Hypertensive Heart Disease

HCVD
Hypertensive heart disease is any of a number of complications of arterial hypertension that affects the heart. Symptoms

        

Fatigue Irregular pulse Swelling of feet Weight gain Nausea Shortness of breath Difficulty sleeping flat in bed Bloating Greater need to urinate at night

Conditions (potential complications)

    

Left ventricular hypertrophy Coronary heart disease Congestive heart failure Hypertensive cardiomyopathy Cardiac arrhythmias

Introduction Background Uncontrolled and prolonged elevation of blood pressure (BP) can lead to a variety of changes in the myocardial structure, coronary vasculature, and conduction system of the heart. These changes in turn can lead to the development of left ventricular hypertrophy (LVH), coronary artery disease, various conduction system diseases, and systolic and diastolic dysfunction of the myocardium, which manifest clinically as angina or myocardial infarction, cardiac arrhythmias (especially atrial fibrillation), and congestive heart failure (CHF). Thus, hypertensive heart disease is a term applied generally to heart diseases, such as LVH, coronary artery disease, cardiac arrhythmias, and CHF, that are caused by direct or indirect effects of elevated BP. Although these diseases generally develop in response to chronically elevated BP, marked and acute elevation of BP can also lead to accentuation of an underlying predisposition to any of the symptoms traditionally associated with chronic hypertension. Pathophysiology The pathophysiology of hypertensive heart disease is a complex interplay of various hemodynamic, structural, neuroendocrine, cellular, and molecular factors. On the one hand, these factors play integral roles in the development of hypertension and its complications; on the other hand, elevated BP itself can modulate these factors. Elevated BP leads to adverse changes in cardiac structure and function in 2 ways: directly by increased afterload and indirectly by associated neurohormonal and vascular changes. Elevated 24-hour ambulatory BP and nocturnal BP have been demonstrated to be more closely related to various cardiac pathologies, especially in African Americans. The pathophysiologies of the various cardiac effects of hypertension differ and are described in this section. Left ventricular hypertrophy Of patients with hypertension, 15-20% develops LVH. The risk of LVH is increased 2-fold by associated obesity. The prevalence of LVH based on electrocardiogram (ECG) findings, which are not a sensitive marker at the time of diagnosis of hypertension, is variable.1,2 Studies have shown a direct relationship between the level and duration of elevated BP and LVH. LVH, defined as an increase in the mass of the left ventricle (LV), is caused by the response of myocytes to various stimuli accompanying elevated BP. Myocyte hypertrophy can occur as a compensatory response to increased afterload. Mechanical and neurohormonal stimuli accompanying hypertension can lead to activation of myocardial cell growth, gene expression (of which some occurs primarily in fetal cardiomyocytes), and, thus, to LVH. In addition, activation of the renin-angiotensin system, through the action of angiotensin II on angiotensin I receptors, leads to growth of interstitium and cell matrix components. In summary, the development of LVH is characterized by myocyte hypertrophy and by an imbalance between the myocytes and the interstitium of the myocardial skeletal structure. Various patterns of LVH have been described, including concentric remodeling, concentric LVH, and eccentric LVH. Concentric LVH is an increase in LV thickness and LV mass with increased LV diastolic pressure and volume, commonly observed in persons with hypertension and which is a marker of poor prognosis in these patients. Compare this with eccentric LVH, in which LV thickness is increased not uniformly but at certain sites, such as the septum. While the development of LVH initially plays a protective role in response to increased wall stress to maintain adequate cardiac output, later it leads to the development of diastolic and, ultimately, systolic myocardial dysfunction. Left atrial abnormalities

Frequently underappreciated, structural and functional changes of the left atrium (LA) are very common in patients with hypertension. The increased afterload imposed on the LA by the elevated LV end-diastolic pressure secondary to increased BP leads to impairment of the LA and LA appendage function plus increased LA size and thickness. Increased LA size accompanying hypertension in the absence of valvular heart disease or systolic dysfunction usually implies chronicity of hypertension and may correlate with the severity of LV diastolic dysfunction. In addition to these structural changes, these patients are predisposed to atrial fibrillation. Atrial fibrillation, with loss of atrial contribution in the presence of diastolic dysfunction, may precipitate overt heart failure. Valvular disease Although valvular disease does not cause hypertensive heart disease, chronic and severe hypertension can cause aortic root dilatation, leading to significant aortic insufficiency. Some degree of hemodynamically insignificant aortic insufficiency is often found in patients with uncontrolled hypertension. An acute rise in BP may accentuate the degree of aortic insufficiency, with return to baseline when BP is better controlled. In addition to causing aortic regurgitation, hypertension is also thought to accelerate the process of aortic sclerosis and cause mitral regurgitation. Heart failure Heart failure is a common complication of chronically elevated BP. Hypertension as a cause of CHF is frequently underrecognized, partly because at the time heart failure develops, the dysfunctioning LV is unable to generate the high BP, thus obscuring the etiology of the heart failure. The prevalence of asymptomatic diastolic dysfunction in patients with hypertension and without LVH may be as high as 33%. Chronically elevated afterload and resulting LVH can adversely affect both the active early relaxation phase and late compliance phase of ventricular diastole. Diastolic dysfunction is common in persons with hypertension. It is often, but not invariably, accompanied by LVH. In addition to elevated afterload, other factors that may contribute to the development of diastolic dysfunction include coexistent coronary artery disease, aging, systolic dysfunction, and structural abnormalities such as fibrosis and LVH. Asymptomatic systolic dysfunction usually follows. Later in the course of disease, the LVH fails to compensate by increasing cardiac output in the face of elevated BP and the left ventricular cavity begins to dilate to maintain cardiac output. As the disease enters the end stage, LV systolic function decreases further. This leads to further increases in activation of the neurohormonal and renin-angiotensin systems, leading to increases in salt and water retention and increased peripheral vasoconstriction, eventually overwhelming the already compromised LV and progressing to the stage of symptomatic systolic dysfunction. Apoptosis, or programmed cell death, stimulated by myocyte hypertrophy and the imbalance between its stimulants and inhibitors, is considered to play an important part in the transition from compensated to decompensated stage. The patient may become symptomatic during the asymptomatic stages of the LV systolic or diastolic dysfunction, owing to changes in afterload conditions or to the presence of other insults to the myocardium (eg, ischemia, infarction). A sudden increase in BP can lead to acute pulmonary edema without necessarily changing the LV ejection fraction.3 Generally, development of asymptomatic or symptomatic LV dilatation or dysfunction heralds rapid deterioration in clinical status and markedly increased risk of death. In addition to LV dysfunction, right ventricular thickening and diastolic dysfunction also develop as results of septal thickening and LV dysfunction. Myocardial ischemia Patients with angina have a high prevalence of hypertension. Hypertension is an established risk factor for the development of coronary artery disease, almost doubling the risk. The development of ischemia in patients with hypertension is multifactorial. Importantly, in patients with hypertension, angina can occur in the absence of epicardial coronary artery disease. The reason is 2-fold. Increased afterload secondary to hypertension leads to an increase in left ventricular wall tension and transmural pressure, compromising coronary blood flow during diastole. In addition, the microvasculature, beyond the epicardial coronary arteries, has been shown to be dysfunctional in patients with hypertension and it may be unable to compensate for increased metabolic and oxygen demand. The development and progression of arteriosclerosis, the hallmark of coronary artery disease, is exacerbated in arteries subjected to chronically elevated BP. Shear stress associated with hypertension and the resulting endothelial dysfunction causes impairment in the synthesis and release of the potent vasodilator nitric oxide. A decreased nitric oxide level promotes the development and acceleration of arteriosclerosis and plaque formation. Morphologic features of the plaque are identical to those observed in patients without hypertension. Cardiac arrhythmias Cardiac arrhythmias commonly observed in patients with hypertension include atrial fibrillation, premature ventricular contractions, and ventricular tachycardia.4 The risk of sudden cardiac death is increased.5 Various mechanisms thought to play a part in the pathogenesis of arrhythmias include altered cellular structure and metabolism, inhomogeneity of the myocardium, poor perfusion, myocardial fibrosis, and fluctuation in afterload. All of these may lead to an increased risk of ventricular tachyarrhythmias. Atrial fibrillation (paroxysmal, chronic recurrent, or chronic persistent) is observed frequently in patients with hypertension.6 In fact, elevated BP is the most common cause of atrial fibrillation in the Western hemisphere. In one study, nearly 50% of patients with atrial fibrillation had hypertension. Although the exact etiology is not known, left atrial structural abnormalities, associated coronary artery disease, and LVH have been suggested as possible contributing factors. The development of atrial fibrillation can cause decompensation of systolic and, more importantly, diastolic dysfunction, owing to loss of atrial kick, and it also increases the risk of thromboembolic complications, most notably stroke. Premature ventricular contractions, ventricular arrhythmias, and sudden cardiac death are observed more often in patients with LVH than in those without LVH. The etiology of these arrhythmias is thought to be concomitant coronary artery disease and myocardial fibrosis. Clinical

History Symptoms of hypertensive heart disease depend on the duration, severity, and type of disease. In addition, the patient may or may not be aware of the presence of hypertension, which is why hypertension has been named "the silent killer."

• •

Left ventricular hypertrophy: Patients with LVH alone are totally asymptomatic unless the LVH leads to the development of diastolic dysfunction and heart failure. Heart failure o Although symptomatic diastolic heart failure and systolic heart failure are indistinguishable, the clinical history may be quite revealing. In particular, individuals who abruptly develop severe symptoms of CHF and rapidly return to baseline with medical therapy are more likely to have isolated diastolic dysfunction. o Heart failure symptoms include the following:

•

Altered mentation in severe cases Patients can present with acute pulmonary edema due to sudden decompensation in LV systolic or diastolic dysfunction caused by precipitating factors such as acute rise in BP, dietary indiscretion, or myocardial ischemia. Patients can develop cardiac arrhythmias, especially atrial fibrillation, or they can develop symptoms of heart failure insidiously over time. Myocardial ischemia o Angina, a frequent complication of hypertensive heart disease, is also indistinguishable from other causes of myocardial ischemia. o Typical symptoms of angina include substernal chest pain lasting less than 15 minutes (versus >20 min in infarction). Pain is often described in the following ways:  Heaviness, pressure, squeezing

      

Exertional and nonexertional dyspnea (NYHA classes I-IV) Orthopnea Paroxysmal nocturnal dyspnea Fatigue (more common in systolic dysfunction) Ankle edema and weight gain Abdominal pain secondary to congested, distended liver

o

•
Physical

Relieved with rest or sublingual nitroglycerin Patients also may present with atypical symptoms without chest pain, such as exertional dyspnea or excessive fatigue, commonly referred to as an angina equivalent. Female patients, in particular, are more likely to present with an atypical presentation o The patient may present with chronic stable angina or acute coronary syndrome, including myocardial infarction without ST-segment elevation and acute myocardial infarction with ST elevation. Ischemic ECG changes may be found in individuals presenting with hypertensive crisis in whom no significant coronary atherosclerosis is detectable by coronary angiography. o Acute coronary symptoms can be precipitated by a ruptured atherosclerotic plaque or by an acute and severe rise in BP leading to a sudden increase in transmural pressure without a change in stability of the plaque. Cardiac arrhythmias: These can cause a variety of symptoms, including palpitations, near or total syncope, precipitation of angina, sudden cardiac death, and precipitation of heart failure, especially with atrial fibrillation in diastolic dysfunction.

o

  

Radiating to neck, jaw, upper back, or left arm Provoked by emotional or physical exertion

Physical signs of hypertensive heart disease depend on the predominant cardiac abnormality and the duration and severity of the hypertensive heart disease. Findings from the physical examination may be entirely normal in the very early stages of the disease, or the patient may have classic signs upon examination. In addition to generalized findings attributable directly to high BP, the physical examination may reveal clues to a potential etiology of hypertension, such as truncal obesity and striae in Cushing syndrome, renal artery bruit in renal artery stenosis, and abdominal mass in polycystic kidney disease.

•

Pulses: The arterial pulses are normal in the early stages of the disease. o Rhythm

o o o •

 
Rate

Regular if the patient is in sinus rhythm Irregularly irregular if the patient is in atrial fibrillation Normal in patients in sinus rhythm and not in decompensated heart failure Tachycardic in patients with heart failure and in patients with atrial fibrillation and a rapid ventricular response Normal

 
Volume

Decreased in patients with LV dysfunction Additional findings - May include radial-femoral delay if the etiology of hypertension is coarctation of the aorta

 

Blood pressure: Systolic and/or diastolic BP is elevated (>140/90 mm Hg). Mean BP and pulse pressure generally are also elevated. The BP in the upper extremities may be higher than that in the lower extremities in patients with coarctation of the aorta. BP may be normal at the time of evaluation if the patient is on adequate antihypertensive medications or the patient has advanced LV dysfunction and the LV cannot generate enough stroke volume and cardiac output to produce an elevated BP.

• •

• • • •

Veins: In patients with heart failure, jugular veins may be distended; the predominant waves depend on the severity of the heart failure and any other associated lesions. Heart o Apex: The apical impulse is sustained and nondisplaced in patients without significant systolic LV dysfunction but with LVH. A presystolic S4 may be felt. Later in the course of disease, when significant systolic LV dysfunction supervenes, the apical impulse is displaced laterally, owing to LV dilatation. o Right ventricle: A lift is present late in the course of heart failure if significant pulmonary hypertension develops. o Heart sounds: S1 is normal in intensity and character. S2 at the right upper sternal border is loud because of an accentuated aortic component (A2); it can have a reverse or paradoxical split due either to increased afterload or to associated left bundle-branch block (LBBB). S4 frequently is palpable and audible, implying the presence of a stiffened, noncompliant ventricle due to chronic pressure overload and LVH. S3 typically is not present initially but is audible in the presence of heart failure, either systolic or diastolic. o Murmurs: An early decrescendo diastolic murmur of aortic insufficiency may be heard along the mid-to-left parasternal area, especially in the presence of acutely elevated BP, frequently disappearing once the BP is better controlled. In addition, an early to mid systolic murmur of aortic sclerosis is commonly audible. A holosystolic murmur of mitral regurgitation may be present in patients with advanced heart failure and dilated mitral annulus. Lungs: Findings upon chest examination may be normal or may include signs of pulmonary congestion, such as rales, decreased breath sounds, and dullness to percussion due to pleural effusion. Abdomen: Abdominal examination may reveal a renal artery bruit in patients with hypertension secondary to renal artery stenosis, a pulsatile expansile mass of abdominal aortic aneurysm, and hepatomegaly and ascites due to CHF. Extremities: Ankle edema may be present in patients with advanced heart failure. CNS and retina o CNS examination findings are usually unremarkable unless the patient has had previous cerebrovascular accidents with residual deficit. o Examination of the fundi may reveal evidence of hypertensive retinopathy, the severity of which depends on the duration and severity of hypertension, or earlier signs of hypertension such as arteriovenous nicking. o CNS changes may be seen in patients who present with hypertensive emergency.

Causes The cause of hypertensive heart disease is chronically elevated BP. The causes of elevated BP are diverse. In adults, the following causes should be considered:

• •

Essential hypertension accounts for 90% of cases of hypertension in adults. Secondary causes of hypertension account for the remaining 10% of cases of chronically elevated BP. These include the following: o Renal causes

o

Intrarenal Vasculitis Endocrine causes

          

Renal artery stenosis Polycystic kidney disease Chronic renal failure

Primary hyperaldosteronism Pheochromocytoma Cushing syndrome Congenital adrenal hyperplasia Hypothyroidism and hyperthyroidism Acromegaly Exogenous hormone (eg, corticosteroids, estrogens), sympathomimetics (including cocaine), monoamine oxidase inhibitors (MAOIs), and tyramine-containing foods Coarctation of aorta Raised intracranial pressure Sleep apnea Isolated systolic hypertension - Can be observed in elderly people, due to increased stiffness of the vasculature Isolated systolic hypertension - Can be observed in thyrotoxicosis, atrioventricular (AV) fistula, aortic regurgitation, beriberi, Paget disease, and patent ductus arteriosus (ie, due to increase cardiac output secondary to a hyperdynamic circulation)

o

Others

    

ETIOLIOGY It is known that neuroendocrine factors (e.g., renin-angiotensin-aldosterone) are associated with the risk of developing HF, and that left ventricular remodeling is an important determinant in the progression to HF. A factor commonly associated with left ventricular remodeling is poorly controlled hypertension (HTN). We propose to delineate the relative importance of polymorphic genetic variation associated with neurohormonal regulatory elements, including 1) renin-angiotensin-aldosterone and 2) vitamin D and its receptor, on ventricular remodeling during hypertensive heart disease (HHD) Although many factors may contribute to the incidence of high-mountain disease, the pathogenesis seems directly related to the chronic hypoxia, hypocapnia, and respiratory alkalosis of a high-altitude environment. These changes collectively result in pulmonary vasoconstriction,

pulmonary hypertension, and ultimately CHF. There is marked interindividual and interspecies variability in hypoxia-induced increases in pulmonary vascular resistance. Strong responses are seen in cattle, horses, and pigs, while humans, dogs, guinea pigs, and llamas are weak responders. These findings and the high incidence of disease in cattle indicate that they are uniquely susceptible. The role of genetics in high-mountain disease is supported by high familial incidence with marked variation in susceptibility between animals and between species. While the cause or genes involved have not been identified, it may be related to altered chemoreceptor activity and myocardial metabolism. Previous damage, such as that caused by bronchopneumonia, interstitial pneumonia, emphysema, pulmonary fibrosis, anemia, or a ruptured diaphragm, all increase dyspnea, pulmonary vascular resistance, and pulmonary hypertension. Although various range plants, both browse and nonbrowse-types, have been associated with increased incidence of high-mountain disease, only locoweed has been experimentally shown to induce the disease. When consumed by cattle at high elevation, locoweeds (certain Oxytropis and Astragalus spp that contain swainsonine), markedly increase the prevalence and severity of CHF. The condition develops relatively more quickly (eg, within 1-2 wk) and the incidence may be as high as 100%. Swainsonine, the locoweed toxin, is excreted in milk, and nursing calves may also develop CHF. Locoweed-poisoned cows often abort and many develop severe hydrops amnii. Poisoned animals have the signs and lesions of both high-mountain disease and locoweed poisoning. Locoweed poisoning probably directly contributes to increased pulmonary vascular resistance and hypertension; immunohistochemistry and electron microscopy studies have shown that poisoning causes severe swelling and cytoplasmic vacuolation of pulmonary intravascular macrophages and endothelial cells. The myocardium also is compromised by locoweed as there is extensive vacuolation of the myocardial interstitial cells. The toxin also inhibits enzymes that have key roles in glycoprotein synthesis, packaging, and excretion. This results in altered glycosylation of key endocrine and paracrine hormones and their receptors. All of these changes probably contribute to the inappropriate pulmonary vascular resistance that appears to be the initiating factor in the pathogenesis of high-mountain disease. --------------------------------------------------------------------------------------------------------------Overview

•

Epidemiology

Hypertension (high blood pressure) is the primary and most important manifesting symptom of hypertensive vascular disease. A diseased vasculature predisposes one to further hypertension, and thus, further vascular disease. Hypertension often progresses with the development of various diseases involving the circulatory system, such as arteriosclerosis, atherosclerosis, coronary heart disease, congestive heart failure, and disorders of coagulation (stroke, hemorrhage, heart attack), immunity (inflammation, infection), and diabetes. All of these disorders are both causative and secondary to the development of hypertension. The purpose of this discussion is to ultimately substantiate and provide a protocol that can be followed that will prevent the development of hypertension, and thus, the development of hypertensive vascular disease and its subsequent and allied disease states. Protocols have been described in other sections of this book that concern the prevention and treatment of most of these other diseases of the cardiovascular system (see Cardiovascular Disease: Overview and Comprehensive Analysis ). Some degree of overlap is inevitable here, however, this section will more specifically focus on understanding the mechanisms behind the development of hypertension; a symptom that frequently precedes and further aggravates the progression of a number of common cardiovascular-related diseases. Hypertension will be defined in terms of the physiological and endocrinological systems that control blood pressure. The genetic and epidemiological basis of hypertension will be characterized, particularly with respect to the role of salt intake (as sodium chloride). Physiological and endocrinological systems that control sodium retention are extremely crucial to the maintenance of blood pressure. Accordingly, all of our most effective drug therapies for hypertension impact one or more of the components in these highly complex and highly interrelated organ systems. At the organ level, sodium intake triggers a well-characterized, coordinated sequence of physiological events that typically causes some degree of hypertension, particularly in those genetically predisposed to the effects of salt, or who, as a result of aging or other nutritional/environmental factors are otherwise sensitized to sodium intake. At the tissue level, there is strong evidence that regulatory processes within vascular smooth muscle or vascular endothelial cells are dysfunctional and/or compromised by the affects of hypertension, declining testosterone levels, and also accumulated age-related damage or other nutritional and hormone imbalances. In summary and in general, disorders of electrolyte balance result in chronic hypertension (and then hypertensive vascular disease), which leads to further cardiovascular disease. This section details the physiology of hypertension, the pharmacological approaches used to treat pathophysiologic states that result from hypertension, and the biochemical basis of nutritional approaches useful in the prevention of hypertension, or as adjuvant therapy to ongoing, traditional medical treatment. Epidemiology It is estimated that over 50 million Americans have hypertension. Eventually, especially if left untreated, they develop the common cardiovascular disease known as hypertensive vascular disease. The disease is primarily a manifestation of elevated arterial pressure (high blood pressure). However, high blood pressure is really a symptom of one or more of the many underlying disease processes that often express the symptom of hypertension. Hypertension is two times more prevalent in Blacks versus Whites, higher in men versus women (until after menopause), and is typically related to many dietary factors, particularly salt intake (Appel et al. 1997). Hypertension is commonly seen in the elderly. Over 70% of women and 50% of men over the age of 70 have hypertension. These latter factors are associated with hypertension because they all are independent risk factors for accelerated atherosclerosis. It is a disorder traditionally characterized by blood pressure persistently exceeding 140/90 mmHg. Current research indicates that an optimal blood pressure is below 120/80 mmHg. It is important to note that damage to the vasculature can occur when the blood pressure is moderately but chronically elevated. Some individuals may not realize they are hypertensive because symptoms such as epistaxis (nosebleed), tinnitus, dizziness, headache, blurred vision, and arrhythmias are not always present. Other risk factors include high cholesterol levels, smoking, obesity, and diabetes (Calvert 2001). There are newer risk factors including homocysteine and C-reactive protein. The lifetime risk for hypertension among middle-aged and elderly individuals is 90%; corrective intervention (at an earlier age) could relieve a huge public health burden (Miura et al. 2001; Vasan et al. 2002). Hypertension refers to the high tension levels (or pressure levels) that must

be developed in the heart to eject blood into the arterial system. Blood pressure is always the result of cardiac output multiplied by the peripheral vascular resistance. The role of salt (sodium chloride) is particularly important in the development of hypertension and in the understanding of the etiology of the disease. It is noteworthy that the amount of salt in the typical American diet greatly exceeds what is derived from a natural diet. In this respect, this level of sodium chloride intake is pharmacological, with pronounced but insidious adverse side effects. Because the isotonicity (salt content) of the blood is very critically regulated by many interconnected systems, elevated retention of sodium chloride and fluid by the body is pathological. This retained salt water expands the volume of the plasma compartment, increases demands on the heart to pump more volume (increased cardiac output), and thus, raises blood pressure. Healthy blood pressure readings are below 120/80 mmHg. Hypertension that requires medical intervention is generally defined as systolic and/or diastolic blood pressures of 140/90 or higher. Naturally, higher blood pressures are associated with more serious degrees of hypertension. It is noteworthy that individuals with pressures in between these values still show an increased risk of cardiovascular disease. Generally, a higher diastolic pressure presents a more serious risk than a higher systolic pressure. Although the symptom of hypertension is the best indicator of developing hypertensive vascular disease, it is a symptom that is usually only detected by more than one measurement of blood pressure. The exact cause of hypertension is not clearly understood in approximately 90-95% of those affected, so it is accordingly referred to as essential hypertension, primary hypertension, or idiopathic hypertension. Secondary hypertension results from defined causes and includes roughly 5-10% of people with hypertension. Many of these cases can be treated because we know n n the cause. A clear understanding of the cause of primary hypertension is critical to properly controlling hypertension, and ultimately treating hypertensive vascular disease and its associated cardiovascular diseases. By instituting treatment regimens to reduce high blood pressure we significantly arrest the development of related cardiovascular diseases, but we may not correct some of the disease processes that are still present, still progressing, or minimally affected by the level of blood pressure. This is the danger of this silent disease, often only detectable through repeated measurement of blood pressure. It is possible that the underlying disease is still progressing, now even more silently, after blood pressure is controlled (Calvert 2001). There are numerous processes that have been identified as contributing causes to hypertension or to the diseases that are related to hypertensive vascular disease. Because of the complex relationships associating the symptom of hypertension with the cardiovascular diseases, diseases such as hypertensive vascular disease, congestive heart failure, renal disease, stroke, arteriosclerosis, atherosclerosis, and diabetes are often interrelated. They all can ultimately express the symptom of high blood pressure or develop as a result of high blood pressure. Each disease can both cause hypertension, and in turn, is aggravated by hypertension. Control of hypertension can sometimes prevent the development of some diseases like congestive heart failure, but only modestly slow the progression of diseases like diabetes and atherosclerosis. In the end, uncontrolled hypertension generally leads to death secondary to atherosclerosis (Williams 2001). Most deaths due to hypertension result from myocardial infarction or congestive heart failure. Etiology

• • • •

Essential Hypertension Genetic Predisposition Environmental Factors Secondary Hypertension

Essential Hypertension Hypertension is generally referred to as either essential or secondary. It's not completely known what causes essential hypertension that accounts for 90% to 95% of cases. Research indicates that significant factors include a complex interaction between genetic, environmental and other variables. Secondary hypertension is caused by known medical conditions, such as kidney disease, pregnancy, hyperthyroidism, or aldosteronism. Otherwise known as primary or idiopathic hypertension, essential hypertension affects a number of physiological systems that regulate (arterial) blood pressure, including the autonomic nervous system, adrenal glands, kidneys, vasculature, and complex hormonal systems that interconnect these systems. It is likely that the causes of essential hypertension are in some ways related to the known causes of secondary hypertension. An understanding of those known causes is useful in hypothesizing and understanding the etiology of essential hypertension. Genetic Predisposition The heritability of hypertension supports a genetic basis to hypertensive vascular disease. Given the many different and interrelated physiological systems affected by hypertension and which contribute to hypertension, it is likely that many different genes and genetic mutations contribute to hypertension and other cardiovascular diseases. Many specific gene defects have been linked to susceptibility for hypertension, most of which control the expression of proteins involved in the renin-angiotensin-aldosterone-axis or endothelial cell function. However, the evidence is particularly strong for linkage of the angiotensinogen gene (Williams 2001). This gene, presumably, codes for a collection of different proteins that participate in the regulation of the renin-angiotensin-aldosterone-axis, not simply the protein structure for angiotensinogen present in the plasma. Environmental Factors

• •

Environmental Salt The Renin-Angiotensin-Aldosterone-Axis

Many environmental factors determine the expression of the degree of hypertension that results in particular individuals. The manipulation of these environmental factors through changes in salt restriction, diet, alcohol intake, and stress, can reduce or eliminate less serious forms of hypertension. Environmental Salt "The environmental factor that has received the greatest attention is salt intake. [T]his factor illustrates the heterogeneous nature of the

essential hypertensive population, in that the blood pressure in only approximately 60% of hypertensives is particularly responsive to the level of sodium intake. The cause of this special sensitivity to salt varies, with primary aldosteronism, bilateral renal artery stenosis, renal parenchymal disease, and low-renin essential hypertension accounting for about half the patients. In the remainder, the pathophysiology is still uncertain, but postulated contributing factors include chloride intake, calcium intake, a generalized cellular membrane defect, insulin resistance, and "nonmodulation" [status] (see below)" (Williams 2001). Because the response to salt is so important to understanding the etiology of hypertension, it is important to know which physiological systems respond to salt intake and how each system influences the function of complementary systems. This understanding is paramount in understanding not only hypertensive vascular disease, but also the other cardiovascular diseases. It is beyond the scope of this writing to provide a detailed understanding of all of these allied diseases; however, some basic understanding of each of the cardiovascular diseases provides insight into the probable etiology of hypertension. Salt sensitivity tells us more about the disease than other environmental factors like smoking, alcohol, exercise, and obesity. The acute and chronic responses to high sodium chloride intake are well-characterized. Without diminishing the importance of these other environmental factors, it is a fairly straight-forward judgment that smoking most likely affects the vasculature through oxidative stress (as does stress, in general). Similarly, chronic obesity clearly increases the work load on the cardiovascular system, and in the long term, alters lipid metabolism, insulin response, and blood pressure adversely. The high correlation of obesity with diabetes is important in understanding pathological changes in the vascular system relevant to hypertension. Diabetes mellitus is associated with physiological changes that potentiate endothelial dysfunction, including hypertension (Brown and Hu 2001). Alcohol causes many metabolic disturbances, drug effects, and alterations to lipid metabolism. Accordingly, a detailed look into its mechanisms of action would be highly confounded, contributing little to our understanding of hypertension. The Renin-Angiotensin-Aldosterone-Axis Drugs that target the renin-angiotensin-aldosterone-axis represent the most effective medications available for hypertensive vascular disease. They are the most selective agents in use that offer the least side effects. This level of drug specificity generally indicates that the critical systems in a given disease are probably being affected. Recall that alterations in the angiotensinogen gene are positively correlated with hypertension and may represent part of the genetic basis for this heritable disease (Williams 2001). The enzyme called renin is secreted by juxta-glomerular cells in the kidney. These cells release the enzyme renin whenever there is increased filtration of sodium (chloride) by the kidney, perhaps secondary to high dietary salt intake. Renin release is the most important endocrine response of the kidney. It exerts pronounced influences o f n the cardiovascular system and blood pressure and is primary controlled by three factors: 1. Beta-1 adrenergic agents directly stimulate renin release by acting on the juxta-glomerular cells. This stimulation of the sympathetic nervous system (through noradrenaline release) prepares the body for potential acute emergencies requiring the maintenance of blood volume and pressure (such as dehydration and hemorrhage) or to redirect blood flow to the muscles for "fight or flight" situations. 2. Blood pressure inhibits renin release via the intrarenal baroreceptor pathway, which may use prostaglandins as mediators (see the section on Membrane Biochemistry and Essential Fatty Acids ). Renin secretion and blood pressure has been shown to be selectively reduced by inhibitors of cyclooxygenase-2 (COX-2). 3. The macula densa cells, that reabsorb almost all of the filtered sodium, inhibit renin release. These specialized kidney cells "sense" the amount of sodium chloride that is not reabsorbed by the kidney. When significant amounts of sodium chloride are not reabsorbed, prostaglandins (of the series-2, PGI2 and PGE2) are released that stimulate renin release (Williams 2001). Macula densa-induced stimulation of renin release may be mediated by both COX-2 and nitric oxide synthase, which generates nitric oxide (NO) from arginine to promote vasodilation (Williams, 2001). Once released, renin enzymatically converts circulating angiotensinogen into angiotensin I. Further and usually immediate conversion into angiotensin II by angiotensinogen-converting enzyme produces the most powerful vasoconstricting substance in the body, causing vasoconstriction of smooth muscle cells in the arterial tree, especially in the vascular capillary beds lined with endothelial cells. This action raises blood pressure by increasing total peripheral vascular resistance. The second primary action of angiotensin II is to stimulate aldosterone release from the adrenal glands, which in turn, acts on the kidney to promote sodium retention in exchange for potassium loss. Water is retained along with sodium in the plasma, volume expands, and the juxtaglomerular cells stop secreting renin. This is an example of a classical negative feedback-loop, typical of all functional endocrine systems in the body. Furthermore, this endocrine system interconnects the physiological functions of the circulatory, renal, and adrenal systems in the highly important physiological function of regulating blood pressure and electrolyte balance. There is a subgroup of people (20%) that have essential hypertension with low plasma renin activity. They have expanded fluid volumes (which probably increases their blood pressure), but normal serum potassium levels (suggesting no stimulation of aldosterone release). This condition prevails more commonly in Blacks. They appear to be more sensitive to angiotensin II (which is why renin can remain low), and which probably accounts for their hypertension and (aldosterone-mediated) sodium retention. Normal and high salt diets in this subgroup do not suppress aldosterone. The subgroup overlaps with people with normal levels of renin and essential hypertension (Williams 2001). These groups are sensitive to salt intake and should eliminate or restrict it. Another 25-30% of people with essential hypertension demonstrate a reduced adrenal (aldosterone) response to sodium. "[S]odium intake does not modulate either adrenal or renal vascular responses to angiotensin II. Hypertensives in this subset have been termed nonmodulators because of the absence of the sodium-mediated modulation of target tissue responses to angiotensin II. These individuals make up 25 to 30% of the hypertensive population, have plasma renin activity levels that are normal to high if measured when the patient is on a low-salt diet, and have hypertension that is salt-sensitive because of a defect in the kidney's ability to excrete sodium appropriately. They also are more insulinresistant than other hypertensive patients, and the pathophysiologic characteristics can be corrected by the administration of a convertingenzyme inhibitor. Furthermore, the nonmodulation characteristic appears to be genetically determined (associated with a certain allele of the angiotensinogen gene). Thus, nonmodulators are probably the most completely characterized intermediate phenotype in the hypertensive population" (Williams 2001). They are not sensitive to dietary intake of salt. There is final subgroup of individuals possessing high renin levels (15%). However, half of these people are not benefited by the highly effective angiotensin II receptor antagonists and it is hypothesized that hypertension in this subgroup is related to over-activity of the adrenergic system (Brown and Hu 2001; Williams 2001).

Secondary Hypertension

• • •

Renal Hypertension Endocrine Hypertension Adrenal Hypertension

Research into the known causes of secondary hypertension tells us that all forms of hypertension may be related to altered kidney function or hormone secretion, and particularly, to altered renal endocrine function. Again, sodium homeostasis and adrenergic factors are the primary and most important considerations to our understanding of chronic and acute hypertension, respectively. Renal Hypertension Activation of the renin-angiotensin-aldosterone-axis is the cause of secondary hypertension caused by "renal hypertension". Renal hypertension generally results when blood flow to one of the kidneys is reduced to less than 30% of normal. Activation of the reninangiotensin-aldosterone-axis is simply the normal physiologic response of the kidney to perform its primary function of filtering the blood. Its sensors principally monitor blood pressure and perfusion to the kidneys, but also the salt and water content of the plasma. Activation of this renal endocrine system can also account for "renal parenchymal disease", a relatively minor contributor to overall hypertension (Williams 2001). Endocrine Hypertension Endocrine hypertension can be directly related to increased levels of aldosterone, a primary component of the renin-angiotensin-aldosteroneaxis. Recall that the endocrine cascade begins with renal release of renin, conversion of angiotensinogen to angiotensin II, then aldosterone release. Sodium retention is the probable cause of this form of secondary hypertension. Even hypertension that is due to hyperaldosteronism is dependent upon sodium intake. Normal people given high levels of aldosterone do not develop hypertension unless they ingest sodium. Hypertension that is caused by over-production of adrenal steroid hormones, as in Cushing's Disease, can also be related to excessive retention of sodium chloride. High amounts of glucocorticoids released in Cushing's Syndrome can stimulate aldosterone receptors and cause hypertension secondary to that hormone's effects in increasing sodium retention (Williams 2001). It is probable that the recently described "normal" decline of testosterone levels with advancing years contributes to hypertension (Fogari et al. 2003; Kannel et al. 2003). The association of hypertension with insulin resistance and/or hyperinsulinemia is more than a coincidence. Insulin resistance is common in noninsulin-dependent diabetes mellitus (NIDDM). As described elsewhere, diabetics do not show sodium chloride-mediated modulation of responses to angiotensin II that increase aldosterone and vasoconstriction. Essentially, salt intake does not exert its normal function in lessening the hypertensive responses to angiotensin II. Consequently, residual levels of angiotensin II still are able to increase sodium retention and maintain higher levels of arterial vasoconstriction (Williams 2001). Insulin may increase blood pressure by a number of possible mechanisms. Hyperinsulinemia produces sodium retention by the kidney and increased activity of the sympathetic nervous system. The mitogenic action of insulin produces vascular smooth muscle hypertrophy and enhances calcium ion transport into the vascular smooth muscle. All of these mechanisms promote increased vascular tone (hypertension) and are consistent with the hypothesis of a defective sodium transporter in vasculature smooth muscle, which may account for 35-50% of people with essential hypertension (Verges 1999; Williams 2001). Adrenal Hypertension Certain tumors of the adrenal gland cause excessive release of adrenaline (epinephrine) and norepinephrine into the circulation. These hormones stimulate the adrenergic receptors of the sympathetic nervous system. The result is high blood pressure secondary to cardiac stimulation and peripheral vasoconstriction. The sympathetic nervous system responds principally to the immediate needs of the body to increase blood pressure, such as following orthostatic hypotension. Adrenaline and norepinephrine of adrenal origin supplement the actions of norepinephrine released from the sympathetic nervous system. Chronic release of these hormones in disease (or prolonged stress) goes beyond the acute physiological need for vasoconstriction (causing moderate hypertension) and is pathological. Some evidence suggests that there might be a form of insulin-induced hypertension. Excess insulin combined with insulin-resistance, a hallmark of Syndrome X, makes the sympathetic nervous system dominant, resulting in the release of catecholamines, (dopamine, epinephrine, and norepinephrine) which cause hypertension via vasoconstriction. Hyperinsulinemia is a condition characterized by retention of salt and water, which increases blood volume and pressure. Half of all hypertensive patients that are insulin-resistant have hyperinsulinemia (Simopoulos 1999; Reaven et al. 2000).

Pathophysiology

• • • • • • • • • •

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 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. Biochemistry Biochemical processes that are important to the etiology or treatment of hypertension include the role of the renin-angiotensin-aldosteroneaxis 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). Metabolism to Prostaglandins The first and rate-limiting step in the metabolism of essential fatty acids to biologically active cellular modulators is controlled by the enzyme D6D. This enzyme activity declines with age (Horrobin 1981), inhibits the synthesis of GLA and DHA, and leads to a prostaglandin imbalance characterized by a decline of the (good) series-1 and series-3 prostaglandins, which exhibit potent anti-inflammatory effects. The diminished capacity to convert EFAs to GLA and DHA is associated with cardiovascular disease and diabetes (Bolton-Smith et al. 1997; Horrobin 19 98 83 ). Supplementation with GLA and DHA can circumvent impaired D6D function by increasing D6D activity, thus reversing the effect of aging on the enzyme (Biagi et al. 1991). GLA supplementation improves metabolism of omega-6 and omega-3 fatty acids. DHA and EPA limit the production of series-2 prostaglandins by preventing release of arachidonic acid from cell membranes. This inhibits further metabolism of arachidonic acid into inflammatory prostaglandins. High dietary linoleic acid (omega-6) limits the availability of alpha-linolenic acid (omega-3) as a precursor for the series-3 prostaglandins and stimulates the release from membranes of arachidonic acid, the precursor to (series-2) prostaglandins and other pro-inflammatory eicosanoids. Prostaglandin E1 relaxes blood vessels, improving circulation, lowering blood pressure and reducing inflammation. GLA increases this beneficial prostaglandin. Prostaglandin E2 promotes sodium retention by the kidney, leading to water retention and inflammation. Diets high in saturated fats (and therefore arachidonic acid) increase levels of inflammatory E2 prostaglandins. Prostaglandin E3 functions similar to prostaglandin E1. Omega-3 fatty acids generate the E3 series. Old animals show a clear decline in delta-6-desaturated metabolites of the omega-6 and the omega-3 series (Biagi et al. 1991). Animals fed GLA show no decline. Aging influences the fatty acid composition of adipose tissue independent of diet (Bolton-Smith et al. 1997). This confirms the age-related decline in delta-6-desaturation. GLA and DHA lower blood pressure and cardiovascular reactions to stress. Beneficial effects of both GLA and DHA on hypertension have been documented in human studies that show a moderate but consistent effect in lowering blood pressure and insulin resistance. Systolic blood pressure increases with aging as a result of increased stiffness of the arteries. Venter et al. (1988) hypothesized that a deficiency of D6D with aging is important in the etiology of essential hypertension. One group of patients with mild-moderate essential hypertension was given 360 mg GLA and 180 mg EPA per day, while the other group received only linoleic acid and alpha-linolenic acid (the parent EFAs that require D6D for metabolism to GLA and EPA/DHA). Systolic blood pressure in the first group was reduced (~ 10%) after 812 weeks, while no significant change occurred in the second group, indicating that deficiency of the enzyme D6D can promote hypertension. Aldosterone plays a key role in hypertension, and aldosterone-reducing drugs are used in the treatment of hypertension (Weber 1999; Oates and Brown 2001). Primary aldosteronism is usually regarded as a rare cause of hypertension (<1%), but some investigators have found that 10% to 15% of patients with essential hypertension had aldosteronism (Fardella et al. 1999 2000 ). Borage oil (23% GLA) and DHA lower blood pressure in hypertensive, normotensive, old and young rats (Engler et al. 1992, 1993). In rats genetically programmed for hypertension (Engler et al. 1998, 1999), EFAs modulate the renin-angiotensin-aldosterone system. GLA and DHA inhibit aldosterone release or production. DHA lowered aldosterone (33%), compared to animals fed corn/soybean oil. A remarkable reduction of the systolic blood pressure was seen. Borage oil (GLA) feeding decreased blood pressure by 12 mmHg after three weeks, and DHA lowered blood pressure by 34 mmHg after six weeks. These studies suggest that borage oil inhibits the adrenal responsiveness to angiotensin II through diminished angiotensin receptor activity in aldosterone producing cells. DHA supplementation could prevent the increase in blood pressure in rats genetically programmed to develop hypertension (Kimura et al. 1995).

In clinical trials on humans (Mori et al. 1999), DHA had lowered blood pressure and heart rate. These results also show that DHA, rather than EPA, is the principal omega-3 fatty acid responsible for the beneficial effects on the cardiovascular system and hypertension. The beneficial effects of the omega-3 fatty acids EPA and DHA had previously been attributed mainly to EPA because of its predominance in fish oil. DHA is the more important of the two. DHA has consistently proven to be more effective than EPA in lowering blood pressure in mildly hypertensive men (Prisco et al. 1998). Genetic Mechanisms A fundamental mechanism for the regulation of fat metabolism in the body involves the interaction of EFAs with nuclear receptors and transcription factors called peroxisome proliferator-activated receptors (PPARs). PPARs have been identified as nuclear hormone receptors, linking metabolism and gene expression. PPARs are transcription factors that regulate the expression of genes involved in fatty acid metabolism (Wahli et al. 1999). Polyunsaturated fatty acids, particularly EFAs and their metabolites, biologically interact with PPARs, binding to and activating these nuclear receptors. The anti-diabetic drugs, including the glitazones or thiazolidinediones, act similarly as PPAR ligands. Forman et al. (1997) discovered that GLA, DHA and other EFAs are efficient activators of PPARs. To activate gene transcription, PPARs must combine with the retinoic X receptor. DHA has been found to directly bind to PPARs and is an RXR-activating factor (de Urquiza M et al. 2000). Membrane Biochemistry To understand the biological significance of the essential fatty acids (EFAs), polyunsaturated fatty acids (PUFAs), saturated and trans -fatty acids, one needs to visualize how these fats are stored and used in our cells at the molecular level. This following technical section will detail several points: 1. Each fatty acid (FA) is structurally different; can be metabolized into potent modulators of inflammation, immunity, and coagulation that reflect these subtle structural differences; and thus, can skew the resultant biological effects (for example, from pro-inflammatory to antiinflammatory). The enzymes that act upon these different FAs are not entirely selective. 2. The source of these FAs is dependent upon the kinds of dietary FAs one has ingested over the last many months to years. In other words, if your diet is skewed to a high saturated and omega-6 FA (soybean) intake, as is the typical American diet, there is a huge buffer of these FAs bound to cell membranes and triglycerides (TGs). These FAs are released in response to various signals that 'activate' the vascular endothelial cells or vascular smooth muscle cells and modulate the responses to these signals (such as angiotensin II or adrenaline). When the cell is stimulated, a mixture of FAs is released for conversion into prostaglandins, thromboxanes, and leukotrienes. The physiological actions exerted by these compounds on inflammation, coagulation, and immune function, respectively, are thus related to the structure of original FA. 3. While these FAs are stored in the cell membrane they influence the fluidity of the membrane, alter the interactions of surface proteins within that membrane, and undergo various degrees of peroxidation, depending upon the degree of desaturation and the status of such antioxidant vitamins as vitamin E, coenzyme Q10, and other detoxifying systems. 4. Some of the EFAs are now known to exert direct actions on the genome, influencing the synthesis of new proteins and enzymes by their presence (Wahli et al. 1999; Forman et al. 1997; de Urquiza et al. 2000). For these reasons, dietary changes may take many months to years to reveal their beneficial effects. Consequently, it can take a long time for a diet supplemented with a greater percentage of omega-3 FAs to displace the excess of omega-6 FAs from binding sites in cell membranes. (Soybean oil is 54 % linoleic acid, an omega-6 FA, with some arachidonic acid.). Biochemically, membranes are composed of TGs containing three FAs esterified to a glycerol backbone. Glycerol is a simple three-carbon chain with alcohol moieties attached to each of three carbon atoms. FAs and EFAs are long-chained hydrocarbons (n = 16-20) with carboxylic acid moieties (or chemical functional groups) at one end. Esterification of these weak (carboxylic) FAs with glycerol creates a TG that is fat soluble. It is stored within (fatty) cellular membranes (and adipose tissue). The PUFAs, including the omega-3 and omega-6 FAs are also linked to the TGs. When a hormone (adrenaline) stimulates the (endothelial) cell, it triggers a reaction inside the cell that allows enzymes (like phospholipase A 2 ) to cleave FAs from the TGs, leaving a diglyceride and, ideally an omega-3 EFA. The free PUFA or EFA then is acted upon by other enzymes which convert it into prostaglandins, thromboxanes or leukotrienes of various classes. The class of cellular mediator created is determined by the starting FA. Omega-3 precursors like DHA and EPA lead to slightly (chemically) different prostaglandins, thromboxanes, and leukotrienes then the omega-6 precursors, arachidonic acid or other PUFAs (that are not essential). Whichever FA is released determines the biological effects of the final metabolite. Some prostaglandins are pro-inflammatory (series-2), others are anti-inflammatory (series 1 and 3); some of the thromboxane series promote platelet aggregation and vasoconstriction (A2), whereas others do not; some of the leukotrienes (B4) induce inflammation, chemotaxis, and adherence. The point is, that our cell membranes are currently overloaded with either saturated fatty acids or omega-6 fatty acids rather than omega-3 fatty acids. When these endothelial or vascular cells are chronically stimulated, mediators are released that often favor vascular and endothelial cell responses that are more inflammatory and vasoconstrictive. This causes a predisposition to hypertension and other cardiovascular diseases (Simopoulos 1999; Brown and Hu 2001). The literature is confounded with favorable in vitro findings for many of the EFAs that are not being reproduced in vivo. This probably results from the fact that it takes many months and/or years to shift the ratio of EFAs back to that resulting from a natural diet, that is, a much lower saturated or omega-6/omega-3 ratio. The composition of the FAs in the cell membrane determines the fluidity of the membrane, the positioning of proteins embedded in the membrane, and the interaction between these proteins in response to hormones. It can be hypothesized that sodium intake might modulate responses of aldosterone to angiotensin II, or adversely effect the microvasculature (see discussion on Environmental Factors, sodium ). Cellular membranes containing a higher percentage of EFAs or PUFAs are more prone to free radical attack and peroxidation. Increased levels of antioxidants are needed to counteract this effect because a badly peroxidized membrane will compromise the function of cellular proteins and hormone-receptor interactions occurring in those membranes. Peroxidized EFAs and PUFAs irreversibly (covalently) bond with these proteins, destroying their function and promoting cell death. Vitamin E and coenzyme Q10 are particularly useful because of known functions as free-radical trapping agents, membrane stabilizers, and antioxidants. Stress

Repeated exposure to stress is a risk factor for hypertension. Elevated levels of stress hormones (catecholamines and glucocorticoids) inhibit the activity of D6D. DHA intake prevents mental stress (Hamazaki et al. 1996; Sawazaki et al. 1999). DHA (1.5 g/day) reduced levels of norepinephrine (-31%), which benefits hypertension (Singer et al. 1990; Christensen et al. 1994). However, dietary omega-6 and omega-3 fatty acids reduced the cardiovascular reaction to stress (Mills et al. 1985, 1986). Both GLA and DHA reduce blood pressure and heart rate responses to stress in humans. Borage oil (GLA) significantly reduced stress-induced rises in systolic blood pressure and heart rate, whereas, fish oil (EPA, DHA) was without effect. Borage oil reduces cardiovascular reactions to many stressors. We need a sufficient amount of EFAs in a balanced proportion. Endocrine Correlates Insulin resistance is strongly linked to type-2 diabetes, obesity, hypertension, and heart disease. Insulin resistance is found in approximately 25% of healthy humans. Insulin resistance is characterized by cells that are desensitized to insulin that otherwise normally take up glucose. To compensate for higher levels of circulating glucose, insulin production increases. Elevated glucose leads to diabetes and degenerative complications in the vasculature. GLA and DHA improve insulin sensitivity. Dietary intake of EFAs increases the proportion of unsaturated fatty acids in phospholipid (cellular) membranes, making the cell more insulin sensitive (Storlien et al. 1986, 1987; Borkman et al. 1993; Vessby et al. 1994; Pan et al. 1995; Storlien et al. 1996). Scientists now understand the mechanisms of EFAs on insulin resistance. Recently developed drugs, called glitazones or thiazolidinediones that bind to and activate PPAR, increase insulin sensitivity. We now know that GLA and DHA, and certain other essential fatty acids, work in the same way by binding to and activating PPARs. It is possible to hypothesize that the different responses noted to sodium intake in hypertensive patients may be related to subtle differences in gene transcription that relate to altered proportions of EFAs in tissue membranes. Dietary Fats Hydrogenation is a common way of changing natural oils to more solid fats with longer shelf life but profoundly altered biochemical properties. Double bonds are either saturated or switched from cis - to trans -configuration. Trans -fatty acids act as antagonists to essential fatty acids and interfere with the production of good prostaglandins. Partially hydrogenated products rich in trans -fatty acids are margarines, shortenings and hydrogenated oils. We need to reduce the intake of omega-6 oils, except GLA, and increase omega-3 fatty acids, particularly DHA. Coldwater fish, nuts and seeds provide a balanced mix of omega-3 and omega-6 fatty acids. Homocysteine Homocysteine is a substance that is worse than cholesterol (Braverman 1987; McCully 1996). Homocysteine damages the artery and is now widely recognized by scientists as the single greatest biochemical risk factor for heart disease. Homocysteine may be a participant in 90% of cardiovascular problems. Two pathways detoxify homocysteine: the remethylation pathway and the trans -sulfuration pathway. If homocysteine is not detoxified, plaque builds up in the endothelial cells lining the arteries. Homocysteine speeds the oxidation of cholesterol, and then macrophages take up the particles to become foam cells in plaque (Naruszewicz et al. 1994; Cranton et al. 2001). Homocysteine plays a key role in every pathophysiologic process that leads to arteriosclerotic plaque (McCully 1996). Homocysteine promotes coagulation factors, favoring clot formation (Magott 1998). About 40% of all stroke victims have elevated homocysteine levels compared to only 6% of controls (Brattstrom et al. 1992). Elevations in homocysteine with peripheral vascular disease (28%) have been reported (Clarke et al. 1991). Hyperhomocysteinemia encourages smooth muscle cell proliferation (Magott 1998; Sandrick 2000). Homocysteine blocks production of nitric oxide, causing vessels to become less pliable and more susceptible to plaque buildup (Boger et al. 2000). Vessels lose their expansion capacities as homocysteine reduces nitric oxide's availability (Tawakol et al. 2002). Homocysteine significantly hampers microvascular circulation by impairing dilation functions. Nitric oxide (also known as endothelium-derived relaxing factor) normally protects endothelial cells from damage by reacting with homocysteine, forming S-nitrosohomocysteine, which inhibits hydrogen peroxide formation. However, as homocysteine levels increase, this protective mechanism becomes overloaded, allowing damage to the endothelial cells to occur (Stamler et al. 1992, 1993, 1996). Homocysteine activates genes in blood vessels, encouraging the coagulation process and the proliferation of smooth muscle cells (Outinen et al. 1999). Based on a random testing of 600 hospitalized elderly patients, researchers found evidence of hyperhomocysteinemia in over 60% of those with serious chronic conditions: 70% presented with vascular disease (Ventura et al. 2001). The use of drugs (particularly diuretics), and malnutrition were suspected as causes of age-related hyperhomocysteinemia. Homocysteine levels should be kept below 7 micromoles/L, however, laboratories regard levels up to 15 micromoles/L as normal, while epidemiological data reveal that homocysteine levels above 6.3 reflect a steep, progressive increase in the risk of a heart attack (Robinson et al. 1995). The incidence of hypertension and peripheral vascular disease escalates as homocysteine levels increase. Homocysteine is a significant biochemical risk factor for heart disease (McCully 1996). A combination of folic acid, vitamin B12, and pyridoxine reduced homocysteine levels (Schnyder et al. 2001). Pretreatment with 800 IU of vitamin E and 1000 mg of C (before an oral methionine load to experimentally produce homocysteine) blocked the damaging effects of hyperhomocysteinemia (Kumar and Das 1993). Coagulation and circulating adhesion molecule levels significantly increased after methionine ingestion alone but not after methionine ingestion with vitamins (Nappo et al. 1999). Medications to treat congestive heart failure commonly result in multiple B vitamin deficiencies, disrupting metabolism of homocysteine (Sinatra 2001). C-Reactive Protein (CRP) CRP is a marker for systemic inflammation. CRP levels indicate chronic low-grade inflammation, with linkage to blood vessel damage and vascular disease (Pasceri et al. 2000). When CRP levels are factored in along with hypertension, there is significant improvement in predicting cardiac health. CRP is more than a measurable antecedent preceding a cardiac problem. CRP acts directly upon the blood vessels to activate adhesion molecules in endothelial cells: the intercellular adhesion molecule (ICAM-1) and the vascular cell adhesion molecule (VCAM-1). VCAM-1 may be an early molecular marker of lesion-prone areas to experimental hypercholesterolemia. CRP appears intricately involved in the inflammatory process, a target for the treatment of atherosclerosis (Pasceri et al. 2000).