Tuesday, 10 October 2017

Angina – Some Questions

Angina — Some Questions

     The heart must deliver oxygenated blood to (inter alia) the brain, skeletal muscle and the heart muscle itself. Exercise increases the oxygen requirement of the skeletal muscles, and the heart pumps harder. That increased effort, in its turn, increases the oxygen requirement of the heart muscle. The consensus view is that ‘diseased’ (or atherosclerotic) arteries, partly occluded with cholesterol-rich plaques, require raised blood pressure, so more effort is required from the heart. If the coronary arteries supplying the heart muscle are healthy, blood pressure would rise, and in time ventricular hypertrophy would be evident. But if they are themselves diseased (>69% occluded), the heart muscle becomes inadequately oxygenated when under this increased work load; this ischaemia causes pain — in the myocardium (and referred areas). This predictable, effort-related, chest pain is called stable angina. (A very similar pain can be caused by emotional stress, where the transient cardiac ischaemia is presumably the result of vaso-constriction caused by adrenaline and the ’stress-response’; a significantly different mechanism.)

Cause of Pain
     Note that ischaemia in the brain causes fainting, but not pain. Ischaemia in the legs might be expected to cause pain there, or at the very least weakness but, by some mechanism, the legs keep working and it is the heart muscle (which also keeps working) that experiences pain. The biochemistry causing the pain is still mysterious but may involve adenosine, and possibly ATP [1]. 

Cause of Sclerosis
     If you ask what ‘causes’ the atherosclerotic obstruction the answer given is indistinct. The literature will tell you that the major (modifiable) risk factors for cardiovascular disease are [2]:
  • Blood Cholesterol (LDLch > 3, HDL< 1.0 for men; mmol/L).
  • High fasting Triglyceride:HDL ratio (>2:1)
  • High Blood Pressure (> 140/90 mmHg).
  • Diabetes [or Impaired Glucose Tolerance] (fasting blood glucose >7mM [>6mM]; HbA1c >48 mM [>42 mM])
  • Smoking
  • Obesity (Waist:Hip > 0.9 for men)
  • Inactivity 
  • Excess alcohol
  • Mental (emotional) Stress.
     But Risk Factors do not in general cause anything; they merely correlate, they are markers. Amongst them there may be one 'cause' that causes all the rest. Or the 'causemay still elude detection. It is said that these risk factors interact, either additively, or possibly even synergistically [3]. But they are clearly linked. For example, it is easy to see that narrowed arteries might necessitate raised blood pressure; but it is harder to see how raised blood pressure could directly cause narrowing of arteries; bloating rather. 
     It is hard to see from this list what mechanism really ‘causes’ atherosclerosis. There are two theories; one is called the “reverse cholesterol transport’” hypothesis, the second theory involves lipid oxidation.
     Evidence for the Reverse Cholesterol Transport hypothesis [3] comes from finding that unloaded HDL apoproteins, capable of binding cholesterol, is protective. So also is contriving (by gene-therapy) to raise circulating levels of various of the protein components of HDL such as apoE and apoA [5].
     The Oxidised Lipids hypothesis [4] notes that the oxidation of phospholipids bound in the LDL particle, and especially phospholipids containing arachidonic acid, are inflammatory. In the presence of such oxidized LDL, HDL is found to be anti-inflammatory. What starts the inflammation is not clear, but an early step is entry of monocytes from the blood into the artery wall [5], possibly recruited by oxidised LDL, or by Cholesterol peroxides, which are particularly inflammatory.. The monocytes then become macrophages and generate cytokines from arachidonic acid.  Apolipoprotein B in LDL becomes tagged with a product of lipid oxidation, and is then accumulated by cells in the artery wall. Lipoxygenase-negative mice have “significantly” less atherosclerosis. (Hmm!). However, in humans, vitamin E and other antioxidants have proved clinically ineffective in combating atherogenesis. It seems that the growing plaque can do one of three things: [a] regress, [b]  stabilise, [c] rupture. Even the ruptured plaque can stabilize, but leaving the artery with a restricted lumen [5]. 
     Accounts emphasise different aspects but none are clear on the first step. Does dietary cholesterol get oxidised by oxygen radicals generated in the intimal layer of the artery wall? Nor is it clear why the body generates all this fuss; is the inflammation and the plaque protective?
     Isoprostanes (peroxidized products of arachidonic acid and other polyunsaturated fatty acids that participate in the perception of pain) flag the presence of oxidative stress. They are found in the urine, particularly of smokers. So, smoking correlates with increased oxidative stress, perhaps by blocking the flow of electrons to oxygen, for smoke contains both CO and CN-. 

     Is there a feedback loop here? with the ischaemia causing radicals, which then attack the intima and cause further occlusion? 

[1]  Belardinelli & Pelleg ( 2012) Adenosine and Adenine Nucleotides: From Molecular Biology to Integrative ...edited by Luiz Belardinelli, & A. Pelleg
[2]  http://www.mayoclinic.org/diseases-conditions/angina/basics/risk-factors/CON-20031194
[3]  Reverse transport review – https://www.jci.org/articles/view/11538; 
[4]  Navab et al. (2004) The Journal of Lipid Research, 45, 993-1007.
[5]  Oka, (2005) Acta Biochim Pol. 2005; 52(2): 311–319. 

See also: 
Temel, RE & Brown, JM (2015) trends Pharm. Sci. 36, 440–451, July 2015
The Joint British Societies third consensus report (JBS3) is published at http://heart.bmj.com/content/100/Suppl_2/ii1
Leach (chatty review) Br J Pain. 2013 Feb; 7(1): 23–30.

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