Circulatory Diseases and Disorders

Angiogenesis and Disease

Angiogenesis, the growth of new blood vessels from existing vessels, contributes to both normal tissue growth and tumorigenesis in cancer.

Learning Objectives

Examine the relationship between angiogenesis and disease

Key Takeaways

Key Points

  • Angiogenesis is a fundamental step in the transition of tumors from a dormant state to a malignant one, leading to the use of angiogenesis inhibitors as possible cancer therapeutics.
  • Angiogenesis is also a target for combating diseases characterized by either poor vascularization or abnormal vasculature.
  • Application of specific compounds that may inhibit or induce the creation of new blood vessels in the body may help combat such diseases as in the case of ischemic chronic wounds and age-related macular degeneration.

Key Terms

  • Malignant tumor: In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the body through the lymphatic system or bloodstream.
  • Angiogenesis inhibitors: A substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are a normal part of the body’s control, some are administered as drugs, and some come from diet.
  • VEGF: Signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate.

Angiogenesis is the physiological process involving the growth of new blood vessels from preexisting vessels. It is a normal and vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. It is also a fundamental step in the transition of tumors from a dormant state to a malignant one, leading to the use of angiogenesis inhibitors. Tumors cannot grow beyond a certain size, generally 1–2 mm, due to a lack of oxygen and other essential nutrients.

Angiogenesis and Cancer

Cancer cells are cells that have lost their ability to divide in a controlled fashion. A malignant tumor consists of a population of rapidly-dividing and growing cancer cells. Mutations quickly accrue within the population. These mutations (variations) allow the cancer cells (or sub-populations of cancer cells within a tumor) to develop drug resistance and escape therapy.

Tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (e.g., VEGF ). Growth factors such as bFGF and VEGF can induce capillary growth into the tumor, which some researchers suspect supply the required nutrients that allow for tumor expansion. Bone marrow cell recruitment also participates in tumor angiogenesis.

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Bone-marrow derived cells in tumor angiogenesis: Diverse chemoattractant factors promote the recruitment and infiltration of bone marrow cells to the tumor microenvironment where they suppress the antitumor immunity or promote tumor angiogenesis and vasculogenesis

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Tumor Angiogenesis: The switch to the angiogenic phenotype occurs during multistage tumorigenesis. As malignancy develops, cells progress from a prevascular stage (normal to early hyperplasia) to a vascular stage (late hyperplasia to dysplasia to invasive carcinoma). Angiogenesis becomes clearly evident during dysplasia and is critical for further growth. Targeting tumor angiogenesis may be a novel strategy for preventing cancer.

In 2007, it was discovered that cancerous cells stop producing the anti-VEGF enzyme PKG. In normal cells (but not in cancerous ones), PKG apparently limits beta-catenin, which solicits angiogenesis. Other clinicians believe angiogenesis really serves as a waste pathway, taking away the biological end products secreted by rapidly-dividing cancer cells. In either case, angiogenesis is a necessary and required step for the transition from a small, harmless cluster of cells, often said to be about the size of the metal ball at the end of a ball-point pen, to a large tumor.

Angiogenesis is also required for the spread of a tumor, or metastasis. Single cancer cells can break away from an established solid tumor, enter the blood vessel, and be carried to a distant site, where they can implant and begin the growth of a secondary tumor.

Evidence now suggests the blood vessel in a given solid tumor may, in fact, be mosaic vessels, composed of endothelial cells and tumor cells. This mosaicity allows for substantial shedding of tumor cells into the vasculature, possibly contributing to the appearance of circulating tumor cells in the peripheral blood of patients with malignancies. The subsequent growth of such metastases will also require a supply of nutrients and oxygen and a waste disposal pathway.

Angiogenesis and Cardiovascular Disease

Angiogenesis also represents an excellent therapeutic target for the treatment of cardiovascular disease. It is a potent, physiological process that underlies the natural manner in which our bodies respond to a diminution of blood supply to vital organs, namely the production of new collateral vessels to overcome the ischemic insult.

A large number of preclinical studies have been performed with protein-, gene- and cell-based therapies in animal models of cardiac ischemia, as well as models of peripheral artery disease. Reproducible and credible successes in these early animal studies led to high enthusiasm that this new therapeutic approach could be rapidly translated to a clinical benefit for millions of patients in the Western world suffering from these disorders.

A decade of clinical testing both gene- and protein-based therapies designed to stimulate angiogenesis in underperfused tissues and organs, however, has led from one disappointment to another. Although all of these preclinical readouts, which offered great promise for the transition of angiogenesis therapy from animals to humans were, in one fashion or another, incorporated into early stage clinical trials, the FDA has, to date (2007), insisted that the primary endpoint for approval of an angiogenic agent must be an improvement in exercise performance of treated patients.

Overexpression of VEGF causes increased permeability in blood vessels in addition to stimulating angiogenesis. In wet macular degeneration, VEGF causes proliferation of capillaries into the retina. Since the increase in angiogenesis also causes edema, blood, and other retinal fluids leak into the retina, causing loss of vision. A novel treatment of this disease is to use a VEGF-inhibiting siRNA to stop the main signaling cascade for angiogenesis.

Varicose Veins

Varicose veins, typically found in the legs, are those that have become enlarged and tortuous due to malfunctioning valves.

Learning Objectives

Describe the cause of varicose veins

Key Takeaways

Key Points

  • Veins have leaflet valves to prevent blood from flowing backwards; this backflow is called retrograde or reflux flow. The muscles of the leg pump the veins to return blood to the heart against the effects of gravity.
  • When veins become varicose, the leaflets of the valves no longer meet properly, and the valves no longer work, a situation called valvular incompetence. This causes pooling of blood and enlargement of the veins.
  • Varicose veins are more common in women than in men, and are linked with heredity. Other related factors are pregnancy, obesity, menopause, aging, prolonged standing, leg injury, abdominal straining, and crossing legs at the knees or ankles.
  • Non-surgical treatments for varicose veins include elastic stockings, elevating the legs, and exercise. The traditional surgical treatment has been vein stripping, or removal of the affected veins.

Key Terms

  • superficial veins: Those veins that are close to the surface of the body.
  • tortuous: Twisted; having many turns; convoluted.

Varicose veins are those that have become enlarged and tortuous, commonly affecting the legs.

Causes of Varicose Veins

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Varicose Veins: This image shows a normal vein with a working valve and normal blood flow. Figure B shows a varicose vein with a deformed valve, abnormal blood flow, and thin, stretched walls. The middle image shows where varicose veins might appear in a leg.

Veins have leaflet valves to prevent blood from flowing backwards; this backflow is called retrograde or reflux flow. The muscles of the leg pump the veins to return blood to the heart against the effects of gravity. When veins become varicose, the leaflets of the valves no longer meet properly, and the valves no longer work. This change is called valvular incompetence, and it allows blood to flow backwards. To accommodate the retrograde or reflux flow, the veins enlarge even more.

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Leg with Varicose Veins: A man with many varicose veins in the lower leg.

Varicose veins are most often found in the superficial veins of the legs, which are subject to high pressure when standing. In addition to cosmetic concerns, varicose veins are often painful, especially when standing or walking. They can often itch, and scratching them can lead to skin ulcers.

Varicose veins are more common in women than in men, and are linked with heredity. Other related factors are pregnancy, obesity, menopause, aging, prolonged standing, leg injury, abdominal straining, and crossing legs at the knees or ankles. They are distinguished from “spider veins,” which are also due to valvular incompetence, by their size. Spider veins are less than one millimeter in diameter, whereas varicose veins are larger than this in diameter.

Treatments

Non-surgical treatments for varicose veins include elastic stockings, elevating the legs, and exercise. The traditional surgical treatment has been vein stripping, or removal of the affected veins. Because most of the blood in the legs is returned by the deep veins, the superficial veins, which return only about 10 per cent of the total blood of the legs, can usually be removed without serious harm.

Syncope

Syncope, the medical term for fainting, is a transient loss of consciousness.

Learning Objectives

Identify the main factor associated with syncope

Key Takeaways

Key Points

  • This loss of consciousness can arise due to changes in postural tone.
  • The two broad categories of syncope are cardiogenic and reflex; of the two, cardiogenic syncope is more likely to result in morbidity or mortality.
  • Vasovagal syncope is situational syncope which may arise in situations where the patient feels scared, threatened, embarrassed, or uneasy.

Key Terms

  • cardiogenic syncope: The form of syncope that is more likely to produce serious morbidity or mortality and require prompt treatment.
  • reflex syncope: Involuntary fainting.
  • vasovagal syncope: Situational syncope which may arise in situations where the patient feels scared, threatened, embarrassed, or uneasy.

Syncope, the medical term for fainting, is defined as a transient loss of consciousness and postural tone characterized by rapid onset, short duration, and spontaneous recovery due to global cerebral hypoperfusion that most often results from hypotension.

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Vagus Nerve: The vagus nerve, labeled at the top left and colored in yellow, may lower heart rate, reducing blood flow to the brain and causing vasovagal syncope.

Many forms of syncope are preceded by a prodromal state that often includes dizziness and loss of vision (“blackout”) (temporary), loss of hearing (temporary), loss of pain and feeling (temporary), nausea and abdominal discomfort, weakness, sweating, a feeling of heat, palpitations, and other phenomena, which–if they do not progress to loss of consciousness and postural tone–are often denoted “presyncope.” Abdominal discomfort prior to loss of consciousness may be indicative of seizure which should be considered different than syncope.

Types of Syncope

There are two broad categories of syncope, cardiogenic or reflex, which underlie most forms of syncope. Cardiogenic forms are more likely to produce serious morbidity or mortality and require prompt or even immediate treatment. Although cardiogenic syncope is much more common in older patients, an effort to rule out arrhythmic, obstructive, ischemic, or cardiomyopathic causes of syncope and circulatory inadequacy is mandatory in each patient.

Variants of reflex syncope often have characteristic histories, including precipitants and time course which are made evident by skilled history taking. Thus, the clinical history is the foremost tool used in the differential diagnosis of syncope. Physical examination, and electrocardiogram are part of the initial evaluation of syncope and other more specific tools such as loop recorders may be necessary in clinically uncertain cases.

Vasovagal Syncope

Vasovagal (situational) syncope, one of the most common types, may occur in scary, embarrassing or uneasy situations, or during blood drawing, coughing, urination, or defecation. In vasovagal syncope, the vagus nerve decreases blood flow to the brain. Other types include postural syncope (caused by a change in body posture), cardiac syncope (due to heart-related conditions), and neurological syncope (due to neurological conditions). There are many other causes of syncope, including low blood sugar levels and lung disease such as emphysema and a pulmonary embolus. The cause of the fainting can be determined by a doctor using a complete history, physical, and various diagnostic tests.

The vasovagal type can be considered in two forms:

  • Isolated episodes of loss of consciousness, unheralded by any warning symptoms for more than a few moments. These tend to occur in the adolescent age group, and may be associated with fasting, exercise, abdominal straining, or circumstances promoting vasodilation (e.g., heat, alcohol). The subject is invariably upright. The tilt-table test, if performed, is generally negative.
  • Recurrent syncope with complex associated symptoms called neurally mediated syncope. It is associated with any of the following: preceding or succeeding sleepiness, preceding visual disturbance (“spots before the eyes”), sweating, and light-headedness. The subject is usually but not always upright. The tilt-table test, if performed, is generally positive.

Hypertension

Hypertension is elevated blood pressure, clinically defined as at or greater than 140/90 (systolic/diastolic) mm/Hg.

Learning Objectives

Evaluate the factors involved in hypertension

Key Takeaways

Key Points

  • Primary hypertension has multiple or unknown causes, and secondary hypertension has known causes.
  • In most cases of primary hypertension, increased peripheral resistance is the reason for the elevated pressure.
  • Even moderate elevation of arterial blood pressure is associated with a shortened life expectancy.
  • Chronically elevated blood pressure leads to widespread damage to the circulatory system, arterial disease, cardiac failure, and even neurological impairments.

Key Terms

  • total peripheral resistance: Total peripheral resistance (TPR) is the sum of the resistance of all peripheral vasculature in the systemic circulation. Vasculature throughout the entire body can be thought of as two separate circuits—one is the systemic circulation, while the other is the pulmonary circulation.
  • hypertension: The disease or disorder of abnormally high blood pressure.
  • blood pressure: The pressure exerted by the blood against the walls of the arteries and veins; it varies during the heartbeat cycle, and according to a person’s age, health, and physical condition.

Hypertension (HTN) or high blood pressure, sometimes called arterial hypertension, is a chronic medical condition in which the blood pressure in the arteries is elevated. This requires the heart to work harder than normal to circulate blood through the blood vessels. Blood pressure involves two measurements, systolic and diastolic, which depend on whether the heart muscle is contracting (systole) or relaxed between beats (diastole).

Normal blood pressure at rest is within the range of 100–140mmHg systolic (top reading) and 60–90mmHg diastolic (bottom reading). High blood pressure is said to be present if it is persistently at or above 140/90 mmHg. The repercussions of chronically elevated blood pressure included widespread damage to the circulatory system, arterial disease, cardiac failure and even neurological impairments

Primary and Secondary Hypertension

Hypertension is classified as either primary (essential) hypertension or secondary hypertension; about 90–95% of cases are categorized as “primary hypertension” which means high blood pressure with no obvious underlying medical cause. The remaining 5–10% of cases (secondary hypertension) are caused by other conditions that affect the kidneys, arteries, heart, or endocrine system. In most people with established essential (primary) hypertension, increased resistance to blood flow (total peripheral resistance) accounts for the high pressure while cardiac output remains normal. This increased peripheral resistance is mainly attributable to structural narrowing of small arteries and arterioles, although a reduction in the number or density of capillaries may also contribute. Secondary hypertension results from an identifiable cause. Renal disease is the most common secondary cause of hypertension. Hypertension can also be caused by endocrine conditions, such as Cushing’s syndrome, hyperthyroidism, hypothyroidism, and acromegaly. Other causes of secondary hypertension include obesity, sleep apnea, pregnancy, and coarctation of the aorta.

There are many complications of chronic hypertension. Hypertension is a major risk factor for stroke, myocardial infarction (heart attacks), heart failure, aneurysms of the arteries (e.g., aortic aneurysm), peripheral arterial disease, and is a cause of chronic kidney disease. Even moderate elevation of arterial blood pressure is associated with a shortened life expectancy. Dietary and lifestyle changes can improve blood pressure control and decrease the risk of associated health complications, although drug treatment is often necessary in people for whom lifestyle changes prove ineffective or insufficient.

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High Blood Pressure Complications: Persistant high blood pressure can affect many areas of the body.