n*L), we get R=(8*n*L)/(pi*r^4), where n= viscosity, L=length, and r=radius. So while viscosity of the blood and length of the lesion (e.g. plaque) are important determinants of resistance to blood follow, radius is much more important. If radius halved, resistance will increase by a factor of 2^4=16. Factors that can affect the radius of the lumen include
      •  external compressive force on the artery (e.g. due to an adjacent tumor)
      • local tissue metabolites (e.g. adenosine, lactate, H+, CO2)
      • endothelial derived factors (e.g. NO, prostacyclin, endothelin-1)
      • sympathetic nervous system (parasympathetic system plays a minor role), e.g. catecholamines
    • The last three factors can be remembered by using the acronym MEN, where M=metabolites, E=endothelial factors, N=neural factors
What factors determine the myocardial oxygen demand?
  • HR
  • contractility
  • wall stress, determined by Laplace’s equation (wall stress = P*r/2*w)
    • pressure (P): aortic stenosis, HTN
    • radius (r): AR, MR,
    • thickness (w): hypertrophied heart has lower oxygen consumption per unit mass of tissue. However, note that while hypertrophied  heart can be compensatory in response to pressure overload (e.g. in response to AS) and help reduce oxygen consumption, it can also lead to overall increase in oxygen consumption (depending on the total mass of the hypertrophied heart). This follows because total oxygen consumption = (oxygen consumption per unit mass) * tissue mass. Hypertrophy of the heart will affect both of these factors, and so the overall effect will depend on which factor is affected more.
What are some of the differences in the presentation of stable and unstable anginas?
  • Stable angina
    • on exertion or emotional stress
    • predictable pattern; does not change much mover time
    • resolves in minutes
  • unstable angina
    • at rest or on small amount of exertion
    • progressive over time
    • lasts longer
    • can lead to MI
Differential diagnosis of chest pain at rest?
  • unstable angina
  • PE
  • aortic dissection
  • pericarditis/myocarditis
  • pneumothorax
  • esophageal spasm
  • GERD
  • panic attack
  • others like peptic ulcer, biliary colic, and musculoskeletal issues
Why are diabetics more likely to have silent ischemia than others?

They have impaired pain sensation due to peripheral neuropathy.

Does the level of chest pain correlate with the amount of ischemia?

No. Even MI can present w/o symptoms.

What are acute coronary syndromes (ACS)?

They are syndromes arising, in most cases, from the rupture of a coronary atherosclerosis plaque and the resulting thrombosis. These syndromes form a spectrum ranging from unstable angina to irreversible necrosis of myocardium (MI). ACS includes unstable angina (UA), NSTEMI, and STEMI.

  • UA
    • partial or complete occlusion (recanalized or with collaterals if complete occlusion)
    • fast healing, damage reversed
    • EKG: (+/- ) ST-depression/T-inversion
    • Biomarkers: -ve
  • NSTEMI
    • partial or complete occlusion (recanalized or with collaterals if complete occlusion)
    • cell death (most likely subendocardial)
    • EKG: ST-depression/T-inversion
    • Biomarkers: +ve
  • STEMI
    • complete occlusion
    • cell death (most likely transmural)
    • EKG: ST-elevation/T-inversion/persistent Q wave. Q wave is >0.04s wide, and >25% of QRS height
    • Biomarkers: +ve
How can EKG help us localize MI?
  • V1-V2: anteroseptal
  • V3-V4: anteroapical
  • V5-V6, I, aVL: anterolateral
  • II, III, aVF: inferior
Which vessel is likely occluded if a patient has ST-elevation in V1-V6?

Left main coronary artery.

Given that we do not have any leads overlying the posterior heart, how can we know if there is a likely infarct there?

There will be a reciprocal of the expected pathological change in the leads directly opposite the posterior wall. So there will be taller than normal R in V1-V2 if there is posterior wall MI. This is equivalent to having pathological Q waves in the non-existent posterior leads. This can be distinguished from RVH, since RVH also causes right axis deviation.

Acknowledgment:
The above note is based, at least in part, on the discussion during a Harvard Medical School tutorial lead by Dr. Sonja K Rakowski, M.D. of Brigham and Women’s Hospital, Boston. Other participants included Annie Nguyen, Bisundev Mahato, Christine Linh-Minh Pham, Joshua Jeffrey Aaron Baugh, Kanika Bharti Sharma,  Lisa Y. Siu, Peter Kirkhoff Olds, and Samira Salari. Errors, if any, are my own.

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