~Hypertension, Part 2 - Pathophysiology

~Hypertension, Part 2 - Pathophysiology
Anatomy and Physiology

The circulatory system is comprised of the heart, aorta, arteries, arterioles, capillary beds, and the veins. Blood pressure is maintained by the systolic contractions of the left ventricle of the heart. Blood ejected from the heart passes through one-way valves into the aorta. Systolic pressure peaks immediately following each contraction of the left heart.

This systolic pressure is measured in the clinic and the laboratory in terms of mmHg. The pressure exerted is measured by a column of the heavy liquid metal known as mercury. Mercury (Hg) is a heavy metal like gold. A systolic pressure of 120 mmHg would approximately equal the downward force of roughly 30 inches (120 cm) of this heavy metal. To put this into perspective, the weight of the column of air that is pressing down on each of us (one "atmosphere" of pressure) is 760 mmHg.

Diastolic pressure is the pressure that remains in the arterial system approximately one second later and immediately before the next systolic contraction of the heart. During this intervening second, arterial blood pressure drops as blood is filtered through the capillary bed. The degree of vasoconstriction of these vascular smooth muscles determines the rate at which blood perfuses through the capillary beds at all tissues and into the venous system. The endothelial cells that line the inside of these capillaries are particularly susceptible to the long-term effects of hypertension, especially when these capillaries supply blood to the tissues of the heart, kidney, brain, and eye. Smooth muscle cells surrounding the capillary beds play an important role in the regulation of blood pressure and are targets for many of the medications used to treat hypertension.

  • Cardiac Effects
  • Neurological Effects
  • Renal Effects
  • Endocrinology and Biochemistry
  • Testosterone
  • Biochemistry
  • Vascular Endothelium and Smooth Muscle Cell Function
  • Stress
  • Endocrine Correlates
  • Dietary Fats
  • Homocysteine
  • C-Reactive Protein
Hypertension can damage your heart, kidneys, eyes and brain. Hypertension can cause significant damage to blood vessels. The brain, heart, and kidneys all suffer irreversible harm from long-term elevation in blood pressure. Even an elevation in one of the pressures (systolic or diastolic) can have long-term health consequences. Isolated high systolic pressure, which is the most common form of high blood pressure in older adults, is thought by many to be a significant indicator of heart attack and stroke. Isolated high diastolic pressure is a strong risk factor for heart attack and stroke, especially in younger adults.

It is human nature to respond to threats to health and safety, however, hypertension can take decades to inflict damage so it is easy to forget, rationalize, or develop an attitude that "it can't happen to me." These attitudes lead to heart disease, impotence, non-Alzheimer's dementia, and early death. By following a healthy lifestyle that includes a diet high in fruits and vegetables, avoiding all tobacco products, maintaining a reasonable weight, and taking safe and effective supplements, insidious diseases such as hypertension can be controlled.

"Because essential hypertension is a heterogeneous disorder, variables other than the arterial pressure modify its course. Thus, the probability of developing a morbid cardiovascular event with a given arterial pressure may vary as much as 20-fold depending on whether associated risk factors are present. Although exceptions have been reported, most untreated adults with hypertension will develop further increases in arterial pressure with time. Furthermore, it has been demonstrated from both actuarial data and experience in the era prior to effective therapy, that untreated hypertension is associated with a shortening of life by 10 to 20 years, usually related to an acceleration of the atherosclerotic process, with the rate of acceleration in part related to the severity of the hypertension. Even individuals who have relatively mild disease that are left untreated for 7 to 10 years have a high risk of developing significant complications. Nearly 30% will exhibit atherosclerotic complications, and more than 50% will have end organ damage related to the hypertension itself, such as cardiomegaly, congestive heart failure, retinopathy, a cerebrovascular accident, and/or renal insufficiency. Thus, even in its mild forms, hypertension is a progressive and lethal disease if left untreated" (Williams 2001).

Cardiac Effects

"Cardiac compensation for the excessive workload imposed by increased systemic pressure is at first sustained by concentric left ventricular hypertrophy, characterized by an increase in wall thickness. Ultimately, the function of this chamber deteriorates, the cavity dilates, and the symptoms and signs of heart failure appear. Angina pectoris may also occur because of the combination of accelerated coronary arterial disease and increased myocardial oxygen requirements as a consequence of the increased myocardial mass. Evidence of ischemia or infarction may be observed late in the disease. Most deaths due to hypertension result from myocardial infarction or congestive heart failure. Recent data suggest that some of the myocardial damage may be mediated by aldosterone in the presence of a normal/high salt intake rather than just the increased blood pressure or an increase in angiotensin II levels" (Williams 2001).

Hypertension increases the risk of cardiovascular disease by affecting the performance of arteries. Normally, arteries expand and contract effortlessly with each heartbeat. With sustained hypertension, the arterial walls become thickened, inelastic, and resistant to blood flow. This process injures arterial linings (arteriosclerosis) and accelerates plaque formation (atherosclerosis). Dysfunctional, blocked vessels (ischemia) are unable to expand to accommodate the flow of blood, requiring the left ventricle to work harder (congestive heart failure). Arterial damage invites spasms in the walls of the arteries. The spasm further impedes the flow of blood, adding more load to the ailing heart. Aneurysm, stroke, angina pectoris, and myocardial infarction are even more likely to occur if there is high cholesterol and elevated blood pressure.

Neurological Effects

"The neurologic effects of long-standing hypertension may be divided into retinal and central nervous system changes. Increasing severity of hypertension is associated with focal spasm and progressive general narrowing of the arterioles, as well as the appearance of hemorrhages, exudates, and papilledema. These retinal lesions often produce scotomata, blurred vision, and even blindness, especially when there is papilledema or hemorrhages of the macular area. Hypertensive lesions may develop acutely and, if therapy results in significant reduction of blood pressure, may show rapid resolution. Rarely, these lesions resolve without therapy. In contrast, retinal arteriolosclerosis results from endothelial and muscular proliferation, and it accurately reflects similar changes in other organs. Sclerotic changes do not develop as rapidly as hypertensive lesions, nor do they regress appreciably with therapy. As a consequence of increased wall thickness and rigidity, sclerotic arterioles distort and compress the veins where the two vessel types cross in their common sheaths " (Williams 2001).

For these reasons, a close examination of your retina by the physician is a valuable predictor of cardiovascular health and is highly recommended by the Life Extension Foundation. The efficacy of standard therapeutic regimens and our adjuvant protocols can be monitored by chronically following the retinal changes over the course of many months to years.

"Central nervous system dysfunction also occurs frequently in patients with hypertension. Occipital headaches, most often occurring in the morning, are among the most prominent early symptoms of hypertension. Dizziness, light-headedness, vertigo, tinnitus, and dimmed vision or syncope may also be observed, but the more serious manifestations are due to vascular occlusion, hemorrhage, or encephalopathy. The pathogeneses of the former two disorders are quite different. Cerebral infarction [stroke] is secondary to the increased atherosclerosis observed in hypertensive patients, whereas cerebral hemorrhage [stroke] is the result of both the elevated arterial pressure and the development of cerebral vascular microaneurysms. Only age and arterial pressure are known to influence the development of the microaneurysms. Thus, it is not surprising that arterial pressure shows a better association with cerebral hemorrhage than with either cerebral or myocardial infarction" (Williams 2001).

Renal Effects

"Arteriosclerotic lesions of the afferent and efferent arterioles and the glomerular capillary tufts are the most common renal vascular lesions in hypertension and result in a decreased glomerular filtration rate and tubular dysfunction. Proteinuria and microscopic hematuria occur because of glomerular lesions, and approximately 10% of the deaths caused by hypertension result from renal failure. Blood loss in hypertension occurs not only from renal lesions; epistaxis, hemoptysis, and metrorrhagia also occur frequently in these patients" (Williams 2001).

Endocrinology and Biochemistry

Hypertension is characterized by two key disturbances to the endocrine systems of the renin-angiotensin-aldosterone-axis (RAAA) and the sympathetic nervous system. The former elevates angiotensin II and aldosterone, causing elevated blood pressure and retention of sodium, respectively. The latter directly stimulates adrenergic receptors in heart, kidney, and smooth muscle vasculature to increase blood pressure predominantly through increased cardiac output and peripheral vasoconstriction. Normally, the RAAA operates over a longer time period such as would accompany dehydration; whereas the sympathetic nervous system is designed to respond to immediate physiologic needs for increased cardiac output or increased blood pressure (see The Renin-Angiotensin-Aldosterone-Axis for more extensive detail.)

Clinical laboratories routinely measure levels of renin, angiotensin II, aldosterone, epinephrine, and norepinephrine. Electrolytes like sodium, chloride, calcium, and magnesium are easily determined. As detailed in other protocols within this book, it is important for each of us to measure those substances in our blood stream because they provide clues to our state of health, particularly the extent and form of our hypertensive vascular disease or its allied diseases. Serum creatinine levels are an extremely important marker of kidney function. High creatinine (>1.7 mg/dL) predicts cardiac outcomes in high blood pressure. Creatinine reflects kidney impairment, which compromises cardiovascular function, resulting in heart attacks and stroke, possibly prior to kidney failure itself (Shulman 1989).

Neuroendocrine influences are not that significant in hypertension. In general, only stress-mediated release of hormones such as vasopressin, which causes retention of water and some vasoconstriction, or stress-related release of adrenocorticotropic hormone (ACTH), might directly or indirectly affect blood pressure. Presently there is little interest in understanding these lesser contributors to hypertensive vascular disease. Rare cases of ACTH-secreting pituitary tumors are less common than the secondary forms of hypertension, the latter only accounting for less than 5-10% of cases of hypertension.


Testosterone exerts important influences on blood pressure. Men with higher levels of testosterone show lower levels of coronary heart disease (Hak et al. 2002). Studies have shown that men with low testosterone levels had higher blood pressure (Muller et al. 2003). Elderly men with isolated systolic hypertension were found to have 14% lower levels of testosterone than normotensive, age-matched men. Low testosterone levels correlated with higher blood pressure values (Fogari et al. 2003). B lood pressure affects cardiovascular disease risk by doubling of risk of mortality with every 20-mmHg increment in systolic pressure or 10-mmHg increment in diastolic pressure (Kannel et al. 2003).

There is overwhelming evidence of a continuous, graded influence of blood pressure on cardiovascular disease morbidity. With higher blood pressure values linked to declining testosterone and cardiovascular disease in both men and women of all ages, aging men may keep blood pressure lower through testosterone supplementation, especially if they have reached that age (>40) when testosterone has already declined and blood pressure is rising.


Biochemical processes that are important to the etiology or treatment of hypertension include the role of the renin-angiotensin-aldosterone-axis and sympathetic nervous system. There is as yet no definitive deficiency in any known metabolic pathway that can be specifically attributed to hypertension. However, deficiencies in the metabolism of homocysteine are clearly related to cardiovascular disease (Brown and Hu 2001), but it is unclear how homocysteine may directly cause hypertension. However, epidemiological studies and findings from research based on nutritional correlates of susceptibility to hypertension, have pointed to functions of the critical metabolites of essential fatty acids, arginine, folic acid, and antioxidant vitamins (Brown and Hu 2001).

Within the larger context of cellular biochemistry and physiology, an important role for essential fatty acids (EFFs) has emerged, particularly in relationship to such risk factors as homocysteine (McDowell and Lang 2000), CRP, and other inflammatory factors. The following section is presented in considerable detail because of the compelling role of fat metabolism in the regulation of smooth muscle vasculature and endothelial cells.

Metabolism of essential fatty acids leads to potent biological substances that act as vasodilators, vasoconstrictors, and mediators of inflammation, coagulation, and immunity. All of these factors are critical in understanding the relationship of hypertension in the etiology of hypertensive vascular disease-associated atherosclerosis, arteriosclerosis, congestive heart failure, stroke, and still further, hypertension. A detailed focus on the biochemistry and physiology of peripheral vascular smooth muscle and the associated endothelial cells is further justified on the basis that this is the primary target tissue of the most importantly implicated mediators of hypertension, angiotensin II, and norepinephrine. Finally, epidemiological studies have clearly shown that essential fatty acids impact the development and progression of hypertensive vascular disease, and regulate many genes important to normal endothelial cell function (Simopoulos 1999).

Recall that at the organ level we have identified increased sodium retention as a primary initiating cause of hypertension. It is our contention that prolonged hypertension, regardless of the etiology, ultimately progresses to more advanced diseases of the vasculature, especially through dysfunction of the endothelial cells (Cooke 2000). This discussion will be presented in the following section.

Vascular Endothelium and Smooth Muscle Cell Function
  • Essential Fatty Acids in Hypertension
  • Essential Fatty Acids as Essential Nutrients
  • Metabolism to Prostaglandins
  • Genetic Mechanisms
  • Membrane Biochemistry
Essential Fatty Acids in Hypertension

Hypertensive vascular disease progression is characterized by injury to the endothelial cells of the vascular tree caused by hypertension and other risk factors, hence the name hypertensive vascular disease. This injury results in the thickening and hardening of the interior walls of the arterioles and major arteries. The development of plaque on these surfaces predisposes the individual to the sudden development of occlusive blocks of such key arteries as the coronary arteries supplying blood to the heart (heart attack), the kidney, and other arteries supplying blood to the brain (stroke) (Brown and Hu, 2000).

The development of microvascular occlusive disease of the kidney is particularly dangerous. The compromised condition of the endothelial cells as the disease progresses is also conducive to the development of microangiopathic hemolytic anemia (a systemic, slow bleeding out into the tissues with associated inflammation, pain, and free-radical attack). As the systolic blood pressure rises, so does the threat of bleeding out into such tissues as the brain (hypertensive encephalopathy) and the retina (retinal hemorrhages).

Considerable research is available that supports a key role for endothelial cell damage in the etiology of hypertension and hypertensive vascular disease. There is good evidence that essential fatty acid metabolism at the vascular level is directly associated with the development of hypertension and amenable to therapeutic intervention. Hypertension adversely affects the endothelial cell synthesis of molecules critical in vasomotor function that are released following local mechanical stimuli (hypertension), hypoxia, and acetylcholine. These molecules include thromboxane A2, prostaglandin H2, and endothelin 1 (Vogel 1997; Shimokawa 1999). Essential fatty acids are very similar to essential amino acids or vitamins in the sense that deficiencies (or imbalances) can have serious consequences or disease.

Essential Fatty Acids as Essential Nutrients

Extensive research has made it clear that a reduced or imbalanced intake of essential fatty acids (EFAs) plays a significant role in the development of hypertension, cardiovascular disease, and related metabolic diseases (Appel et al. 1993, 1994; Morris et al. 1994; Simopoulos 1999). There are two families of EFAs: omega-3 and omega-6 fatty acids. Experimental studies confirm that a balanced combination of these two families is essential in lowering blood pressure and reducing atherosclerosis (Khalilov et al. 1997).

Two particular fatty acids, gamma-linolenic acid (GLA) and docosahexaenoic acid (DHA), when administered in the proper balance, protect the cardiovascular system and lower blood pressure. They reduce stress reactions, and may ameliorate insulin resistance. Borage oil contains 23% GLA, while DHA is plentiful in cold-water fish. Omega-3 and omega-6 fatty acids serve as components of vasculature cell membranes and are converted to biochemical messengers such as prostaglandins. These products function as local hormones. EFAs cannot be produced within the body (hence the name 'essential', like essential amino acids) and must be provided by diet. If the diet lacks essential fatty acids, saturated fats replace EFAs within cell membranes, reducing membrane fluidity and efficiency, and encouraging disease. The right EFAs in the right proportions can maximize production of beneficial prostaglandins and other chemical messengers, while minimizing production of harmful ones (which promote inflammation).

An ideal combination of omega-6 and omega-3 fatty acids (GLA and EPA) is in a proportion ranging from 2:1 to 4:1 (van Jaarsveld et al. 1997). This finding conforms to recommendations of the World Health Organization, the British Nutrition Foundation, and the Japan Society for Lipid Nutrition. An elevated ratio of omega-6 to omega-3 fatty acids is a major risk factor for many chronic diseases (Horrocks et al. 1999). Due to the disproportionate level of omega-6 oils in the typical American diet, it is preferable to supplement at the lower end of this range, at a ratio of two parts omega-6 to one part omega-3 oils (Simopoulos 1999).

The two dietary EFAs ( linoleic acid, an omega-6 and alpha-linolenic acid, an omega-3) are metabolized into GLA ( gamma-linolenic acid from linoleic acid), DHA ( docosahexaenoic acid ), and EPA ( eicosapentaenoic acid, both from alpha-linolenic acid). Because of the high ratio of linoleic acid (omega-6) in Western diets, linoleic acid will inhibit the uptake and conversion of alpha-linolenic acid (omega-3) by competition for the enzyme delta-6 desaturase (D6D) (Simopoulos 1999).

Continued . . .

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