Cardiovascular disorders

I/2.4: A significant risk factor of cardiovascular diseases: hypertension

I/2.4.1: Types of hypertension

Based on its etiology, hypertension  can be ‘primary’ or ‘secondary’, and in consideration of its biological behaviour and clinical course we distinguish ‘benign’ and ‘malignant’ hypertension. Hypertension is called primary or essential if its cause is not obvious, and secondary if there is a known pathology or syndrome in its background. The course of benign hypertension typically lasts for years through decades, the blood pressure disorders can be treated well medically, and if the blood pressure values are well set, then the patient’s life expectancies don’t differ significantly from healthy control population. However, in malignant hypertension, extreme blood pressure values develop within a few months, they are difficult to control medically, and the patient’s life expectancies are unfavourable.

I/2.4.1.1: Primary (essential) benign hypertension

In primary (essential) hypertension the cause of the disease is unknown, and this makes 90 to 95 percent of all cases. Multiple factors contribute to its development, and three of them should be emphasized:

• 1) sodium balance disorder,

• 2) environmental effects maintaining and aggravating vasospasm, and

• 3) structural maladaptation of resistance vessels.

1. Sodium balance regulation disorders are caused by a susceptibility showing polygenic inheritance, and a yet not further outlined genetic damage of the renin-angiotensin-aldosteron-sodium system is thought to be responsible for it. Mutations of 8 genes are known so far, and each of them affects sodium reabsorption in the tubuli. Therefore sodium excretion decreases in the kidney, and the consequent water retention causes hypervolemia in the blood vessels. The left ventricle adapts, and increases the amount of blood pumped into the aorta during systole. The resistance vessels contract in order to prevent hyperperfusion in the tissues. Vasospasm, which is unstable at the beginning, is characterized by thickening of the media and luminal diameter decrease.

2. Several environmental effects maintaining and aggravating vasospasm are known: e.g. social situation, diet rich in NaCl, alcohol consumption, lack of physical activity, success-oriented, competitive personality, stressful, too active life style, and obesity. Among these, we emphasize salty food consumption over decades, overstrained life style leading to increased catecholamine secretion (permanent stress) and lack of physical activity. Excessive sodium intake increases the resistance vessels’ pressor response to angiotensin II and catecholamines (through hyperreactive smooth muscle cells of the media).

3. Structural maladaptation of resistance vessels means that vasospasm becomes permanent. As a result of vasospasm lasting for years, such structural changes take place in these vessels that don’t allow normal relaxation for smooth muscle cells anymore; the vessels’ narrowed status becomes fixed, that is the proportion of the vascular wall’s and lumen’s diameter increases (this structural change is the so-called remodeling), and thus the increased vascular resistance, and therefore hypertension itself becomess permanent. Permanent hypertension causes hyaline arteriosclerosis in the resistance vessels, and so-called hypertensive cardiopathy in the heart (concurrent appearance of myocardial hypertrophy and ischemic cardial alterations – e.g. interstitial fibrosis, coronary sclerosis), and it might deteriorate atherosclerosis in the aorta and in the large muscular arteries.

In hyaline arteriolosclerosis a homogenous, eosinophil, not specified material with protein nature (hyaline) deposits in the intima and media of small and medium size vessels. The lesion is usually segmental, excentric, and rarely concentric. Vascular lesions can also be identified as definitive target organ damages. In the brain it mostly affects the little vessels of the basal ganglia. Demarcated enlargements, so-called Charcot-Bouchard microaneurysms often form in the affected vascular sections. Hypertension related cerebral hemorrhages are suspected to originate from the rupture of these microaneurysms. Clinical manifestations of hypertensive cerebral damages are TIA, ischemic stroke, hemorrhage, and the complex of hypertension related central neural system disorders (hypertensive encephalopathy).

Structural realignment of the heart’s small vessels unfavourably influences myocardial blood supply, causes ischemia, and ccontributes to the development of hypertensive heart disease. Its clinical manifestations may be angina pectoris, myocardial infarction, and heart failure. Morphologically arteriosclerotic nephrosclerosis occurs in the kidneys, functional alterations manifest in elevated serum creatinine levels and proteinuria.

Hypertensive small vessel alterations of the retina are detected by fundoscopy. It is of special clinical significance that the fundus is the only place in our body where vascular alterations can be seen by direct inspection, and that the severity of hypertensive alterations in the fundus is commensurate with the severity of hypertension (‘the eye is the mirror of hypertension’). Macrovascular fundal lesions according to Keith’s classification are the following: Grade 1: caliber fluctuation, increased light reflex, copper wire arterioles; Grade 2: Grade 1 + crossing phenomenon; Grade 3: Grade 2 + fundal hemorrhages, focal areas of degeneration; Grade 4: Grade 3 + retinal and papilledema (malignant phase hypertension).

I/2.4.1.1.1: Hypertensive cardiopathy and arterial hardening (arteriosclerosis)

Increase of peripheral vascular resistance leads to pressure load in the left ventricular muscle mass. First concentric and later dilated (eccentric) left ventricular hypertrophy develops, and the heart’s weight exceeds 500 g. Since essential hypertension is one of the most significant risk factors of arteriosclerosis, hypertensive patients usually suffer from arteriosclerosis, and as a part of the phenomenon, from coronary sclerosis too. Stenosis in the heart’s large vessels and resistance vessels leads to occasionally fatal complications, arrhythmias and left ventricular failure. The kidney’s resistance vessels are the small interlobular arteries and afferent arterioles. Their vasospasm restrains filtration pressure increase in the glomerular capillaries, therefore GFR remains stable.

In permanent hypertension, arteriolosclerotic nephrosclerosis (benign nephrosclerosis) develops. The kidneys look smaller with naked eye, their weight is usually 130 g, apiece, and their surfaces are finely and evenly granulated. Histologically, focal vascular lesions are found, the small interlobular arteries show medial hypertrophy and intimal fibroelastosis is seen; and the arterioles develop medial hypertrophy (2-3 smooth muscle cell layers) and segmental hyalinosis. In the glomerules of the most stenotised small vessels, global sclerosis (extending to the whole of the affected glomerule) is seen, and in the surroundings of the scarred glomerules, focal interstitial fibrosis and atrophized tubuli are found. Fibrotic areas sink in as compared to intact areas, and this is the reason of the macroscopic granulation.

Although smaller kidneys with granulated surfaces, concentric left ventricular hypertrophy and destructive cerebral hemorrhage  are the typical autopsy findings of benign essential hypertension, it is expedient to verify arteriolosclerotic nephrosclerosis histologically, since smaller kidneys with granulated surfaces can be caused by diabetic nephropathy or chronic glomerulonephritis too. Although kidneys are target organs of hypertension, their lesions usually don’t cause substantial renal function decrease. Clinically, hypertension starts smouldering, probably between 25-35 years of age. Elevated blood pressure remains on a constant level for many years, and the diastolic value doesn’t exceed 115 mmHg. The disease remains symptom free for long years, and it is usually discovered due to some of its organic manifestations, after the age of 45-55 years.

Due to symptom free period lasting for years or even decades, hypertension is often discovered only by autopsy (‘benign essential hypertension: the silent murderer’). The disease’s incidence increases by the age. In the USA, it is twice more frequent in black people than in white. Benign essential hypertension is endemic in developed countries. According to estimations, 25 percent (!) of the adult population suffers from hypertension in Hungary; and this is the main cause of cerebrovascular mortality. Direct causes of death include cerebral hemorrhage, left ventricular insufficiency, aortic dissection, and subarachnoid hemorrhage.

Dissection in cystic medial degeneration of the aorta and rupture in cerebral basal berry aneurysm usually follows a sudden blood pressure jump. Direct causes of death are related to arteriosclerosis. This group includes acute myocardial infarction, sudden cardiac death and emollition in the pons due to basilary arterial thrombosis. In decompensated benign nephrosclerosis a small number of patients develop progressive glomerulosclerosis with consequent significant proteinuria and slowly increasing serum creatinine levels. Pathomechanism of glomerular damage is not yet clarified. In spite of antihypertensive medication, the patients develop chronic renal failure.

I/2.4.1.2: Primary (essential) malignant hypertension

This disease form is rare, only cca. 5 percent of all hypertension cases. Its onset is sudden, and usually develops in normotensive men between 30 and 40 years of age. It might also emerge in patients with benign essential hypertension, and in these cases it is called accelerated hypertension. Hyperreninemia is detected in the serum, and the blood pressure elevates rapidly, within a few weeks, over 200/130 mmHg. Macroscopically, pointlike bleedings are seen in the renal cortex, and fresh and older small anemic infarctions might be present. No substantial renal shrinkage is seen though. Histologically hyperplastic arteriolosclerosis is seen, smooth muscle cells in interlobular arteries and afferent arterioles thicken and multiply, myocytes are located concentrically like onion layers in the media and intima; collagen is deposited among them, and the lumen is very narrow, barely discernible.

In the arterioles, these alterations may be accompanied by fibrinoid necrosis of the smooth muscle cells with moderate reactive inflammation (necrotizing arteriolitis, malignant nephrosclerosis) with consequent thrombosis. Necrosis often affects the glomerular segments as well, and necrotizing glomerulonephritis occurs with semilunar deposit formation. Histologically thrombotic microoangiopathy is seen. Extreme high blood pressure leads to rupture of the necrotic small vessels, and this is the reason of pointlike bleedings in the cortex.

Clinically bleedings and papilledema develop in the retina due to extreme blood pressure levels, the left ventricle gets exhausted, and left heart failure occurs. Very high blood pressure causes hypertensive encephalopathy, and there is a permanent risk of destructive cerebral hemorrhage. Encephalopathy manifests in headache, vision disorders, nystagmus, focal neurologic signs, and positive plantar reflexes. Renal function deteriorates steadily. If left untreated, 80 percent of the patients die within a year. Death is caused by uremia, left heart failure or destructive cerebral hemorrhage (cerebral apoplexy).

I/2.4.1.3: Secondary hypertension

The cause of hypertension is known in 5 to 10 percent of the cases. These include: chronic renal parenchymal disease (renal parenchymal hypertension); unilateral renal artery stenosis or renal vascular disease (renovascular hypertension); endocrine diseases (aldosteronism, phaeochromocytoma, Cushing’s disease, hyperthyreosis); other vascular cause (aortic coarctation, arteritis); neurological cause (intracranial pressure increase).