[ Scientific Activities - Actividades Científicas ]
Hypertension in the
Roberto M. Michelson, MD
|HBP In pre and postmenopausal women|
|HBP Haemodynamics in the elderly|
|Treatment advantages of systodiastolic or isolated systolic HBP in the elderly|
|Main secondary HBP causes in the elderly|
|HBP and diabetes mellitus|
Patients older than 65 are arbitrarily defined as elderly. In them, hypertension diagnosis, follow-up and therapeutic alternatives are different from those of young adults. This concept is not always clear for practical physicians, who tend to consider both categories as basically similar. On the contrary, there are even evidences according to which therapeutics must be different not only on the basis of age but also of gender. It is our intention to lay the foundation of these affirmations, when it is possible, both on animal and human experimentation, and on the most recent clinical studies.
In the elderly patient, besides, there is a tendency to apply certain concepts, long ago refuted by investigation and clinical experience, which persist may be due to a certain inertia usually seen when new knowledge looks for its place in everyday practice.
A good example of what we have just said is the conviction according to which high blood pressure (HBP) is a physiologic compensation tending to maintain an adequate blood flow to vital organs such as brain, heart or kidneys in old age. Many believe also that high isolated systolic blood pressure (HISBP) in the elderly is a benign condition, not related to a significant increase of morbidity or mortality in this group.
We shall try to analyse briefly on the basis of which physiopathological findings it is considered nowadays that these concepts are wrong.
Among controllable cardiovascular risk factors, HBP is in the first place in the list of those that can worsen the morbidity and mortality prognosis in old age population. There is no doubt at all that its correct treatment and control is accompanied by even better consequences among the elderly than among young people. In a recent metanalysis of last decades studies [Mulrow, 1995] the number of acute events suffered by hypertensive people treated and non-treated during a period of five years was compared. The conclusion was that, out of every eighteen patients, a cardiovascular event can be avoided when the patients are correctly treated, what is specially evident in the prevention of stroke. It must be recognised that, for causes that are still discussed, prevention of coronary events is less efficient.
When studies performed on elderly patients are compared to those accomplished on young adults, it can be concluded that, in the latter, the number of patients treated in relation to every registered death is twice as much as in old people.
In westernised societies the obvious tendency is towards an older population, so that we can expect a similar augmentation in HBP prevalence. Final numbers can be discussed, because different studies have employed divergent criteria to define this condition, but the ratio is never lower than 30 % and sometimes it is almost 50 % [National Center of Health Statistics, 1977; Kannel, 1980; Emeriau, 1988; Forette, 1975]. In the study FRICAS  performed in the Argentine Republic, numbers in the control group of 1 071 cases were as follows: between 64 and 74 years 32.1 % of men and 40.8 % of women suffered HBP, and among those older than 75 the ratio was 40.8 % and 40.3 % respectively for both sexes.
Generally speaking, below 40 years of age, men predominate clearly in all cross-sectional studies. Between 40 and 50 yet, curves tend to crossover and beyond that age female gender predominates. But longitudinal studies have not confirmed this change. They always show masculine predominance. A possible explanation could be that the HBP group has a greater mortality, so that men suffering this illness are less represented among the oldest people.
Race can eventually be a differential factor, because HBP is certainly more prevalent among Black westernised people than among White people of the same age and condition.
In the elderly, special forms of HBP must be considered, which do not appear in other age groups, such as isolated or disproportionate high blood pressure and pseudohypertension due to stiff arteries, which can be found in almost 15 % of the population.
HBP In pre and postmenopausal women
We shall speak briefly about known differences in HBP consequences in both sexes because, as life expectancy is longer in woman than in man, it is clear that most old hypertensive patients will be people belonging to that sex.
Cardiac output and arterial peripheral resistance, that is to say, what is known as total peripheral resistance (TPR) are the two haemodynamic determinants of BP. Any disproportionate increase of one of these factors with relation to the other causes HBP. Characteristically, young hypertensive patients in stage I present an increased cardiac output, without significant alterations of TPR at rest though, during exercise, TPR does not decrease so much as it does in normotensive people. As HBP worsens, the typical haemodynamic alteration is the increase of TPR with normal or even low cardiac output.
A classical study by Messerli  has demonstrated yet that essential HBP premenopausal women have a different haemodynamic pattern from that of same age male HBP patients. It has been suggested that this would correlate with a better prognosis and with oestrogen influence. Women have a higher cardiac index, left ventricular ejection time and pulse pressure than men. Heart rate is slightly faster and TPR lower at the same BP level. Blood volume of female patients is slightly smaller than that of male patients, as well as total blood volume and red cells mass.
Norepinephrine, epinephrine, dopamine and plasma renin activity levels at rest are not significantly different between both sexes. Yet, pulse pressure increase caused by isometric stress was almost 50 % higher in men than in women. Other haemodynamic indices response was not significantly different between both groups.
As TPR in premenopausal woman is lower than that of the same age man, the risk represented by hypertensive cardiovascular illness to her is also lower. And yet, beyond the age of 45, differences between sexes, in spite of persistence, give up being statistically significant. That is to say, "young" haemodynamic behaviour characterising premenopausal benign HBP woman, with a lower TPR and a higher systemic blood flow, is lost beyond menopause. This fact suggests that sex hormones could be the potential cause of this different haemodynamic pattern between hypertensive pre and postmenopausal women.
On the other hand, the most important adaptation to HBP,
that is to say left ventricular hypertrophy [LVH] is not the same in both sexes. In women,
considering echocardiographic criteria as a reference, LVH prevalence is lower than in
men, independently of BP level. Left ventricle posterior wall is thinner, systolic and
diastolic left ventricular diameters are smaller, and so is the left ventricular mass,
even if the values obtained are indexed on the basis of body surface area.
And besides, left ventricular function indices, such as ejection fraction, fibre circumference shortening speed and load-independent contractility index, are greater in women than in men.
In the specific case of IHSBP, women tend to develop a concentric LVH, without dilation, but men on the contrary, develop not only dilation but also a greater ventricular mass without wall thickening. It is the same case with relation to aortic estenosis.
HBP Haemodynamics in the elderly
In the elderly patient, HBP has special haemodynamic characteristics [Messerli, 1993]. Cardiac output is low, due to a diminished stroke volume and a relative bradycardia. Compared to that of young adults, the cardiac output decrease can be as much as 20 to 30 % with similar BP levels and even in the absence of congestive heart failure. Other differential characteristics are a higher SBP and a lower DBP, with a clear increase of TPR. Elderly normotensive people have a diminished cardiac output too, but in a lesser degree. Age by itself is not an obstacle to cardiac output increase, but the mechanism through which this is reached is different. Elderly patients increase their cardiac output through the Frank-Starling mechanism, while young adults do it through an increase in heart rate and a decrease in the end systolic volume caused by a better contractility. The latter is related to a better response to sympathetic stimuli. In hypertensive elderly patients, finally, cardiac output is diminished and TPR increased, and this makes them prone to serious consequences, such as nephroesclerosis, brain vascular lesions and hypertensive cardiopathy.
It has been repeatedly suggested that HBP would represent an "accelerated ageing" [Lakatta, 1987]. This opinion is based upon the similarity between the arterial wall changes in both cases. It must be considered that arteries are not passive conduits through which blood passes without practical consequences, but that the different haemodynamical factors modulate the composition and organisation of the arterial wall through the whole life. And so, in the elderly, changes associated to HBP in the arterial media layer are responsible for that condition continuation long after the initial factors have disappeared. It has been suggested that vascular stiffening augments BP, essentially the systolic, even within those limits considered normal. This suggests a similar physiological process between chronic HBP and what happens in advanced age in man.
Let us briefly compare those changes caused by HBP in the arterial wall and those caused by ageing. Chronic HBP, in animal models and in man, presents an important increase of TPR caused by arterial wall thickening and stiffening. Both thickening and rigidity are caused by increases in the smooth muscle cell mass and in the protein matrix absolute quantity. These structural changes cause mechanical changes in the arterial wall, which decrease compliance. The latter means the capacity to modify volume according to pressure.
Animal investigation and experience in human beings show that, independently of any difference in physiopathological causes, HBP consequences on the arterial structure and function remain the same. HBP causes an augmentation in mechanical forces acting on large and mid-sized arteries walls. According to Laplaces law, the increase in parietal tension is inversely proportional to wall thickness, and that is the reason why thickening is considered an adaptive response which tries to maintain normal tensions in the medial muscle elastic unit.
Both endothelial cells replication and morphology are modified as a consequence of increase in pressures. Replication rate increases, and morphology goes through structural deformations that cause an increase in permeability caused by discontinuity and disorganisation of tight cell unions.
The media, as it has already been mentioned, becomes thicker as a consequence of an increase in smooth muscle cell mass and the extracelular matrix absolute quantity, essentially caused by cell hypertrophy, with increases of protein synthesis and genome mass, and also of fractions of collagen, elastin or both. According to findings from different experimental models, the mentioned thickening depends basically on cell hypertrophy caused by an increase in its metabolic activity. On the other hand, the protein matrix increase is caused by collagen, in such a way that the ratio between the latter and elastin tends to augment. The haemodynamic consequence of these changes is an important decrease in compliance with similar BP levels. Hypertrophy is also associated to a complicated remodelling of intercellular junctions responsible of linkage and cohesion among muscle cells, as a consequence of which they become wider and disorganised. Some people consider that this is a factor favouring arterial aneurysms.
In those arteries which are less than one millimetre wide, smooth muscle cell contraction causes an increase of BP as a consequence of a higher TPR at a constant flow rate. Cells contraction is due to vasopressor agents or an increased presence of vasoconstrictor substances such as endothelin, which increase free intracellular calcium and trigger the contraction mechanism through associated proteins such as calmodulin. All these substances can also enhance smooth muscle cell growth. Structural lesions in the arterial wall in these cases can be differentiated as hypertrophy-hyperplasia and fibrinoid necrosis.
The information we have just mentioned comes from animal experimentation. The situation is more difficult in the case of man, as even the data from autopsies are not worthy of confidence. Nowadays we can fortunately study patients with ultrasound. In hypertensive people, the great arteries diameter remains the same or increases, but compliance is always impaired. This happens because thickening is the only mechanism that can sustain wall tension, and this can be clearly seen in experimental models. In the human being, yet, the presence of arterial wall hypertrophy is controversial, though we have a lot of indirect evidence. Folkow  has demonstrated that 5 % changes in the internal diameter of resistance vessels can cause 25 % increases in TPR.
The arterial wall thickening, then, is the chronic HBP final common result both in experimental animals and in man and this is a structural contribution to an increase in TPR and a decrease in compliance.
When the intention is to study those structural changes caused only by ageing, the methodological problem is far more important. It can always be discussed whether findings are caused by ageing or by pathologies that were not identified. This has been widely discussed in specialised literature. And yet, the study of pressure and flow curves can give reliable information. The rate between BP and mean flow allows us to estimate the resistance vessels size, and compliance can be used to have an estimation of the system elasticity. It is well known that, in the elderly, pressure/volume curve shifts to the right, and its slope, which represents compliance, decreases.
At all levels of the arterial system the intima, the media and the adventitia are affected. As man becomes older, four lesion patterns have been described in the large arteries, which can be always more often found: cystic medial necrosis, elastin fragmentation, medial fibrosis and areas of medionecrosis. The changes found are not regularly distributed but some sectors are more affected than others. Mid-sized arteries are the most important place of age-related changes, among which the principal is the calcinosis of the media. Tibial and coronary arteries are most affected by the changes we are talking about. In the latter, it seems important that the arterial wall is subject to pulsatile flow during cardiac cycle, both in ageing and in atherosclerosis. The changes found in arterioles are caused by hyalinosis, a plasma process that impairs in different degrees local blood flow. All these age-related changes have a differential chronology, since they appear first in the greater vessels proximal area, and only afterwards in the smallest distal one. This could be related to pulsatile flow, which only reaches the most distant sectors when the increase in rigidity in the proximal areas allows it.
It must be considered that HBP accelerates the above-mentioned process. The normal ageing of the cardiovascular system is more important in the hypertensive than in the normotensive patients, and this causes a greater decrease in vascular and cardiac compliance, in muscular strength, in contraction speed and renal functional capacity. This is the main reason of our first affirmations: it is more difficult to treat elderly hypertensive patients because they have suffered an upwards structural resetting with higher pressure values, with cardiac, renal and blood flow decreased reserves. The latter especially in the coronary, brain and kidney circuits. The decrease of the blood flow depends on an increased TPR, and this worsens when atherosclerosis is present.
Another interesting study alternative, which is an objective guaranty when we consider certain changes as age-related and not caused by cardiovascular pathologies, essentially HBP, is what can be done with experimental laboratory animals not affected by that illness.
The most important finding in a study that employed male rats was an age-related increase in large arteries size [Michel, 1994]. This structural phenomenon was associated to an age-dependent increase in functional artery rigidity and with increases in the media and intima thickness. The age-dependent changes observed in the arterial wall were associated with a significant cardiac hypertrophy, with an increased auricular natriuretic factor and with a decreased plasma renin activity. Many of these phenomena are strictly age-dependent, and independent of HBP since they were observed in rats whose blood pressures did not change with age. Moreover, the ACEI, which decrease blood pressure throughout these rats lives, could diminish certain converting enzyme-dependent or stress-dependent parameters, such as medial or intimal thickening or cardiac hypertrophy, without avoiding their age-dependent increase and without any change in the augmentation of artery size or matrix-dependent artery wall rigidity observed with age. In this study, aortic and carotid circumferences increased progressively and regularly with age and were not modified by hypotensive treatment. These findings confirm previous ones, both in rats and in man, according to which, by postmortem ex situ analysis or by in vivo echographic methods a similar and pressure-independent increase in the artery width with age. Elastic arteries enlargement is associated with a wall rigidity increase, and the age-related increase in aortic impedance and the decreases in global systemic and in situ carotid compliance demonstrate this. Enlargement and rigidity of large arteries can increase cardiac afterload by augmenting the residual blood volume present in large arteries at the end of diastole, which is mobilised during systole, and also characteristic impedance, what can explain partially the increase in age-related cardiac hypertrophy and also that of the age-related plasma auricular natriuretic factor. Smooth muscle cell hypertrophy seems to be influenced independently of age or ACEI. Finally, artery enlargement can also influence endothelial function. Endothelial nitric oxide production depends essentially on its activation by shear stress. Shear stress depends positively on blood speed and viscosity, and is inversely dependent on arterial size. The latter increases with age, so that this probably causes a shear stress chronic decrease.
Treatment advantages of systodiastolic or isolated systolic HBP in the elderly
The most recent trials show clearly that an appropriate treatment of HBP in the elderly is particularly favourable in relation to the pathological consequences decrease of this illness. We shall briefly mention some of the most important ones.
SHEP trial (Systolic Hypertension in the Elderly Program) [SHEP Cooperative Research Group, 1991] included 4736 patients, mean age 72 years at the study beginning, with a 177/70 mmHg mean blood pressure. The most important findings, after a mean follow-up of a little more than four years, was a 37 % reduction in fatal and non fatal strokes after active treatment, 27 % in fatal and non fatal AMI, 25 % in coronary artery disease, and 32 % in all-cause cardiovascular events. Total mortality decreased 13 % but that was not considered significant.
STOP-Hypertension trial (Swedish Trial in Old Patients with Hypertension) [Dahlöf, 1991] included even older patients, since mean age at the beginning was 76 years. 1627 both sexes patients were included. The Safety Committee prematurely interrupted the trial, but patients were treated during a 2.1 years mean follow-up. No patient was lost. Morbidity and mortality secondary to stroke diminished 47 %, while all-cause cardiovascular events and total mortality decreased respectively in a 40 and a 43 %. All these results were highly significant in relation to those of the placebo group.
MRC trial (Medical Research Council) [MRC Working Party, 1992] was performed in the United Kingdom and included 4400 men and women between 65 and 74 years of age. The most important findings were a 25 % and a 17 % reduction in stroke and all-cause cardiovascular events, respectively.
With this information there can be no more doubts about the convenience of lowering HBP in the elderly, including HISBP.
Main secondary HBP causes in the elderly
Secondary HBP prevalence varies from 2 to 20 % according to the sort of statistics considered, be them from general or specialised centres. Such a difference suggests that, in the first, an important number of secondary cases are undetected and treated similarly to essential HBP, what would cause a great number of useless long pharmacological treatments and even avoid cure in a certain sort of patients.
1. Renal HBP
HBP can be caused by renal illness or can, on the contrary, cause it. HBP can impair renal function through glomerular hypertension, which causes glomerular sclerosis. On the other hand, an impaired kidney can cause HBP in different ways: it can cause an increase of blood volume, alter Na+ excretion, increase vasopressor substances production or decrease that of those which are vasodilators, and this can happen in an isolated or combined way.
Kidney weight decreases with age, and the cortical layer becomes thinner, reducing thereby the number of functional glomeruli. The senile kidney vessels suffer atherosclerotic changes and the organs capacity to maintain homeostasis also decreases. This is caused partially by an important decrease in renal plasmatic flow, which practically diminishes 50 %, causing a great decrease of the glomerular filtration rate and the creatinine clearance. Plasma creatinine, in spite of what we have said, does not increase, because old peoples muscular mass is smaller than that of young adults. The angiotensin-renin system activity also decreases markedly.
In the elderly, the most usual illnesses which can be accompanied by HBP are primary and secondary glomerulopathies, especially that of diabetes mellitus, pyelonephritis, obstructive uropathies and tubular-interstitial sickness.
The remaining kidney function tends to be protected with pharmacological control of HBP, especially when angiotensin converting enzyme inhibitors (ACEI) are used, through a decrease of glomerular hypertension, what is extremely evident in diabetic patients. Loop diuretics and calcium blockers can be used too but, in general, beta-blockers are not so useful, may be because the elderly have less beta-receptors.
2. Renovascular HBP
The most usual ethiology in the elderly is atherosclerotic renal artery obstruction. Lesions tend to be found in the aorta, causing an occlusion of the renal artery ostium or its proximal portion, and are progressive. Renal artery obstruction causes a downfall in the kidney perfusion, and the latter begins to release more renin in the venous blood. This causes an increase in angiotensin I and II plasma levels. This mechanism produces an increase in TPR and systemic BP in order to improve the kidney perfusion beyond the obstruction. If perfusion keeps low, yet, angiotensin II plasma levels decrease, even if there is still HBP.
Early diagnosis is more essential than ever, because after a certain time vascular and glomerular lesions caused by the obstruction do not allow HBP disappearance once the latter is surgically corrected. In the following picture, we can see those circumstances that can create the suspicion of secondary renovascular HBP in the elderly patient.
Renovascular HBP can only be cured through surgery or angioplasty. Pharmacological treatment can only be used while surgery is awaited. Diagnosis confirmation is done nowadays preferentially through renography with captopril challenge test, but renal arteriography is the only precise way to detect and find obstructions in renal artery.
3. Suprarrenal HBP
The incidence of this ethiology in hypertensive elderly people is extremely low. We shall mention briefly primary aldosteronism and pheochromocytoma.
3.1. Primary aldosteronism:
It is caused by an increase in aldosterone production independent of renin-angiotensin system. Diagnosis of this ethiology is based on the laboratory, because clinical manifestations are secondary to hypokalemia, and thereby inespecifical. It can be suspected when plasma potassium is lower than 3.5 mEq/Lt. It can be confirmed measuring plasma renin activity at rest and after walking, plasma aldosterone under both circumstances too, and 24 hours urinary aldosterone. The aldosterone-producing adenoma must be differentiated from idiopathic hyperaldosteronism caused by bilateral hyperplasia. In the first case treatment is surgical, in the second is medical.
It is a chromaffin cell tumour, which can appear in the adrenal medulla and less frequently in the extrarrenal chromaffin tissue. It can be diagnosed through the biochemical measurement of urinary catecholamines and vanillylmandelic acid in 24 hours urine. It can be found through abdominal CT, MRI or scintillation camera. Naturally, treatment is surgical, once BP has been controlled with drugs.
HBP and diabetes mellitus
Compared to non-diabetic people, hypertensive patients are twice as much among diabetics. HBP in diabetics without nephropathy is more frequent in patients older than 65 years. HBP is higher as the evolution time of diabetes is longer.
Reaven  used the expression "metabolic X syndrome" to distinguish a situation in which insulin resistance is characterised by a high prevalence of NIDDM, HBP, obesity, dislipemia and cardiovascular illness. Nowadays, the name "insulin resistance syndrome" is preferred. Afterwards the very Reaven concluded that insulin resistance could be a primary defect in hypertensive patients, were they diabetic or not. Insulin resistance and hyperinsulinism can be responsible for HBP pathogenesis and this could be genetically determined.
Insulin resistance and hyperinsulinism are cardiovascular risk factors independently of HBP. Neither every patient with hyperinsulinism is hypertensive, nor every hypertensive patient is hyperinsulinemic, so that his or her participation in the appearance of HBP cannot be generalised.
We can say that in the first stage of diabetes there is a blood volume expansion, which can cause an increase in cardiac output. Afterwards, in the chronic stage, impairment in TPR regulation predominates. Corporal sodium is augmented both in hypertensive and diabetic patients, with a significant alteration of the internal medium. It is unknown why this is not accompanied by an increase in plasma volume, something that normally happens in non-diabetic patients. Diabetics have an exaggerated cardiovascular reactivity to angiotensin II. Insulin capacity to cause HBP even with normal glycemia values has been related to its capacity to increase renal sodium retention, stimulate the release of catecholamines and cause smooth muscle hypertrophy.
In the untreated hypertensive elderly patient there is a decrease in brain blood flow that is considered a risk factor in relation to stroke and dementia. Selfregulation is a characteristic that brain has in order to adapt its blood requirements through the active modification of the brain vessels as a response to variations in perfusion pressure in order to maintain a constant brain blood flow. When the limits of selfregulation are overpassed a forced vasodilatation in brain arteries happens, brain blood flow increases and as a result brain hyperaemia, tisular oedema and may be brain haemorrhages can be caused. All this is called hypertensive encephalopathy.
The critical point after which these limits are surpassed, about 180 mmHg of mean arterial pressure, lies around 150 mmHg in previously normotensive patients. On the contrary, when blood flow is insufficient to maintain perfusion, that is to say when mean arterial pressure is under 60 mmHg, there are hypoperfusion and ischemia.
It must be seriously considered that, in chronic hypertensive elderly patients the selfregulation curve shifts to the right, and therefore the above mentioned limits are higher than those of normotensive people. An aggressive hypotensive treatment with the goal of reaching those BP values considered normal in young adults can be severely iatrogenic if this circumstance is ignored.
It has been established that old patients with this syndrome can present hypoxia, episodes of awakening and increases in BP in pulmonary and aortic arteries. And yet, there is not in them a coincidence between this syndrome and HBP, unlike what happens in young adults [McGinty, 1982].
The obstructive sleep apnoea syndrome is related to a higher prevalence of HBP, higher risk of coronary artery disease and stroke, and also to a greater ventricular hypertrophy and a decreased response to antihypertensive treatment. Some of these findings can be related to obesity. In fact, HBP appearance in those who suffer sleep apnoea is being discussed, but haemodynamical changes, sympathetic nervous activity and neuroendocrine dysfunction have been found, and tend to disappear when the syndrome is controlled.
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