Sunday, December 23, 2012

Hypertension

Summary
 
When you get your blood pressure taken systolic blood pressure is the higher number and diastolic blood pressure is the lower number.  Two other measurements can be taken from systolic and diastolic blood pressure: mean arterial pressure is one third systolic plus two thirds diastolic; and pulse pressure is systolic minus diastolic.
 
Cardiac output (which is equalled to heart rate multiplied by stroke volume (stroke volume is affected by blood volume)), arterial width/peripheral resistance and arterial stiffness are some main factors that could affect blood pressure.
 
Salt reduces blood pressure, but not much or in amounts that would suggest that high salt diet causes hypertension or low salt would reverse it.  Restricting salt increases activation of the renin-angiotensin-aldosterone system (RAAS) and noradrenaline, which has some undesirable effects such as increasing insulin resistance and oxidative stress.
 
Obesity, insulin resistance, endothelial dysfunction, atherosclerosis and poor kidney function are some of the mechanisms of hypertension and tend to affect blood pressure by increasing the activity of the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system and arterial stiffness.
 
 
Some Strategies for Hypertension
 
This is for informational purposes only and is not meant to diagnose or treat any medical condition.
 
Obesity
 
Obesity, even without insulin resistance, is one of the major factors in hypertension.  See Obesity
 
Insulin Resistance and Type 2 Diabetes
 
It’s estimated that 50% of people with hypertension are insulin resistant [1].  Insulin resistance increases SNS and RAAS activity and impairs endothelial function, and type 2 diabetes is the major cause of kidney failure [2].  See What Causes Insulin Resistance? Part VII
 
Cardiovascular Disease
 
Endothelial dysfunction and atherosclerosis can increase arterial stiffness and blood pressure (particularly systolic).  See Cardiovascular Disease
 
Stress/Anxiety
 
Psychological stress/anxiety can definitely increase blood pressure in the short term and is a factor in white coat hypertension, but it’s debatable as to whether it causes hypertension.  That being said, meditation reduces blood pressure in people with mild hypertension [3]
 
Nutrients
 
Reducing salt does reduce blood pressure, but not by much, although more so in people with hypertension, poor kidney function and African Americans.  Don’t expect that reducing salt will normalise your blood pressure.  Most sources of salt are in processed foods, take-away foods, restaurants and added salt.  Whole foods are usually very low in salt*
 
Potassium supplementation may be more effective than sodium at reducing blood pressure.  However, it also has a fairly minor effect and seems to only be effective in those with hypertension.  Potassium also doesn’t seem to increase SNS and RAAS activity like salt restriction does [4].  Although another meta-analysis found no benefit [5]
 
Sun exposure is associated with lower blood pressure [6].  Vitamin D inhibits the RAAS [7], but supplementing vitamin D may not as sunlight increases nitric oxide [6]
 
Vitamin K2 may be helpful as it prevents calcification of arteries

Sunday, December 16, 2012

Mechanisms of Hypertension

Overweight/Obese
 
Overweight/obesity is associated with hypertension and most people with hypertension are also overweight.  Weight gain increases blood pressure and weight loss reduces it [1].  The interaction of weight and blood pressure involves few mechanisms:
 
  • Elevated leptin levels promote sympathetic overactivity resulting in sodium/water retention and vasoconstriction* [1] [2]
  • Increased sodium retention and extracellular fluid volume (therefore increased cardiac output) to service more tissue (despite this there’s an increase in RAAS activation in obesity, probably mainly due to over-activation of the SNS) [1]
  • The physical compression of the kidneys, resulting in lower blood flow to the kidneys, then the kidneys upregulate the RAAS (increase sodium/water retention and total peripheral resistance) to increase blood pressure to maintain GFR [1]
  • In insulin resistant obesity, increased free fatty acids, oxidative stress and inflammation in adipose tissue increases the RAAS and SNS in a positive feedback relationship [2] [3]
 
* People who are overweight/obese are leptin resistant, but the leptin resistance is selective to the arcuate nucleus in the hypothesis, so leptin signalling for body weight regulation is impaired, whereas leptin signalling elsewhere is elevated [2]
 
** Insulin doesn’t seem to raise blood pressure [1].  In addition there’s a lot more evidence for the RAAS increasing IR than IR increasing the RAAS.
 
Cardiovascular Disease
 
Endothelial Dysfunction
 
Nitric oxide is one of the main vasodilators and promotes arterial elasticity [4].  Insufficient nitric oxide impairs endothelial function, which may precede hypertension and lead to kidney failure [5].  Endothelial dysfunction strongly correlates with arterial stiffness, systolic blood pressure and pulse pressure [6].  Superoxide can merge with nitric oxides, which depletes nitric oxide and forms peroxynitrite.  Superoxide is formed mainly by mitochondria, NADPH oxidase and xanthine oxidase (the latter two are activated by the RAAS).  Insulin resistance can also reduce nitric oxide by failing to stimulate Akt production (Akt activates nitric oxide synthase) [7].
 
Atherosclerosis
 
Atherosclerosis is one form of arteriosclerosis, which refers to the stiffening of arteries.  Atherosclerosis is degenerative disease where the artery wall thickens as a result of accumulation of cholesterol, fats, LDLs and immune cells.  Arterial calcification is a common feature of atherosclerosis and it too increases arterial stiffness [8].  As the arteries accumulate more stuff the radius of the artery decreases, which increases total peripheral resistance.  Atherosclerosis in the arteries leading to the kidneys (renal artery stenosis) can cause renovascular hypertension, which is mediated by the RAAS.  Atherosclerosis is associated with increased systolic blood pressure [9].  Hypertension is a risk factor for cardiovascular disease, which may be explained by the effects on blood pressure by atherosclerosis and endothelial dysfunction.  There are many potential factors in atherosclerosis, see Cardiovascular Disease
 
Kidney Function
 
Some of the main functions of the kidneys include the filtering of wastes (urea, ammonia) and the regulation of electrolytes (sodium, potassium, calcium and chlorine).  By regulating electrolytes the kidneys also help to regulate blood volume and blood pressure.  If kidney function is impaired then wastes such as uric acid, creatinine and excess electrolytes aren’t cleared as well and remain elevated in the blood stream, which promotes water retention (through osmosis) and the kidneys will stimulate the RAAS to increase glomerular filtration rate (GFR)*.  Kidney function is a strong influence on blood pressure.
 
“Blood pressure goes with the kidney.  Normotensive recipients of kidneys from hypertensive donors become hypertensive and hypertensive recipients of normotensive kidneys become normotensive” [10]
 
Hypertension is almost certain in end stage renal disease with 80-90 of those needing dialysis being hypertensive [10].  Impaired kidney function reduces blood pressure regulation and makes blood pressure more sensitive to increases in vasoconstriction hormones such as noradrenaline and vasopressin [1].  Poor kidney function (GFR <60) is associated with the metabolic syndrome [11] and diabetic nephropathy is the most common form of renal failure (mediated through hyperglycemia and oxidative stress) [12].
 
* The rate at which the kidneys filter blood.  Healthy kidneys have a GFR of >90 mL/min/1.73m2

Sunday, December 9, 2012

Salt and Blood Pressure

One of the common diet recommendations is that we should reduce our salt (sodium chloride) intake.  The rationale is that lowering salt reduces water retention, which will lower blood volume, therefore lower blood pressure. 

However, blood levels of sodium and blood pressure are some of the most tightly regulated things in the body.  There are many negative feedback mechanisms from the brain, heart, blood vessels and kidneys to maintain blood pressure and sodium levels within a normal range.  For example, on a standard blood test the recommended range for sodium is 135-145 mmol/L, which is only a deviation of 3.6% either way from 140. 

Despite salt being portrayed as the main driver of hypertension, meta-analyses of randomised controlled trials that have reduced salt have only found very mild reductions in blood pressure (see tables below), which suggests dietary sodium doesn’t cause hypertension and is consistent with the negative feedback systems.

[1]
Systolic
Diastolic
Mainly Caucasians – High Blood Pressure
-4.18
-1.98
Mainly Caucasians – Normal Blood Pressure
-1.27
-0.54
African Americans – Normal and High Blood Pressure
-6.44
-1.98

[2]
Systolic
Diastolic
Hypertension
-3.70
-0.90
Normal Blood Pressure
-1.00
-0.10

[3]
Systolic
Diastolic
High Blood Pressure
-3.90
-1.90
Normal Blood Pressure
-1.20
-0.26

[4]
Systolic
Diastolic
Normal and High Blood Pressure
-1.10
-0.60

[5]
Systolic
Diastolic
High Blood Pressure
-4.90
-2.60
Normal Blood Pressure
-1.70
-0.70

[6]
Systolic
Diastolic
Children
-1.17
-1.29
Infants
-2.47

Reducing sodium is not only ineffective for hypertension it also has some undesirable effects.  The sodium reduction in these trials roughly tripled renin and aldosterone levels, increased noradrenaline (norepinephrine) by 30% and adrenaline (epinephrine) by 12% [1] [3].  Renin and aldosterone are part of the renin-angiotensin-aldosterone system (RAAS) and noradrenaline and adrenaline are part of the sympathetic nervous system (fight or flight response).  The RAAS and noradrenaline retain sodium and water.  Reducing sodium can lead to an increase in insulin resistance through noradrenaline [7] and an increase in oxidative stress though the RAAS [8].  It seems that low sodium intakes invoke somewhat of a stress response. 

* Despite being considered ‘heart healthy’, reducing sodium increases total cholesterol by 3.0%, LDL-C by 4.6% and triglycerides by 5.9% [1] 

** A reason why sodium levels are thought to be more important than potassium in blood pressure is because there is much more sodium in the fluid outside of cells (extracellular fluid, ECF) and more potassium in the fluid inside of cells (intracellular fluid, ICF).  Blood is extracellular fluid so changes in sodium would have more effect on blood volume and blood pressure than potassium.  For example on a blood test the recommended range for potassium is 3.7-5.3 mmol/L, whereas sodium is 135-145 mmol/L.

*** Salt-resistance is the norm and means that blood pressure stays relativity constant despite variations in dietary salt, within reason.  Salt-sensitivity is the opposite and refers to blood pressure being sensitive to the amount of salt in the diet.  Salt-sensitivity can occur when the RAAS is unresponsive to changes in salt intake due to the RAAS being too high or being blocked by ACE inhibitors [9].  However, several other systems involved in sodium balance may be impaired in salt-sensitivity [10]

Further Reading
(1) Shaking Up the Salt Myth 

Sunday, December 2, 2012

Blood Pressure

Blood Pressure Basics

When you get your blood pressure measured there are two numbers:

  • Systolic blood pressure (SBP) is the higher number and it measures the pressure in arteries following a contraction of the heart, when the pulse of blood reaches the cuff
  • Diastolic blood pressure (DBP) is the lower number and it measures the pressure in arteries at baseline.  This value reflects how well blood travels from arteries to capillaries and is returned by veins.

From systolic and diastolic you can get two more values:

  • Pulse pressure (PP) is the difference between systolic and diastolic.  It reflects the stroke volume of the heart (the amount of blood pumped each heart beat) and the elasticity of the arteries
          PP = SBP – DBP
  • Mean arterial pressure (MAP) is the average pressure in the arteries, which at 60-70 beats per minute can be estimated by one third systolic and two thirds diastolic or diastolic plus one third pulse pressure, whichever is easiest.  (As heart rate increases mean arterial pressure will increase because there is more pulses from the heart muscle contracting, but the equations assume a normal heart rate)
          MAP = ⅓SBP + ⅔DBP
          MAP = DBP + ⅓PP 

The classification of blood pressure is as follows: 

Systolic (mmHg)
Diastolic (mmHg)
Hypotension
<90
<60
Normal
90-119
60-79
Prehypertension
120-139
80-89
Stage 1 Hypertension
140-159
90-99
Stage 2 Hypertension
≥160
≥100
Isolated Systolic Hypertension
≥140
≤90

* Blood pressure measurements only measure the pressure in arteries.  Blood pressure in veins is much lower (<20 mmHg) 

Factors That Affect Blood Pressure 

Mean arterial pressure is proportional to cardiac output multiplied by the resistance in the arteries (MAP CO x R).  Cardiac output is equal to the stroke volume of each heart beat multiplied by the number of heart beats per minute (CO = SV x HR).  A factor that influences stroke volume is the overall blood volume, which is the idea behind reducing salt.  The resistance in the arteries is proportional to length multiplied by viscosity divided by radius to the power of four* (R Lμ/r4), but viscosity and length don’t really vary much.  The last main factor on blood pressure is arterial elasticity which affects systolic and pulse pressure 

So we have four main factors that could affect blood pressure: cardiac output, blood volume, arterial width/peripheral resistance and arterial stiffness. 

* The body often regulates blood pressure by contracting the smooth muscles of the arteries (vasoconstriction), which decreases the radius, or by relaxing them (vasodilation), which increases the radius.

Sunday, November 25, 2012

Should I Take a Statin?

This blog post is for informational purposes only and is not meant to diagnose or treat any medical condition.
 
If you haven't already see Troubleshooting High Cholesterol Part 1 and Part 2
 
What Are Statins? 

HMG-CoA reductase is part of the mevalonate pathway, which ultimately synthesises cholesterol, but also some other molecules like coenzyme Q10, squalene and Rho.  Statins inhibit HMG-CoA reductase and so are also referred to as HMG-CoA reductase inhibitors.  By inhibiting HMG-CoA reductase statins reduce cholesterol synthesis, but they also reduce the synthesis of other products of the mevalonate pathway.  To compensate the liver increases activity of the LDL receptor, which lowers LDL-C and LDL-P levels. 

Statins are thought to have other cardio-protective independent of lowering cholesterol such as increasing nitric oxide and (which supports endothelial function), having an anti-inflammatory effect [1].  However, statins have adverse side effects which may be related to it decreasing cholesterol and consequently steroid hormone levels like testosterone [2] and decreasing coenzyme Q10 [3] [4], squalene [5] and isoprenes [6

The Benefits vs. the Costs 

Drugs (and other interventions) should improve quality of life (lower morbidity/symptoms) and/or improve longevity (lower total mortality).  However, many drugs have adverse side effects so a drug should either:

  • Improve quality of life and improve longevity (ideal)
  • Improve quality of life greater than it decreases longevity 
  • Improve longevity greater than it decreases quality of life 

The nature of statins and CVD means you’re likely trading an increase in longevity for a decrease in quality of life (although non-fatal heart attacks and strokes decrease quality of life), but to what degree depends on the context. 

The Number Needed to Treat (meta-analysis of statin trials)
Benefits in Percentage
Harms in Percentage
Statin Drugs Given for 5 Years for Heart Disease Prevention (Without Known Heart Disease) [7]
60 for non-fatal heart attack
·         98% saw no benefit
·         0% were helped by being saved from death
·         1.6% were helped by preventing a heart attack
·         0.4% were helped by preventing a stroke
·         2% were harmed by developing diabetes
·         10% were harmed by muscle damage
Statins Given for 5 Years for Heart Disease Prevention (With Known Heart Disease) [8]
83 for mortality
·         96% saw no benefit
·         1.2% were helped by being saved from death
·         2.6% were helped by preventing a repeat heart attack
·         0.8% were helped by preventing a stroke
·         2% were harmed by developing diabetes
·         10% were harmed by muscle damage

However, statins are ineffective at reducing mortality in all women and men aged 80 or over, regardless of whether it’s for primary or secondary preventions.  Also, most of the RCTs for statins were funded by drug companies.  RCTs funded by drug companies are more likely to report better outcomes and fewer side effects, so the benefits are likely exaggerated while the harms are underreported [9].  Something you can’t tell from the NNT data is the minor quality of life issues (muscle pain, memory loss, loss of libido, etc) that can occur from statins and are more common but less severe than muscle damage and type 2 diabetes 

That being said statins are probably more therapeutic for people with FH or ApoE4 genotypes. 

Also, consider your individual risk.  How likely are you to have a heart attack or stroke?  How much atherosclerosis do you currently have?  How much of my list on Part 1 applies to you?  The lower your risk, the less benefit statins are to you 

Remember that diet and lifestyle are far more powerful than most drugs.  Statins come nowhere near close to the 72% reduction in cardiac events, 65% reduction in cardiac deaths and 56% reduction in total mortality observed in the experimental group of the Lyon Diet Heart Study [10

Dealing with the Adverse Side Effects 

Should you decide to take statins it’s in your interests to prevent and deal with the side effects: 

CoQ10.  I mentioned before that statins lower CoQ10, which is a suspected cause of several of the side effects.  However, there have been conflicting results as to whether CoQ10 supplementation is effective at reducing the adverse side effects of statins [3], though probably on balance the evidence is in favour of benefit [11].  That being said, I would err on the side of supplementing the CoQ10 because statins lower CoQ10 levels, the proposed mechanisms are pretty sound, several studies do find a benefit, CoQ10 supplementation is safe and well tolerated and the side effects of CoQ10 are generally only going to be positive.  The only real negative would be the cost as they are more expensive than your average supplement 

Vitamin D.  One of the potential symptoms of vitamin D deficiency (< 20 ng/dl) is myalgia (muscle pain).  There seems to be a relationship between low vitamin D levels (< 30 ng/dl) and statin-induced myalgia, as vitamin D activates enzymes that metabolise some, but not all classes of statins.  Vitamin D supplementation appears to be very therapeutic in these contexts.  (Interestingly some statins appear to increase vitamin D) [12

There seems to be less research on sides effects resulting from a lack of steroid hormones, squalene and isoprenes and on supplementing any of them to prevent some of the adverse side effects.  (I suppose funding research to investigate and minimise the adverse side effects legitimises them, whereas it’s probably in the drug companies interests to sweep them under the rug).  Squalene seems to have anti-cancer effects and protects the skin from UV and singlet oxygen [13].  Squalene is mainly found in olive oil, a fairly health promoting food anyway (squalene may inhibit the cholesterol lowering effect of statins, not sure).

Sunday, November 18, 2012

Troubleshooting High Cholesterol: Part 2

This blog post is for informational purposes only and is not meant to diagnose or treat any medical condition.

If you haven't already see Part 1

Possible Causes of High Cholesterol or LDL-P

If you have high LDL-C or LDL-P, and whether you said yes to any of the things on the list above or not, it’s important to find to why you have high LDL-C or LDL-P as it could suggest an underlying problem that should be fixed 

Losing Abdominal and/or Liver Fat 

If you got your cholesterol tested and it came back high shortly after you changed your diet/lifestyle it could be that active weight loss and/or clearance of liver fat is temporarily increasing your cholesterol or LDL-P levels [1]. 

  • Both active weight loss and clearance of liver fat will increase triglycerides as more of them enter the circulation
  • LDL-P may increase slightly as more LDL particles may be needed to transport the extra triglycerides
  • These LDL particles stay in the bloodstream for longer, which increases their exposure to cholesterol ester transfer protein (CETP).  CETP may then exchange the triglycerides from the triglyceride rich VLDL particles with cholesterol from HDL particles, resulting in higher LDL-C and lower HDL-C 

Simply wait until your weight has stabilised, and then wait another a month or so until your next test.  You could be clearing liver fat even if you haven’t lost weight (especially if you were insulin resistant, drinking a lot of alcohol or had IBS and are now eating more eggs/liver), once again wait a few months.

Hypothyroidism 

While thyroid hormone increases both cholesterol synthesis and cholesterol metabolism (increases LDL receptor activity), people with hypothyroidism tend to have higher LDL-C and LDL-P with minimal differences in triglycerides and HDL-C [2].  People with subclinical hypothyroidism (high TSH but in the reference range) also have higher TC, non-HDL-C and triglycerides, but and lower HDL-C [3] 

Key nutrient deficiencies (iodine, iron, selenium) can impair thyroid function, although the most common cause of hypothyroidism in developed countries is autoimmune attacks against the thyroid (like Hashimoto’s thyroiditis).  Likely common causes of subclinical hypothyroidism include calorie restriction, overtraining [4] and very low carb diets [5] [6] [7] 

Insulin Resistance 

Insulin resistance results in higher triglycerides and LDL-P, which in turn can result in smaller increases in LDL-C and decreases in HDL-C [8] probably via an increased activity of CETP.  See Stephan Guyenet’s seven part series on: What Causes Insulin Resistance? 

Elevated LPS 

One function of lipoproteins, particularly LDL, is to neutralise LPS in the bloodstream.  LPS-binding protein binds to LPS and transfers it to either lipoproteins or CD14 expressing monocytes/macrophages [9].  LPS increases LDL-C levels: 

  • Administration of LPS increases cholesterol synthesis, LDL-C and triglycerides, but lowers HDL-C [10]
  • People with periodontitis have higher LDL-C (1.0 mmol/l), lower HDL-C (0.3 mmol/l) and higher triglycerides (0.6 mmol/l) [11] 

Inflammation 

One of the functions of the cholesterol transport of LDL is to repair cells and tissues, specifically the vasculature* [12].  So a high cholesterol level could indicate vascular injury.  Besides LPS, other source of inflammation are associated with high cholesterol: 

  • Copper deficiency promotes CVD [13] and increases LDL-C [14]
  • Homocysteine is a risk factor for CVD.  In children with high homocysteine, folate supplementation decreased homocysteine and cholesterol levels (0.6 mmol/l) [15] 
  • Severe vitamin C deficiency increases LDL-C [16] 
  • Ferritin is associated with LDL-C [17] [18] [19] 

* This function was actually one of the main ideas behind the response to injury hypothesis, where vascular injury (desquamation of endothelial cells) increased cholesterol transport to that area and if there was prolonged injury then the cholesterol would build up and form plaques. 

Stress 

Stress seems to raise cholesterol: 

  • Mental stress (10 minutes of mental arithmetic with harassment) raised TC, HDL-C, LDL-C and triglycerides (by ~20%), which was partially due to a reduction in plasma volume [20] 
  • Cholesterol levels in male medical students were on average 11% higher during examination week [21] [22] and 16.5% higher during the winter quarter exams [22] 

* On the effect of plasma volume on cholesterol levels: there is a minor seasonal variation, where cholesterol levels are slightly lower during summer, probably due to an increase in plasma volume during summer [23].  Also, salt restriction causes a minor increase in TC, LDL-C and triglycerides [24], which may be related to a slightly lower plasma volume 

See Chris Kresser’s blog post on 9 Steps to Perfect Health – #6: Manage Your Stress 

Genetics 

Like many things, genes explain a fair bit of the individual variation in cholesterol levels.  Some genetic determinants of high cholesterol include: 

  • Familial hypercholesterolemia (FH) is a rare inherited disorder, often resulting from a defect in the LDL receptor.  Only 1 in 500 people have the milder form (heterozygous), which results in very total cholesterol levels (~8-10 mmol/l) and LDL-C.  People with FH will have had very high cholesterol for their whole lives 
  • ApoE is a protein on LDL particles.  The ApoE4 polymorphism has a frequency of 14.7% and results in higher LDL-C, particularly in the context of a high fat or high cholesterol diet [25], and a greater risk of other diseases such as Alzheimer’s disease

See Should I Take a Statin?