The International Network of Cholesterol Science

Discussions Jan 2003  About hypertension

Peter Langsjoen
Uffe Ravnskov

Comments to the new hypertension guidelines by

Eric Freedland
Martin Sturman
Fred and Alice Ottoboni

Read also:

Paul Rosch: Prehypertension And The Emperor´s Invisible Suit
Paul Rosch: The Salt Controversy: The Diet "Dictocrats" Are At It Again!
Peter Langsjoen: To Reduce The Risk of Heart Disease, Why Don´t We All Cut Off Our Ear Lobes?

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Peter Langsjoen
I really enjoyed Malcolm's recent RFW article on hypertension and it motivated me to communicate some of my long time interests to all of you, my fellow skeptics. Malcolm brings up some excellent points and I completely agree that essential HTN is another very good example of a symptom or a number attaining a disease status.  This is certainly prevalent in medicine as it is much easier to attack a number than to address the difficulty of causation.  In the case of elevated BP it is a very simple thing to lower the number with a wide variety of pharmaceuticals and thus declare a victory, making both the doctor and patient happy.  This is certainly analogous to labeling hypercholesterolemia a disease and lowering the cholesterol levels with drug therapy, again, treating a number and declaring victory.  Even in the case of adult onset diabetes mellitus there is a strong tendency to attack the elevated blood sugar as if this in and of itself was a disease.  Again, the number can conveniently be lowered with a variety of drugs while completely ignoring the underlying metabolic disturbance related to excess carbohydrate intake.  Patients and physicians have a strong tendency to prefer taking/prescribing a pill to treat a number rather than make any alteration in lifestyle or eating habits.

Essential hypertension was for years attributed to excess dietary sodium.  This brought about the well-known anti-salt crusade which, although diminished, is still with us today and, as we know, has been a complete failure.  This brings us to the very interesting question of what is causing essential hypertension and on this I would like to throw out a couple of thoughts and observations.

Although there is logic to Malcolm's theory that elevated BP is a necessary compensation to maintain blood flow in the setting of arterial narrowing by atherosclerotic narrowing/plaques, I do not think that this applies to the majority of patients with essential hypertension.  I can only envision this phenomenon in settings of advanced atherosclerotic disease.  The onset of essential HTN in most patients is in their 30's & 40's at a time when advanced atherosclerosis is uncommon. 

For many years I was fascinated with the work of Leopold Dintenfass and other scientists devoted to blood viscosity (hemorheology).  In fact, back in the 60's and 70's they had a very active International society that met annually for scientific sessions.  Most of the members were basic scientists interested in the physiology of microcirculation.   One of the interesting theories of this group was that elevated BP was an adaptive response to an elevation in blood viscosity.  Enhanced red blood cell aggregation dramatically increases whole blood viscosity and causes impaired microcirculation.  This aggregation can be offset by increasing cardiac output which increases the shear forces and has a disaggregating effect thereby improving microcirculation.  The downside of this adaptation is of course the elevation of BP.  Common examples of factors which enhance red blood cell aggregation are:

1.  Stress, which causes an increase in blood fibrinogen levels which causes red blood cell aggregation thereby increasing blood viscosity.  The negative charge on the outer membrane of red blood cells normally prevents these cells from getting too close.  Red cells can only aggregate when they are cross-linked by the long fibrinogen molecules. 

2. Anything that increases concentration of red blood cells (elevation in hematocrit).  For example, the intermittent hypoxia of sleep apnea is associated with an increase in hematocrit and hypertension, both of which return to normal upon treatment of the sleep apnea.  Elevated hematocrit also commonly occurs in smokers who are frequently hypertensive.

Another commonly encountered factor in whole blood viscosity is the decrease in red blood cell deformability that is frequently present in diabetics.  Red blood cells are approximately 9 microns in diameter and must be capable of folding like an umbrella or elongating like a hot dog to pass through the 5 micron diameter capillaries of our microcirculation.  Diabetics commonly have hypertension.  This brings up the Malcolm theory whereby a higher pressure head must be established to squeeze these little stiff cells through.  At any rate, these are just some interesting thoughts that should be considered.

Another interesting possible causative factor in essential HTN relates to diastolic dysfunction of the myocardium.  Diastolic dysfunction is an impairment in the relaxation (filling) phase of the cardiac cycle which is actually the phase requiring much more cellular ATP than the systolic (contraction) phase.  It takes a great deal of ATP to re-establish trans-membrane Ca++ gradients which allows the uncoupling of actin/myocin.  Rigor mortis is a very good example of muscles remaining in a contracted state when deprived of cellular energy (ATP).  Diastolic dysfunction is the earliest manifestation of heart failure and can be easily measured non-invasively by echocardiography.

This brings us to my field of current research interest.  The heart muscle requires more ATP than any other tissue and accordingly has a huge concentration of mitochondria - approximately one third of the volume of heart muscle is mitochondria, far more than any other cell type and with the high proportion of mitochondria, the heart muscle also has the highest level of my favorite molecule, CoQ10.  Heart muscle is thereby uniquely vulnerable to CoQ10 depletion or deficiency.  Beginning at about the age of 25-30, biosynthesis of CoQ10 begins to decline and blood and tissue levels have been documented to steadily fall after this age.  There is, of course, a lot of individual variation.

The vast majority of patients presenting with essential HTN have diastolic dysfunction regardless of whether or not the BP is treated or untreated, BP controlled or uncontrolled.   Supplemental CoQ10 is unique in its ability to improve diastolic dysfunction (see abstracts 1 & 2 below) and although there have been many attempts, there is, as yet, no known pharmaceutical capable of favorably altering this fundamental aspect of cardiac physiology.  It is important to stress the word "favorably" in so far as statins cause diastolic dysfunction, presumably by way of CoQ10 depletion.  After 3-4 moths of CoQ10 supplementation, this diastolic dysfunction improves and BP drifts down gradually over the same period of time such that one fourth of patients attain completely normal blood pressures and require no more anti-hypertensive medication.  The remainder of patients require substantially less anti-hypertensive drug therapy (see abstract 3 below).

By definition, patients with diastolic dysfunction have an impairment of the filling phase of the cardiac cycle which causes a major limitation in one's ability to increase cardiac output.  A human can increase cardiac output from 5 liters/min at rest to 25 liters/min with exercise by doing three things:

1.  By increasing heart rate, e.g., 70 beats per minute at rest to 160 BPM with exercise
2.  By an increase in contractility, e.g., ejection fraction goes from 55% at rest to 75% during exercise
3.  By an increase in the ability of the heart to expand and fill more to accept the enhanced venous return

With an impairment in diastolic function one can only increase cardiac output through the first and second mechanisms which can only be enhanced through an increase in catecholamines (high adrenaline state).  Thus, patients with diastolic dysfunction tend to have high resting ejection fractions, for example 65%, and high resting heart rate, for example 90 BPM, and when called upon to walk even a short distance on a treadmill, these patients will rapidly attain their maximum heart rate within as short time as 1-2 minutes as opposed to the normal of 9-12 minutes.  To summarize, patients with diastolic dysfunction virtually always have an adaptive high catecholamine state with associated elevations in heart rate and BP.  Since CoQ10 has not been shown to have any direct vasodilating effect, one can postulate that the normalization of BP in many of these patients can be explained by the normalization of their diastolic function.  It would appear that this early heart muscle dysfunction is in large measure related to the deficiency of a simple, but very essential nutrient, CoQ10. 

My above postulate is contrary to the standard dogma in cardiology which has long held that elevated BP is the primary "disease" and left ventricular hypertrophy and diastolic dysfunction are secondary phenomena.  This may be the case in secondary hypertension, which represents only about 10% of the HTN cases.  My guess is that in essential hypertension it's actually the reverse.  In other words, it's a myocardial disease causing an elevation of BP.  As is the case in many adaptive responses, they can, in and of themselves, cause harm in a vicious cycle whereby elevated pressures further impair heart muscle function.

As always, I would very much appreciate your thoughts. 

Sincerely,
Peter

1.  Isolated diastolic dysfunction of the myocardium and its response to CoQ10 treatment. Langsjoen PH, Langsjoen PH, Folkers K Clin Investig 1993;71(8 Suppl):S140-4 Symptoms of fatigue and activity impairment, atypical precordial pain, and cardiac arrhythmia frequently precede by years the development of congestive heart failure. Of 115 patients with these symptoms, 60 were diagnosed as having hypertensive cardiovascular disease, 27 mitral valve prolapse syndrome, and 28 chronic fatigue syndrome. These symptoms are common with diastolic dysfunction, and diastolic function is energy dependent. All patients had blood pressure, clinical status, coenzyme Q10 (CoQ10) blood levels and echocardiographic measurement of diastolic function, systolic function, and myocardial thickness recorded before and after CoQ10 replacement. At control, 63 patients were functional class III and 54 class II; all showed diastolic dysfunction; the mean CoQ10 blood level was 0.855 micrograms/ml; 65%, 15%, and 7% showed significant myocardial hypertrophy, and 87%, 30%, and 11% had elevated blood pressure readings in hypertensive disease, mitral valve prolapse and chronic fatigue syndrome respectively. Except for higher blood pressure levels and more myocardial thickening in the hypertensive patients, there was little difference between the three groups. CoQ10 administration resulted in improvement in all; reduction in high blood pressure in 80%, and improvement in diastolic function in all patients with follow-up echocardiograms to date; a reduction in myocardial thickness in 53% of hypertensives and 36% of the combined prolapse and fatigue syndrome groups; and a reduced fractional shortening in those high at control and an increase in those initially low.  Isolated diastolic dysfunction associated with moderately low CoQ10 blood levels is an extremely frequent finding in patients with three varied clinical entities sharing similar symptoms and CoQ10 replacement results in clinical improvement, lowering of elevated blood pressures, improved diastolic function, a decrease in myocardial thickness, and a normalization of systolic function.

2.  The Aging Heart: Reversal of Diastolic Dysfunction Through the Use of Oral CoQ10 in the Elderly. Langsjoen P, Langsjoen A, Willis A, Folkers, K Anti-Aging Medical Therapeutics, (1997) R.M.Klatz and R. Goldman eds., Health Quest Publications, pp.113-120.
The observations on the clinical utility of CoQ10 in cardiology have gradually shifted from an emphasis on systolic left ventricular function towards the broader and more fundamental observations on diastolic function and dysfunction.  Our experience with CoQ10 began in 1981 with the initiation of a double blind placebo controlled trial in idiopathic dilated cardiomyopathy, followed by a six year open label study involving 126 patients.  By 1993, it became apparent that diastolic dysfunction was an easily measured abnormality in early myocardial disease that showed clear improvement with the use of CoQ10.  In 1994, 424 patients with six different diagnostic categories of cardiovascular disease were shown to have a significant improvement in diastolic function as well as a significant reduction in the associated finding of left ventricular hypertrophy.  Overall medication requirement in this group dropped considerably and the quality of life was enhanced both directly by the effects of CoQ10 on myocardial function and indirectly by easing the burden of multi drug therapy.  Our current data demonstrate a significant improvement of diastolic function in patients with advanced age (average age 84 years) when treated with oral CoQ10 (average dose 220 mg/day).  Along with the reversal of diastolic dysfunction, we observed marked improvement in patients' exercise tolerance and quality of life.  This refutes the common assertion that a stiff and non-compliant myocardium is a normal and irreversible aspect of the aged heart.

3.  Treatment of essential hypertension with coenzyme Q10. Langsjoen P, Langsjoen P, Willis R, Folkers K Mol Aspects Med 1994;15 Suppl:S265-72
A total of 109 patients with symptomatic essential hypertension presenting to a private cardiology practice were observed after the addition of CoQ10 (average dose, 225 mg/day by mouth) to their existing antihypertensive drug regimen. In 80 per cent of patients, the diagnosis of essential hypertension was established for a year or more prior to starting CoQ10 (average 9.2 years). Only one patient was dropped from analysis due to noncompliance. The dosage of CoQ10 was not fixed and was adjusted according to clinical response and blood CoQ10 levels. Our aim was to attain blood levels greater than 2.0 micrograms/ml (average 3.02 micrograms/ml on CoQ10). Patients were followed closely with frequent clinic visits to record blood pressure and clinical status and make necessary adjustments in drug therapy. Echocardiograms were obtained at baseline in 88% of patients and both at baseline and during treatment in 39% of patients. A definite and gradual improvement in functional status was observed with the concomitant  need to gradually decrease antihypertensive drug therapy within the first one to six months. Thereafter, clinical status and cardiovascular drug requirements stabilized with a significantly improved systolic and diastolic blood pressure. Overall New York Heart Association (NYHA) functional class improved from a mean of 2.40 to 1.36 (P < 0.001) and 51% of patients came completely off of between one and three antihypertensive drugs at an average of 4.4 months after starting CoQ10. Only 3% of patients required the addition of one antihypertensive drug. In the 39% of patients with echocardiograms both before and during treatment, we observed a highly significant improvement in left ventricular wall thickness and diastolic function. We observed no side effects or drug interactions from CoQ10.  The time course to improvement in functional class, blood pressure control, and myocardial function is in keeping with an improvement in myocardial bioenergetics by CoQ10 and not a pharmacological effect.  The reduction in blood pressure seems likely to be secondary to a decrease in the neurohumoral response to an early impairment in myocardial function which is primarily diastolic in nature.  The gratifying improvement in patient's quality of life was enhanced by a marked reduction in their need for antihypertensive drugs along with the substantial medical and financial burden that those drugs entail.

13. jan.
Uffe Ravnskov
I agree with Malcolm and Peter - hypertension, just as hypercholesterolemia, is a symptom, not a disease. There are more similarities; the small effect achieved by hypotensive treatment is most probably not due to the lowered blood pressure, but to other effects of the drugs, and/or to the inclusion of a few patients with malignant hypertension. As a previous nephrologist I have seen several such cases with very high blood pressure (>280/160), severe retinal vascular changes (FH 3-4) and rapidly deteriorating renal function. If these patients are treated energetically with hypotensive drugs (administered intravenously by continuous infusion, aiming at a blood pressure below, say 110/70) you will see that renal function continues to go down for a short time, but after that it will in most cases slowly return to normal or near normal. (This effect does of course not necessarily mean that the high blood pressure is primary, just that it most likely is causing the retinal and renal damage).

The effect of hypotensive treatment on other patients is even smaller than the effect of statin treatment; see table translated to English from a paper of mine about medical prevention published recently in Tidskriften Medikament
(http://www.medikament.nu/PDF-filer/8-02/uffe_ravnskov.pdf ).

Effect of four types of preventive measures

a. Non-smokers’ total mortality compared with that of heavy smokers’ (>25 cigarettes per day) [1].
b. Mortality from breast cancer in screened women compared with non-screened women in the most beneficial mammography study [2].
c. Total mortality in screened women compared with non-screened women in the most beneficial mammography study [2].
d. Cardiovascular mortality in treated and untreated patients with hypertension in a meta-analysis of 17 controlled, randomised studies [5]
e. Total mortality in statin-treated, high-risk individuals compared with non-treated in 4S  [10]
f. Total mortality in statin-treated, healthy, hypercholesterolemic individuals compared with non-treated [12].

References

1. Doll R et al.. Mortality in relation to smoking: 40 years' observations on male British doctors. BMJ 1994; 309: 901-11.

2. Bjurstam N et al. The Gothenburg breast screening trial: First results on mortality, incidence, and mode of detection for women ages 39-49 years at randomisation. Cancer 1997; 80: 2091-9.

5. Hebert PR et al. Recent evidence on drug therapy of mild to moderate hypertension an decreased risk of coronary heart disease. Arch Int Med 1993; 153: 578-81.

10. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383-9.

12. Shepherd J et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1987; 333: 1301-1307.

 As you see from the table the absolute risk reduction from hypotensive treatment as regards cardiovascular mortality was only -0.8%, whereas the effect on total mortality in the best statin trial, 4S, was -3.5%. (In the table I had selected the results from the most optimistic studies; all other studies were less favourable).

The effect of hypotensive treatment on total mortality is even smaller, but I did not find any figures for all ages. In a meta-analysis of 15 trials including old people only performed by Cochrane, that effect was statistically significant in two trials only (absolute risk reduction -1.6%; note that the effect on CVD mortality mentioned in the table regarded all ages). This did not prevent the reviewers to conclude that "treating healthy older persons with hypertension is highly efficacious".

The figures in the table were taken from a meta-analysis of 17 trials by Hebert et al. and included in a systematic report published by The Swedish Council on Technology Assessment in Health Care nine years ago, when Lars Werkö, a member of our group, was its director. Other shocking observations from that report worth mentioning were that in some of the trials half of the members of the untreated control group had normal blood pressure at follow-up, that the effect on heart disease was trivial, and that the effect in women and young people in most trials was trivial, if not absent.

The hypotensive effect of CoQ10, described by Peter, was unknown to me - most fascinating. These results are close to revolutionary. They, or a review of them, should be published in a major medical journal, but I realize that they are probably too controversial to become accepted.

Uffe

Read also Malcolm Kendrick´s article in Red Flags Daily that generated the following comments:

23. May
Eric Freedland
I share these thoughts. Elevated BP is a marker for other systemic problems such as metabolic syndrome. The lowering of BP will lead to an increase in prescription drugs that will lower the BP at the expense of exacerbating metabolic syndrome and incurring other increased risks. It continues to be a numbers game with advantages for drug companies but a bleak picture for patients—all of us. Whatever happened to treating patients and patients with diseases not diseases as conjured up entities in and of themselves in  a vacuum? We know from Jeppesen’s work (Copenhagen Men’s Study) that those with elevated BP and elevated TGs and low HDLs, when treated with conventional meds, actually increase their risk of an MI. Beta blockers and diuretics—first line antihypertensive drugs—may increase the risk of developing type 2 diabetes by 28% or more and increase risk for CVD. They increase insulin resistance and worsen metabolic syndrome. But, as long as the numbers look nice…  Many anti-hypertensives have adverse effects on lipid profiles which is probably reflecting worsening of endothelial function. What a sad state is “modern” medicine…

Martin Sturman
Thanks Malcolm for your own wonderful article in Red Flags Weekly.  I estimate 10-15 million Americans will be labeled pre-hypertensive on the basis of these new "guidelines" on the URL; http://www.nhlbi.nih.gov/guidelines/hypertension/jncintro.htm and http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf -pg 18, where the Framingham Study is quoted as stating that 90% of normotensives over the age of 55 will become hypertensive.  Perhaps we all ought to start antihypertensives (if not statins) at birth. Creating new patients and people at risk by redefining cutoff points of continuous variables (see recent changes in "definition" of diabetes) has a profound effect on the definition of universal ill health, and will certainly worsen the financial crisis in healthcare.

Fred and Alice Ottoboni

Read also:

Paul Rosch: Prehypertension And The Emperor´s Invisible Suit
Paul Rosch: Do You Have a Good Blood Pressure? 
Paul Rosch: The Salt Controversy: The Diet "Dictocrats" Are At It Again!
Peter Langsjoen: To Reduce The Risk of Heart Disease, Why Don´t We All Cut Off Our Ear Lobes?