Cardiovascular System week #2: High-Yield Review

Published on May 15, 2018

Atherosclerosis

A 38-year-old male was transported to the ED by ambulance for evaluation of chest pain x 1 h. The history, physical examination, and EKG were consistent with a mild anterior wall MI. He had no known medical problems and was on no medication. He was overweight (BMI=32 kg/m2) and smoked 2 packs of cigarettes per day. A CT scan was performed and the Agatson score was elevated.

Comment on how fissuring or erosion of atherosclerotic plaque triggers formation of a thrombus

A large number of diseases with totally different clinical presentations are basically atherosclerosis related, and among these, myocardial infarction, stroke, abdominal aneurysms and lower limb ischemia determine to a large extent the morbidity and mortality in Western style populations. But, despite this broad spectrum of clinical disease, most of the acute manifestations of atherosclerosis share a common pathogenetic feature: rupture of an atherosclerotic plaque. Plaque disruptions may vary greatly in extent from tiny fissures or erosions of the plaque surface to deep intimal tears which extend into the soft lipid core of lesions…

Large mural thrombi due to large surface erosions or superficial fissures in the fibrous cap have found in many of the lesions underlying unstable angina.

The abrupt closure of an artery by an occlusive thrombus
is the main cause of myocardial infarcts and other
thrombotic sequelae of atherosclerosis. This thrombosis is
often associated with a fissure that develops in the underlying
atherosclerotic plaque.1–6

Plaque fissures often have very complex geometry and are not
always easily recognizable on the two-dimensional tissue sections.
Moreover, artificial cracks and other tissue displacements may occur
during specimen preparation

• Discuss atherosclerosis as a chronic inflammatory condition

Inflammation is a process that plays an important role in the initiation and progression of atherosclerosis and immune disease, involving multiple cell types, including macrophages, T-lymphocytes, endothelial cells, smooth muscle cells and mast cells. The fundamental damage of atherosclerosis is the atheromatous or fibro-fatty plaque which is a lesion that causes several diseases.

Considerable evidence indicates that mast cells and their products play a key role in inflammation and atherosclerosis. Activated mast cells can have detrimental effects, provoking matrix degradation, apoptosis, and enhancement as well as recruitment of inflammatory cells, which actively contributes to atherosclerosis and plaque formation.

Discuss the events leading to fatty streak formation

Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions.

Almost all children older than 10 in developed countries have fatty streaks, with coronary fatty streaks beginning in adolescence.[2]

fatty streak is the first grossly visible (visible to the naked eye) lesion in the development of atherosclerosis. It appears as an irregular yellow-white discoloration on the luminal surface of an artery. It consists of aggregates of foam cells, which are lipoprotein-loaded macrophages,[1] located in the intima, the innermost layer of the artery, beneath the endothelial cells that layer the lumina through which blood flows. Fatty streaks may also include T cells, aggregated platelets, and smooth muscle cells. It is the precursor lesion of atheromasthat may become atheromatous plaques.

IT IS DUE is due to an accumulation of lipid-laden foam cells in the intimal layer of the artery. With time, the fatty streak evolves into a fibrous plaque, the hallmark of established atherosclerosis. Ultimately the lesion may evolve to contain large amounts of lipid; if it becomes unstable, denudation of overlying endothelium, or plaque rupture, may result in thrombotic occlusion of the overlying artery.

• Review risk factors for atherosclerosis

Emerging Risk Factors

Scientists continue to study other possible risk factors for atherosclerosis.

High levels of a protein called C-reactive protein (CRP) in the blood may raise the risk for atherosclerosis and heart attack. High levels of CRP are a sign of inflammation in the body.

Damage to the arteries’ inner walls seems to trigger inflammation and help plaque grow.

People who have low CRP levels may develop atherosclerosis at a slower rate than people who have high CRP levels. Research is under way to find out whether reducing inflammation and lowering CRP levels also can reduce the risk for atherosclerosis.

High levels of triglycerides in the blood also may raise the risk for atherosclerosis, especially in women. Triglycerides are a type of fat.

Studies are under way to find out whether genetics may play a role in atherosclerosis risk.

Other Factors That Affect Atherosclerosis

Other factors also may raise your risk for atherosclerosis, such as:

  • Sleep apnea. Sleep apnea is a disorder that causes one or more pauses in breathing or shallow breaths while you sleep. Untreated sleep apnea can raise your risk for high blood pressure, diabetes, and even a heart attack or stroke.
  • Stress. Research shows that the most commonly reported “trigger” for a heart attack is an emotionally upsetting event, especially one involving anger.
  • Alcohol. Heavy drinking can damage the heart muscle and worsen other risk factors for atherosclerosis. Men should have no more than two drinks containing alcohol a day. Women should have no more than one drink containing alcohol a day.
  • Unhealthy blood cholesterol levels. This includes high LDL cholesterol (sometimes called “bad” cholesterol) and low HDL cholesterol (sometimes called “good” cholesterol).
  • High blood pressure. Blood pressure is considered high if it stays at or above 140/90 mmHg over time. If you have diabetes or chronic kidney disease, high blood pressure is defined as 130/80 mmHg or higher. (The mmHg is millimeters of mercury—the units used to measure blood pressure.)
  • Smoking. Smoking can damage and tighten blood vessels, raise cholesterol levels, and raise blood pressure. Smoking also doesn’t allow enough oxygen to reach the body’s tissues.
  • Insulin resistance. This condition occurs if the body can’t use its insulin properly. Insulin is a hormone that helps move blood sugar into cells where it’s used as an energy source. Insulin resistance may lead to diabetes.
  • Diabetes. With this disease, the body’s blood sugar level is too high because the body doesn’t make enough insulin or doesn’t use its insulin properly.
  • Overweight or obesity. The terms “overweight” and “obesity” refer to body weight that’s greater than what is considered healthy for a certain height.
  • Lack of physical activity. A lack of physical activity can worsen other risk factors for atherosclerosis, such as unhealthy blood cholesterol levels, high blood pressure, diabetes, and overweight and obesity.
  • Unhealthy diet. An unhealthy diet can raise your risk for atherosclerosis. Foods that are high in saturated and trans fats, cholesterol, sodium (salt), and sugar can worsen other atherosclerosis risk factors.
  • Older age. As you get older, your risk for atherosclerosis increases. Genetic or lifestyle factors cause plaque to build up in your arteries as you age. By the time you’re middle-aged or older, enough plaque has built up to cause signs or symptoms. In men, the risk increases after age 45. In women, the risk increases after age 55.
  • Family history of early heart disease. Your risk for atherosclerosis increases if your father or a brother was diagnosed with heart disease before 55 years of age, or if your mother or a sister was diagnosed with heart disease before 65 years of age.

• Describe the processes that develop when LDL particles are trapped in the artery wall

Atherosclerosis disease is the hardening of artery walls due to the growth of fatty plaques in medium and large arteries. Because fatty plaques are mainly composed of plasma lipoprotein particles, such as LDL, investigating the phenomenon of the mass transfer of LDL particles in the artery wall is an important subject in diagnosing this disease.

5.1. Concentration polarization (CP) phenomenon

Due to the existence of a filtration rate on the wall, and not passing through the endothelial, LDL particles accumulate on the artery wall, creating a very thin concentration boundary layer.

• Describe the uptake of oxidized LDL by macrophages through their scavenger receptors and their transformation into foam cells

Foam cell formation from macrophages with subsequent fatty streak formation plays a key role in early atherogenesis. Foam cell formation is thought to be induced by Low Density Lipoproteins (LDL), including oxidized LDL (OxLDL) or minimally modified LDL (mmLDL).

Scavenger receptors appear to play a key role
in uptake of OxLDL…

Taken together, scavenger receptors, peroxisome proliferator-activated
receptors and eicosanoids interact during
foam cell formation, and thus could all be targets for
therapeutic intervention. All these groups of molecules have
both pro- and anti-atherogenic effects. Any effects on foam cell
formation should not be seen in isolation, but must be
evaluated in the context of pro- and anti-inflammatory
effects that represent independent risk factors for coronary
artery disease and stroke.
• Briefly describe the proposed role of T cells in atherogenesis

The idea that atherosclerosis is an inflammatory disease is no longer controversial. Instead, much of the current research is now focused on understanding what drives this inflammation and how it is regulated. Adaptive immunity, in particular T cells, is highly involved in atherogenesis. It is well known that different subsets of T cells can drive or dampen inflammatory processes, but we still have much to learn about the regulation of this balance in the context of atherosclerosis.

… T cells can aggravate or attenuate this disease through cross-talk with other cells within or outside the atherosclerotic plaque.

The fine-tuning between pro-inflammatory and antiinflammatory factors may determine whether an atherosclerotic lesion will develop into a silent stable plaque or if a cascade of activating events will lead to immune activation, loss of EC matrix, weakening of the fibrous cap, and, finally, a rupture that leads to myocardial infarction or a stroke. T cells play important roles on both sides of this balance.
• Describe triglyceride-rich remnant particles and their adverse effects on endothelial function, and how ??inflammation may inhibit clearance of these TG remnants??

Remnant-like lipoprotein particles (RLPs), also known as remnant lipoproteins or remnant-like particles, are derived from VLDLs and chylomicrons, which are the major carriers of plasma triglycerides.

There may be an indirect mechanism by which RLPs could impair endothelial function by stimulating secretion of inflammatory factors, such as CRP, IL-6, and TNF-α, from multiple origins. Further studies are needed to test these hypotheses.

inflammation may inhibit clearance of these TG remnants??

increased apoC-III inhibits the lipolysis of VLDL-triglycerides by lipoprotein lipase (27) and interferes with the hepatic uptake of TRL remnants by LDL receptors
• Describe the anti-atherogenic role of HDL particles

…plasma HDL levels correlate inversely with cardiovascular disease risk

In some settings increasing high density lipoprotein (HDL) levels has been associated with a reduction in experimental atherosclerosis. This has been most clearly seen in apolipoprotein A-I (apoA-I) transgenic mice or in animals infused with HDL or its apolipoproteins.

A major mechanism by which these treatments are thought to delay progression or cause regression of atherosclerosis is by promoting efflux of cholesterol from macrophage foam cells. In addition, HDL has been described as having anti-inflammatory and other beneficial effects. Some recent research has linked anti-inflammatory effects to cholesterol efflux pathways but likely multiple mechanisms are involved.
• Describe the growth of early atherosclerotic lesions and formation of a sub-endothelial cap, in which collagen fibers are a major component

growth of early atherosclerotic lesions

High serologic lipid levels, infections, and genetic susceptibility have been proposed as possible etiologic factors of initial atherosclerotic lesions of the coronary arteries in infancy. At a recent WHO annual meeting, it was stated that breast milk substitutes cause irreparable damage in infants.

A significant correlation was observed between the early atherosclerotic lesions and the risk factors considered. In particular, different morphologic patterns related to formula feeding and cigarette smoking. Baby formula feeding and parental cigarette smoking might have an atherogenic effect on the coronary walls as from the first months of life. The lesions appear to be larger and more diffuse when both these atherogenic factors are present.

formation of a sub-endothelial cap, in which collagen fibers are a major component

Beneath the endothelium there is a “fibrous cap” covering the atheromatous “core” of the plaque. The core consists of lipid-laden cells (macrophages and smooth muscle cells) with elevated tissue cholesterol and cholesterol ester content, fibrin, proteoglycans, collagen, elastin, and cellular debris. In advanced plaques, the central core of the plaque usually contains extracellular cholesterol deposits (released from dead cells), which form areas of cholesterol crystals with empty, needle-like clefts.
Discuss the importance of remodeling

Arterial remodeling is currently being recognized as an important determinant in vascular pathology in which narrowing of the lumen is the predominant feature. Not only expansive remodeling (enlargement), but also constrictive remodeling (shrinkage) is observed in de novo atherosclerosis, in restenosis and in transplant vasculopathy. Expansive remodeling prevents and constrictive remodeling enhances luminal narrowing by plaque formation or intimal hyperplasia. The mechanisms of the opposite remodeling modes is unknown. Insight into the processes that determine the direction of local arterial remodeling may help to develop new strategies to prevent arterial occlusive disease.

Arterial remodeling is a major determinant of obstructive cardiovascular disease. Compared to plaque/neointima formation, the mechanisms of the different remodeling modes have been relatively unexplored

With rapidly accumulating knowledge of the mechanisms of arterial remodeling, potential targets for intervention are being identified that have great potential for future therapeutic strategies in the treatment of obstructive arterial disease.

• Describe the contribution of rupture vs. erosion in causing myocardial infarction

Plaque erosion causes 30% of ST‐segment elevation myocardial infarctions, but the underlying cause is unknown. Inflammatory infiltrates are less abundant in erosion compared with rupture in autopsy studies.

Plaque erosion is a major cause of ST‐segment elevation myocardial infarction (STEMI), accounting for ≈30% to 40% of cases,123 yet little is known about the triggers for this pathological process, in contrast to a more detailed understanding of the complex inflammatory processes leading to atherosclerotic plaque rupture.4 There is increasing interest in plaque erosion, and tailored treatments for this pathology are being tested.5

Autopsy studies suggest that markers of inflammation are significantly lower in plaque erosion compared with plaque rupture, with sparse infiltration of macrophages and T lymphocytes within the vessel wall.67 Other studies, however, have suggested an important role for neutrophil infiltrates at sites of plaque erosion.8 Demonstrating inflammatory profiles of patients that are concordant with autopsy data is important to validate clinical research aiming to identify the triggers of plaque erosion. Nevertheless, evidence that inflammatory differences between erosion and rupture are detectable in patients at the time of myocardial infarction is contradictory

• Describe processes that are believed to contribute to plaque rupture and the impact of failure of removal of dead/dying cells by phagocytes (efferocytosis)

 Macrophages uptake oxLDL sequestered in the subendothelium eventually becoming lipid-laden foam cells. Vascular smooth muscle cells (VSMCs) can migrate to the subendothelium where they lose expression of SMC markers and gain expression of macrophage markers. This allows them to ingest lipids and eventually become foam cells contributing to plaque progression. (C) These foam cells eventually undergo apoptosis and necroptosis, and, if not effectively cleared by M2 macrophages via efferocytosis, undergo secondary necrosis contributing to the formation of the necrotic core. As the necrotic core grows and the fibrous cap thins, the plaque is vulnerable to rupture, which may result in acute cardiovascular events such as thrombosis. (D) VSMCs near the cap of the plaque secrete extracellular matrix components that contribute to the formation of a fibrous cap that protects the plaque from rupturing. M2 macrophages express anti-inflammatory markers that act to reduce the inflammation of the plaque. They also perform efferocytosis, thereby reducing the apoptotic and necrotic cells within the plaque and promoting plaque stability.

 Plaques with a thin fibrous cap and large necrotic cores are likely to rupture leading to thrombosis, heart attack, or stroke (). Furthermore, macrophages play a primary role in the clearance of dead and dying cells within the plaque enabling plaque regression (Figure  (Figure1D).1D). Thus, macrophages play a critical role in the progression of atherosclerotic plaques. Particularly, the balance between macrophage death and the clearance of dead cells by macrophages is a determining factor in plaque progression and vulnerability.

Efferocytosis is the clearance of dead and dying cells by phagocytes. Efferocytosis functions to clear cells in early stages of cell death while the plasma membrane is still intact. It also prevents secondary necrosis, thereby preventing the extracellular release of the cytotoxic and inflammatory contents of the dying cell (). Dying cells release “find me” signals such as fractalkine or CXC3CL1, which establish a chemotactic gradient that stimulates the phagocyte to migrate toward the dying cell (). The dying cells also display “eat me” signals on their surface, which are recognized by specific receptors on the phagocyte.

List the principles of anti-atherosclerotic therapy, including life-style modifications, statins, aspirin, and other inhibitors of platelet aggregation

Treatment

Lifestyle changes, such as eating a healthy diet and exercising, are often the most appropriate treatment for atherosclerosis. Sometimes, medication or surgical procedures may be recommended as well.

Medications

Various drugs can slow — or even reverse — the effects of atherosclerosis. Here are some common choices:

  • Cholesterol medications. Aggressively lowering your low-density lipoprotein (LDL) cholesterol, the “bad” cholesterol, can slow, stop or even reverse the buildup of fatty deposits in your arteries. Boosting your high-density lipoprotein (HDL) cholesterol, the “good” cholesterol, may help, too.Your doctor can choose from a range of cholesterol medications, including drugs known as statins and fibrates. In addition to lowering cholesterol, statins have additional effects that help stabilize the lining of your heart arteries and prevent atherosclerosis.
  • Anti-platelet medications. Your doctor may prescribe anti-platelet medications, such as aspirin, to reduce the likelihood that platelets will clump in narrowed arteries, form a blood clot and cause further blockage.
  • Beta blocker medications. These medications are commonly used for coronary artery disease. They lower your heart rate and blood pressure, reducing the demand on your heart and often relieve symptoms of chest pain. Beta blockers reduce the risk of heart attacks and some heart rhythm problems.
  • Angiotensin-converting enzyme (ACE) inhibitors. These medications may help slow the progression of atherosclerosis by lowering blood pressure and producing other beneficial effects on the heart arteries. ACE inhibitors can also reduce the risk of recurrent heart attacks.
  • Calcium channel blockers. These medications lower blood pressure and are sometimes used to treat angina.
  • Water pills (diuretics). High blood pressure is a major risk factor for atherosclerosis. Diuretics lower blood pressure.
  • Other medications. Your doctor may suggest certain medications to control specific risk factors for atherosclerosis, such as diabetes. Sometimes specific medications to treat symptoms of atherosclerosis, such as leg pain during exercise, are prescribed.

• Briefly describe new therapeutic approaches

Alternative medicine

It’s thought that some foods and herbal supplements can help reduce your high cholesterol level and high blood pressure, two major risk factors for developing atherosclerosis. With your doctor’s OK, you might consider these supplements and products:

  • Alpha-linolenic acid (ALA)
  • Barley
  • Beta-sitosterol (found in oral supplements and some margarines, such as Promise Activ)
  • Black tea
  • Blond psyllium (found in seed husk and products such as Metamucil)
  • Calcium
  • Cocoa
  • Cod liver oil
  • Coenzyme Q10
  • Fish oil
  • Folic acid
  • Garlic
  • Green tea
  • Oat bran (found in oatmeal and whole oats)
  • Sitostanol (found in oral supplements and some margarines, such as Benecol)
  • Vitamin C

Peripheral Vascular Disease
A 58-year-old male diabetic smoker presents complaining of pain on walking of 6 months duration. He has a history of hypertension, for which he takes atenolol. He states that he has bilateral calf cramping with walking. The pain is worse in the right calf than the left and subsides when he stops walking. Recently, he has noticed that is able to walk less and less before the onset of symptoms. The impression is lower extremity peripheral arterial disease.

Review the key features of lower extremity atherosclerotic peripheral arterial disease, including narrowing of the lumen and possible aneurysm or thrombus formation

Over 150 years ago, Virchow postulated that three features predispose to thrombus formation: abnormalities in blood flow, blood constituents and the vessel wall.8 Although Virchow was referring to venous thrombosis, these concepts can also be applied to arterial thrombosis.

The subintimal accumulation of lipid and fibrous material can narrow the vessel lumen, or the plaque can rupture, causing embolism. Multiple factors contribute to the pathogenesis of atherosclerosis, including endothelial dysfunction, dyslipidemia, inflammatory and immunologic factors, plaque rupture, and tobacco use. (See “Pathogenesis of atherosclerosis”.)

The symptoms related to atherosclerotic narrowing of the aorta or lower extremity arteries depend upon the location and severity of disease. Atherosclerotic disease tends to be well localized and usually occurs in the proximal or midportions of a given arterial bed. Atherosclerotic disease follows anatomic patterns, which also have a bearing on the natural history and progression of disease. Patients with diabetes or with end stage renal disease generally present with more distal disease.

When PVD affects only the arteries and not the veins, it is called peripheral arterial disease (PAD). The main forms that PVD may take include blood clots (for example, deep vein thrombosis or DVT), swelling (inflammation), or narrowing and blockage of the blood vessels.

• Describe the ankle-brachial index

The anklebrachial pressure index (ABPI) or anklebrachial index (ABI) is the ratio of the blood pressure at the ankle to the blood pressure in the upper arm (brachium). Compared to the arm, lower blood pressure in the leg suggests blocked arteries due to peripheral artery disease (PAD).

The normal range for the ankle-brachial index is between 0.90 and 1.30. An indexunder 0.90 means that blood is having a hard time getting to the legs and feet: 0.41 to 0.90 indicates mild to moderate peripheral artery disease; 0.40 and lower indicates severe disease.

• Review risk factors for atherosclerosis, including cigarette smoking, hypertension, lipid abnormalities, and diabetes mellitus

Emerging Risk Factors

Scientists continue to study other possible risk factors for atherosclerosis.

High levels of a protein called C-reactive protein (CRP) in the blood may raise the risk for atherosclerosis and heart attack. High levels of CRP are a sign of inflammation in the body.

Inflammation is the body’s response to injury or infection. Damage to the arteries’ inner walls seems to trigger inflammation and help plaque grow.

People who have low CRP levels may develop atherosclerosis at a slower rate than people who have high CRP levels. Research is under way to find out whether reducing inflammation and lowering CRP levels also can reduce the risk for atherosclerosis.

High levels of triglycerides (tri-GLIH-seh-rides) in the blood also may raise the risk for atherosclerosis, especially in women. Triglycerides are a type of fat.

Studies are under way to find out whether genetics may play a role in atherosclerosis risk.

Other Factors That Affect Atherosclerosis

Other factors also may raise your risk for atherosclerosis, such as:

•Sleep apnea. Sleep apnea is a disorder that causes one or more pauses in breathing or shallow breaths while you sleep. Untreated sleep apnea can raise your risk for high blood pressure, diabetes, and even a heart attack or stroke.

•Stress. Research shows that the most commonly reported “trigger” for a heart attack is an emotionally upsetting event, especially one involving anger.

•Alcohol. Heavy drinking can damage the heart muscle and worsen other risk factors for atherosclerosis. Men should have no more than two drinks containing alcohol a day. Women should have no more than one drink containing alcohol a day.
• Describe the pathobiology of acute limb ischemia

— Acute lower extremity ischemia is overwhelmingly related to arterial occlusion, though extensive venous occlusion can lead to extremity ischemia as well (ie, phlegmasia), but this is rare. Venous occlusion is discussed briefly below and in separate topic reviews.

Acute arterial occlusion is most commonly related to acute thrombosis of a diseased but previously patent, often atherosclerotic artery [10] but can also be due to acute thrombosis of a stent or graft, dissection of an artery, direct trauma to an artery, or the result of an embolus from a proximal source lodging into a more distal vessel (table 1).
Describe the pathobiology of chronic limb ischemia

Chronic critical limb ischemia is manifested by pain at rest, nonhealing wounds and gangrene. Ischemic rest pain is typically described as a burning pain in the arch or distal foot that occurs while the patient is recumbent but is relieved when the patient returns to a position in which the feet are dependent. Objective hemodynamic parameters that support the diagnosis of critical limb ischemia include an ankle-brachial index of 0.4 or less, an ankle systolic pressure of 50 mm Hg or less, or a toe systolic pressure of 30 mm Hg or less.

Atherosclerosis underlies most peripheral arterial disease. Narrowed vessels that cannot supply sufficient blood flow to exercising leg muscles may cause claudication, which is brought on by exercise and relieved by rest.

Chronic critical limb ischemia is defined not only by the clinical presentation but also by an objective measurement of impaired blood flow. Criteria for diagnosis include either one of the following (1) more than two weeks of recurrent foot pain at rest that requires regular use of analgesics and is associated with an ankle systolic pressure of 50 mm Hg or less, or a toe systolic pressure of 30 mm Hg or less, or (2) a nonhealing wound or gangrene of the foot or toes, with similar hemodynamic measurements.2 The hemodynamic parameters may be less reliable in patients with diabetes because arterial wall calcification can impair compression by a blood pressure cuff and produce systolic pressure measurements that are greater than the actual levels.
Describe the clinical manifestations of acute limb ischemia

PRESENTATIONS — Arterial occlusion results in a sudden cessation of blood supply and nutrients to the tissues in the distribution of the vessel, including skin, muscle, and nerves. The clinical presentation of acute arterial occlusion depends upon the time course of vessel occlusion; the location of the affected vessels, ranging from proximal large vessel occlusion resulting in ischemia of the entire extremity to distal small vessel occlusion resulting in digital ischemia; whether there is underlying vascular disease; and the ability to recruit collateral channels to provide flow around the occlusion (figure 1). Symptoms can develop over a period of hours to days and can range from new or worsening claudication to relatively sudden paralysis of the affected limb.

It is important to determine if the patient had symptoms of chronic ischemia prior to the acute event.
• Describe the clinical manifestations of chronic stable lower limb ischemia, especially claudication

It is a condition in which cramping pain in the leg is induced by exercise, typically caused by obstruction of the arteries

s. Restriction of blood flow due to arterial stenosis or occlusion often leads patients to complain of muscle pain on walking (intermittent claudication).

Although many patients with claudication remain stable, about 150 to 200per million of the population progress to critical limb ischemia (Fontaine IIIor IV) each year. Many patients with critical limb ischemia can undergorevascularization, which has a reasonable chance of saving the limb. A recent audit by the Vascular Surgical Society found a success rate of over 70% for these patients. Many patients, however, still require major amputation.Rehabilitation of elderly patients after amputation can prove difficult and costly.
• Describe the clinical manifestations of chronic critical lower limb ischemia

Chronic limb ischaemia is peripheral arterial disease that results in a symptomatic reduced blood supply to the limbs. It is typically caused by atherosclerosis (rarely vasculitis) and will commonly affect the lower limbs (however the upper limbs and pelvis can also be affected).

Around 15-20% individuals over 70yrs have peripheral arterial disease.

The clinical features of chronic limb ischaemia depend on its severity, as shown in Table 1.

One of the earlier symptoms is intermittent claudication, a cramping-type pain in the calf, thigh, or buttock after walking a fixed distance (the ‘claudication distance’), relieved immediately by rest within minutes.

Stage I Asymptomatic
Stage II Intermittent claudication
Stage III Ischaemic rest pain
Stage IV Ulceration or gangrene, or both

Table 1 – Fontaine classification of chronic leg ischaemia

Buerger’s test involves lying the patient supine and raising their legs until they go pale and then lowering them until the colour returns (or even becoming hyperaemic). The angle at which limb goes pale is termed Buerger’s angle; an angle of less than 20 degrees indicates severe ischaemia.
• Review the diagnosis of acute limb ischemia

To find out where the occlusion is located one of the things that can be done is simply a pulse examination to see where the heart rate can be detected and where it stops being sensed. Also there is a lower body temperature below the occlusion as well as paleness. A Doppler evaluation is used to show the extent and severity of the ischaemia by showing flow in smaller arteries. Other diagnostical tools are duplex ultrasonography, computed tomography angiography (CTA), and magnetic resonance angiography (MRA). The CTA and MRA are used most often because the duplex ultrasonography although non-invasive is not precise in planning revascularization. CTA uses radiation and may not pick up on vessels for revascularization that are distal to the occlusion, but it is much quicker than MRA.[1] In treating acute limb ischaemia time is everything.

In the worst cases acute limb ischaemia progresses to critical limb ischaemia, and results in death or limb loss. Early detection and steps towards fixing the problem with limb-sparing techniques can salvage the limb. Compartment syndrome can occur because of acute limb ischaemia because of the biotoxins that accumulate distal to the occlusion resulting in edema.[1]
• Review the diagnosis of chronic limb ischemia

The presence of rest pain can sometimes be difficult to discern in patients with other chronic leg pain, such as that caused by peripheral neuropathy. Labeling a wound as nonhealing can also be a subjective assessment. However, a number of physical findings and objective hemodynamic parameters can be used to substantiate a diagnosis of chronic critical limb ischemia.

Typical physical findings include absent or diminished pedal pulses, shiny smooth skin of the feet and legs, and muscle wasting of the calves.

An objective measurement of blood flow is easily accomplished with the use of a hand-held Doppler probe and a blood pressure cuff.1 The cuff is inflated until the pulse distal to the cuff is no longer heard by Doppler. The cuff is then slowly deflated until the pulse is again detected. This measurement is recorded as the systolic pressure. As previously mentioned, an ankle systolic pressure of 50 mm Hg or less or a toe systolic pressure of 30 mm Hg or less suggests the presence of critical limb ischemia.

Another widely used parameter is the ankle-brachial index, which is a ratio of the systolic pressure at the dorsalis pedis or posterior tibial artery divided by the systolic pressure at the brachial artery. Patients with claudication typically have an ankle-brachial index of 0.5 to 0.8, while patients with critical limb ischemia usually have an ankle-brachial index of 0.4 or less.9,10

Vascular laboratories also use Doppler probes to measure the pulse volume waveform at segmental locations in the leg arteries. A change in the Doppler waveform from triphasic to biphasic to monophasic and then stenotic waveforms can identify sites of arterial blockage.
Describe the imaging procedures to diagnose vascular obstruction and estimate lesion severity

Combinations of novel MRI techniques are currently being used in PAD research (Figure 2). Anderson et al. performed first-pass gadolinium calf muscle perfusion and 31P-MRS on 85 patients with mild to moderate PAD. Lesion severity was determined by MRA and symptoms were assessed by treadmill testing with VO2 max and a 6-minute walk test. They demonstrated multifactorial contributions to claudication. They found symptomatic PAD to be related to the severity of macrovascular obstruction along with atherosclerotic plaque burden, reduced tissue perfusion and abnormal energy metabolism

Several imaging tests can be used to diagnose PAD:

  • Vascular ultrasound. This exam uses sound waves to create pictures of the arteries and locate blockages.
  • Doppler ultrasound: Doppler ultrasound is a special ultrasound technique that can help detect areas of restricted blood flow through an artery.
  • Catheter angiography: This minimally invasive imaging exam relies on a contrast agent and x-rays to show blood flow in the arteries in the legs and to pinpoint any blockages that may be present. The contrast agent is injected through a tube or catheter that is usually placed through a blood vessel in the groin. See the Safety section for more information about x-rays.
  • CT angiography (CTA): CT angiography uses a CT scanner to produce detailed views of the arteries in your abdomen, pelvis and legs. This test is particularly useful in patients with pacemakers or stentsSee the Safety section for more information about CT.
  • MR angiography (MRA): MR angiography is a noninvasive test that gives information similar to that of a CT without the ionizing radiation. See the Safety sectionfor more information about MRI.

• Describe the treatment options for acute limb ischemia

Treatment[edit]

Surgery[edit]

The primary intervention in acute limb ischaemia is emergency embolectomy using a Fogarty Catheter, providing the limb is still viable within the 4-6h timeframe.[8] Other options include a vascular bypass to route blood flow around the clot.[9]

Medications[edit]

Those unsuitable for surgery may receive thrombolytics. In the past, streptokinase was the main thrombolytic chemical. More recently, drugs such as tissue plasminogen activator, urokinase, and anisterplase have been used in its place. Mechanical methods of injecting the thrombolytic compounds have improved with the introduction of pulsed spray catheters—which allow for a greater opportunity for patients to avoid surgery.[10][11] Pharmacological thrombolysis requires a catheter insert into the affected area, attached to the catheter is often a wire with holes to allow for a wider dispersal area of the thrombolytic agent. These agents lyse the ischemia-causing thrombus quickly and effectively.[12] However, the efficacy of thrombolytic treatment is limited by hemorrhagic complications. Plasma fibrinogen level has been proposed as a predictor of these hemorrhagic complications. However, based on a systemtic review of the available literature until January 2016, the predictive value of plasma is unproven.[13]

Mechanical thrombolysis[edit]

Another type of thrombolysis disrupts the clot mechanically using either saline jets or, more recently, ultrasound waves. Saline jets dislodge the clot using the Bernoulli effect. Ultrasound waves, emitted at low frequency, create a physical fragmentation of the thrombus.[14]

Considerations in treatment[edit]

The best course of treatment varies from case to case. The physician must take into account the details in the case before deciding on the appropriate treatment. No treatment is effective for every patient.

Treatment depends on many factors, including:

  • Location of lesions
  • Anatomy of lesions
  • Patient risk factors
  • Procedural risk
  • Clinical presentation of symptoms
  • Duration of symptoms
  • etc.[10]

Describe the treatment options for chronic lower limb ischemia

The primary goal is to preserve limb function. Revascularization is a fundamental strategy to limb preservation, but in some patients, this does not improve limb function and mobility.

Patients with CLI have a high risk of limb loss without revascularization and a high short term risk of cardiovascular events compared to less severe forms of chronic peripheral artery disease. Revascularization is indicated if it will prevent limb loss and preserve ambulation and function, while intensive medical therapy targets the risk factors for atherosclerosis progression and cardiovascular events. Endovascular revascularization offers a lower initial risk than open surgery, but recurrent disease from restenosis or new de-novo disease is common in patients with CLI. New drug-eluting balloons and stents offer better longer term outcomes after some endovascular revascularizations, but further long-term data on durability is required in order to assess their overall benefit given the increased costs of initial treatment. Close follow-up focusing on wound care and prevention, risk factor management, and surveillance for new and recurrent disease is required.
Review risk factor modification

The major risk factors for PAD are the well defined atherosclerotic risks such as diabetes mellitus, cigarette smoking, advanced age, hyperlipidemia, and hypertension. Due to the presence of these risk factors, the systemic nature of atherosclerosis, and the high risk of ischemic events, patients with PAD should be candidates for aggressive secondary prevention strategies including aggressive risk factor modification, antiplatelet therapy, lipid lowering therapy and antihypertensive treatment.
• Describe exercise therapy

Exercise therapy combined with comprehensive secondary prevention has the potential to benefit patients with PAD by preserving or improving functional capacity and reducing cardiovascular events.

Exercise training using treadmill walking has been used most frequently in clinical trials. The treadmill walking exercise prescription for patients with PAD and symptoms of intermittent claudication is outlined in Table 2. Patients with leg symptoms are instructed exercise to mild to moderate pain (3–4 of 5 on the claudication scale) and then stop. When claudication has resolved, the patient begins walking on the treadmill again.PAD patients without intermittent claudication should follow the exercise prescription for patients with cardiovascular disease as outlined in Table 3, where exercise intensity is guided by exercise tolerance test using heart rate reserve or oxygen uptake reserve.,In all patients with PAD, treadmill walking exercise is the preferred modality, but supplemental exercise using other exercise modalities including resistance training as recommended for patients with cardiovascular disease (Table 3) may be of additional benefit.,
Describe anti-platelet and anti-thrombotic therapy

Antiplatelet therapy reduces the risk of cardiovascular events and progression of local disease in patients with PAD. Low dose aspirin is the first – line antiplatelet drug since it is safe, easily accessible and most cost – effective among antiplatelet agents and clopidogrel is its effective alternative. There is no evidence to support the efficacy of combined antiplatelet treatment.
Oral anticoagulation therapy with warfarin alone or in combination with aspirin in not indicated to reduce the risk of cardiovascular events in PAD patients. However oral anticoagulants should be considered in certain patients with thrombembolic state or history of peripheral graft occlusions.
Describe the role of pentoxifylline and cilostazol in the treatment of intermittent claudication

Pentoxifylline and cilostazol are the only 2 prescription drugs labeled for treatment of intermittent claudication.

pentoxifylline

Pentoxifylline can decrease the muscle aching/pain/cramps during exercise, including walking, that occur with intermittent claudication. Pentoxifylline belongs to a class of drugs known as hemorrheologic agents. It works by helping blood flow more easily through narrowed arteries.

cilostazol

Cilostazol is an antiplatelet drug and a vasodilator. It works by stopping blood cells called platelets from sticking together and prevents them from forming harmful clots. It also widens blood vessels in the legs. Cilostazol helps the blood to move more easily and keeps blood flowing smoothly in your body.

Using a treadmill protocol and assessed by intention-to treat analysis, cilostazol increased the maximal walking distance by 54% over baseline (average=107 m), compared with a 30% increase with pentoxifylline (P <.001) and a 34% increase in the placebo group (P <.001)
Briefly review revascularization procedures

Endovascular intervention for the treatment of limb ischemia has become the first line of therapy in many centers.7-9 Vascular surgeons and cardiologists perform endovascular interventions in most centers;10

There are several reasons for the rapid growth of endovascular revascularization. First, endovascular interventions fall under the broad category of minimally invasive surgery, making it more attractive to patients. In the past, patients with critical limb ischemia would have undergone surgical revascularization provided their general condition allowed it; if not, they would either receive no treatment or perhaps undergo an amputation. However, studies have shown that even in octogenarians, endovascular interventions are associated with improved outcomes.11 Similarly, patients with claudication who would have avoided surgery in the past now elect to have endovascular revascularization because of the minimally invasive nature of these procedures.3
• Discuss the prognosis of peripheral arterial disease

Especially in patients with PAD, high incidences of coronary artery disease (CAD) have been observed, which may be asymptomatic or symptomatic. The prognosis of patients with PAD is related to the presence and extent of underlying CAD. In patients with PAD undergoing major vascular surgery, cardiac complications are the major cause of perioperative morbidity and mortality and indicate a high-risk for adverse long-term cardiac outcome. In order to improve outcome for PAD patients, assessment and aggressive therapy of atherosclerotic risk factors and usage of cardio-protective medications is recommended. Unfortunately, substantial differences in risk factor management and treatment and long-term outcome have been reported between PAD and CAD patients.


Hypertensive Crisis
A 26-year-old primigravida presents for her routine 6-week postpartum evaluation. Other than fatigue, which she attributes to doting on her newborn, she has no complaints. The pregnancy was complicated by pregnancy-induced hypertension, which required induction at 34 + 2 weeks and culminated in an abdominal delivery due to a protracted latent phase. The physical examination was significant for a BP of 210/130 mmHg. Of note, the pre-pregnancy BP was 110/72 mmHg and the BP was 118/84 mmHg on methyldopa (500 mg bid) at the time of discharge from the postpartum ward.

• Discuss the determinants of blood pressure regulation

  • Blood Volume – the more volume of blood present means that the vessels and heart have to work hard to pump that blood through the Circulatory system.
  • Overall Compliance – the elastic characteristics of the vessels contribute to the overall pressure in the vessels. When the vessels have expanded the blood pressure is lowered and if it recoils blood pressure will increase.
  • Cardiac Output – CO is related to two other factors: heart rate and stroke volume. When the heart rate is fast, CO is increases and when stroke volume is high, CO also increases. Therefore when CO increases, then the arterial pressure will also increase.
  • Peripheral Resistance – the resistance of the arteries is related to the Overall Compliance Characteristic. When peripheral resistance increases, the overall compliance decreases and thus the arterial blood pressure increases.

Genetic: 

Blood pressure homeostasis in humans reflects the coordinate interactions of cardiac output, peripheral vascular resistance, renal volume control, and CNS integration in response to short- and long-term environmental stimuli. Variations in mean arterial pressure within the population include a significant hereditary component. The clearest examples of this genetic contribution occur in rare forms of monogenic hypertension (glucocorticoid remediable aldosteronism, apparent mineralocoid excess, Liddle’s syndrome) or hypotension (pseudohypoaldosteronism type I, Bartter’s syndrome, Gitelman’s syndrome). Primary hypertension, which comprises approximately 95% of hypertensives and is a major risk factor for coronary heart disease, stroke, and renal disease in the U.S., represents a multifactorial and polygenic disease with incremental contributions from genetic and environmental determinants.

The kidneys provide a hormonal mechanism for the regulation of blood pressureby managing blood volume. The renin‐angiotensin‐aldosterone system of the kidneys regulates blood volume. … Angiotensin II constricts blood vessels throughout the body (raising blood pressure by increasing resistance to bloodflow).
• Discuss the role of chemoreceptors in blood pressure regulation

Chemoreceptors are chemicals that collect information about the environment affecting an organism. In the human body, chemoreceptors collect information about the level of oxygen or carbon dioxide in the bloodstream.

Central chemoreceptors: Located within the medulla, they are sensitive to the pH of their environment. peripheral chemoreceptors: The aoritic and carotid bodies, which act principally to detect variation of the oxygen concentration in the arterial blood, also monitor arterial carbon dioxide and pH.

  • Chemoreceptors sense levels of oxygen, carbon dioxide, and pH
  • Peripheral chemoreceptors
    • carotid bodies in the carotid sinus and aortic bodies along the aortic arch
    • sensitive to
      • ↓ partial pressure of oxygen (PO
        2) (< 60 mmHg)
      • ↓ pH
      • ↑ partial pressure of CO
        2 (PCO
        2)
    • chemoreceptors are more sensitive to changes in PO
      2 if ↑ PCO
      2 or ↓ pH
    • response to ↓ arterial PO
      2

      • ↑ firing of afferent nerves
      • ↑ sympathetic outflow
        • ↑ vasoconstriction
      • ↑ parasympathetic outflow
        • ↓ heart rate (transient)
      • ↑ ventilation
  • Central chemoreceptors
    • located in the medulla
    • sensitive to ↑ or ↓ in PCO
      2 or pH
    • response to brain ischemia
      • ↓ pH and ↑ PCO
        2 immediately
      • ↑ sympathetic outflow
        • ↑ vasoconstriction → ↑ TPR
        • blood flow shunted to the brain to maintain perfusion

• Discuss the role of the renin-angiotensin-aldosterone system in blood pressure regulation

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The renin-angiotensin system or RAS regulates blood pressure and fluid balance in the body. When blood volume or sodium levels in the body are low, or blood potassium is high, cells in the kidney release the enzyme, renin. Renin converts angiotensinogen, which is produced in the liver, to the hormone angiotensin I. An enzyme known as ACE or angiotensin-converting enzyme found in the lungs metabolizes angiotensin I into angiotensin II. Angiotensin II causes blood vessels to constrict and blood pressure to increase. Angiotensin II stimulates the release of the hormone aldosterone in the adrenal glands, which causes the renal tubules to retain sodium and water and excrete potassium. Together, angiotensin II and aldosterone work to raise blood volume, blood pressure and sodium levels in the blood to restore the balance of sodium, potassium, and fluids. If the renin-angiotensin system becomes overactive, consistently high blood pressure results.
• Discuss the relationship between extracellular fluid volume and blood pressure

 

Differences in plasma volume cap influence choice of antihypertensive therapy; patients with expanded volume tend also to have slightly exchangeable sodium and greater extracellular fluid (ECF) volume and to respond well to diuretic therapy. There is also some evidence that low plasma renin activity is more frequent among hypervolemic patients.

Regharding sodium:

Dietary salt is the major cause of the rise in the blood pressure with age and the development of high blood pressure in populations. However, the mechanisms whereby salt intake raises the blood pressure are not clear. Existing concepts focus on the tendency for an increase in extracellular fluid volume (ECV), but an increased salt intake also induces a small rise in plasma sodium, which increases a transfer of fluid from the intracellular to the extracellular space, and stimulates the thirst center. Accordingly, the rise in plasma sodium is responsible for the tendency for an increase in ECV. Although the change in ECV may have a pressor effect, the associated rise in plasma sodium itself may also cause the blood pressure to rise. There is some evidence in patients with essential hypertension and the spontaneously hypertensive rat (SHR) that plasma sodium may be raised by 1 to 3 mmol/L. An experimental rise in sodium concentration greater than 5 mmol/L induces pressor effects on the brain and on the renin-angiotensin system. Such a rise can also induce changes in cultured vascular tissue similar to those that occur in the vessels of humans and animals on a high sodium diet, independent of the blood pressure. We suggest that a small increase in plasma sodium may be part of the mechanisms whereby dietary salt increases the blood pressure.
• Discuss pressure natriuresis

  • Pressure Natriuresis appears to be the dominant physiological mechanism that connects changes in the systemic arterial pressure to changes in total body sodium amount. Pressure natriuresis acts by increasing renal sodium excretion when incoming arterial pressure to the kidneys rises. The mechanism operates completely autonomously within the kidneys and independently of any external neurohormonal regulatory mechanisms. Its importance in connecting renal sodium transport to arterial pressure renders pressure natriuresis the dominant mechanism of both ECF Volume Regulation and Systemic Arterial Pressure – Long-term Regulation.
Mechanism
  • The mechanism of pressure natriuresis is not completely understood but changes in the peritubular capillary transport likely underlie its operation. As incoming arterial pressure to the kidneys increases, the hydrostatic pressure within the peritubular capillaries also increases. This reduces the starling force for fluid resorption into the capillaries from the renal interstitial fluid. With reduced peritubular capillary resorption, water and salt appear to backleak into the tubule, yielding enhanced urinary sodium excretion.

• Discuss the pro- and anti-hypertensive properties of endothelin-1

ET-1 contributes to the vascular dysfunction associated with cardiovascular disease, particularly atherosclerosis and hypertension.[14] The ETA receptor for ET-1 is primarily located on vascular smooth muscle cells, mediating vasoconstriction, whereas the ETB receptor for ET-1 is primarily located on endothelial cells, causing vasodilation due to nitric oxide release.[14]

The binding of platelets to the endothelial cell receptor LOX-1 causes a release of endothelin, which induces endothelial dysfunction.[15]

Endothelins are the most potent vasoconstrictors known.[1][11] Overproduction of endothelin in the lungs may cause pulmonary hypertension, which was treatable in preliminary research by bosentansitaxentan or ambrisentan.[1]

Endothelins have involvement in cardiovascular function, fluid-electrolyte homeostasis, and neuronal mechanisms across diverse cell types.[1] Endothelin receptors are present in the three pituitary lobes[12] which display increased metabolic activity when exposed to endothelin-1 in the blood or ventricular system.[13]

• Discuss the role of nitric oxide in hypertension

We know that – Hypertension is a major risk factor for cardiovascular disease, and reduction of elevated blood pressure significantly reduces the risk of cardiovascular events.

Endothelial dysfunction, which is characterized by impairment of nitric oxide (NO) bioavailability, is an important risk factor for both hypertension and cardiovascular disease and may represent a major link between the conditions. Evidence suggests that NO plays a major role in regulating blood pressure and that impaired NO bioactivity is an important component of hypertension.

Mice with disruption of the gene for endothelial NO synthase have elevated blood pressure levels compared with control animals, suggesting a genetic component to the link between impaired NO bioactivity and hypertension.

Clinical studies have shown that patients with hypertension have a blunted arterial vasodilatory response to infusion of endothelium-dependent vasodilators and that inhibition of NO raises blood pressure. Impaired NO bioactivity is also implicated in arterial stiffness, a major mechanism of systolic hypertension. Clarification of the mechanisms of impaired NO bioactivity in hypertension could have important implications for the treatment of hypertension.
• Discuss the role of ANP in blood pressure regulation

Atrial natriuretic peptide (ANP) or Atrial natriuretic factor (ANF) is a peptide hormone which reduces an expanded extracellular fluid (ECF) volume by increasing renal sodium excretion. ANP is synthesized, and secreted by cardiac muscle cells in the walls of the atria in the heart. These cells contain volume receptors which respond to increased stretching of the atrial wall due to increased atrial blood volume. ANP is one of a family of nine natriuretic peptides: seven are atrial in origin.

ANP acts on the kidney to increase sodium and water excretion (natriuresis) in the following ways: 1) it dilates the glomerular afferent and constricts efferent arterioles, and relaxes the mesangial cells. This increases pressure in the glomerular capillaries, increasing the glomerular filtration rate (GFR), resulting in an increased amount of sodium and water being filtered and excreted. 2) It increases blood flow through the vasa recta, which washes the solutes sodium chloride (NaCl) and urea out of the medullary interstitium – the lower osmolarity here leads to less reabsorption of tubular fluid and increased excretion. 3) It decreases sodium reabsorption in the distal convoluted tubule and cortical collecting duct. 4) It inhibits renin secretion, thereby inhibiting the production of angiotensin and aldosterone. 5) It inhibits the renal sympathetic nervous system. ANP has the opposite effect of aldosterone on the kidney: aldosterone increases renal sodium retention and ANP increases renal sodium loss.[5][6]

Reduction of blood volume by ANP can result in secondary effects such as reduction of extracellular fluid (ECF) volume (edema), improved cardiac ejection fraction with resultant improved organ perfusion, decreased blood pressure, and increased serum potassium. These effects may be blunted or negated by various counter-regulatory mechanisms operating concurrently on each of these secondary effects.
• What is the differential diagnosis for a hypertensive crisis?

Anxiety Disorders
Panic attack
Obstructive Sleep Apnea
Steroid use
Use of over-the-counter drugs
Recreational sympathomimetic drugs
Amphetamine Toxicity
Phencyclidine Toxicity
Cocaine-Related Cardiomyopathy
Pheochromocytoma
Acute vasculitis
Serotonin syndrome
Coarctation of the aorta
Aortic Dissection
Heart Failure
Hyperthyroidism; Thyrotoxicosis; Thyroid Storm; Graves Disease
Hypertrophic Cardiomyopathy
Myocardial Infarction
Primary Aldosteronism
Subarachnoid Hemorrhage
Stroke, Hemorrhagic
Stroke, Ischemic
CNS pathology
Eclampsia; Preeclampsia
Acute Kidney Injury
Chronic Kidney Disease
Renal Artery Stenosis
Thrombotic Thrombocytopenic Purpura (TTP)
Hypercalcemia

**Among other things, consider to r/o the causes of secondary hypertension in patients with hypertensive urgency or emergency.
• Discuss the drugs which are indicated for hypertensive emergencies

PARENTERAL DRUGS — A variety of parenteral and oral antihypertensive drugs are available for use in these patients (table 1) [1-5]. Few studies have compared these agents with one another, and all are tolerated reasonably well [6,7]. Thus, the drug of choice is often dictated by the type of hypertensive emergency and the local hospital formulary. (See “Moderate to severe hypertensive retinopathy and hypertensive encephalopathy in adults” and “Evaluation and treatment of hypertensive emergencies in adults”.)

Nitrates — Nitrovasodilators such as nitroprusside and nitroglycerin provide nitric oxide that induces vasodilatation (of both arterioles and veins) via generation of cyclic GMP, which then activates calcium-sensitive potassium channels in the cell membrane [8].

Nitroprusside — Sodium nitroprusside, when administered by intravenous infusion, begins to act within one minute or less, and once discontinued, its effects disappear within 10 minutes or less. Frequent monitoring is required since this drug can produce a sudden and drastic drop in blood pressure.

The recommended starting dose of nitroprusside is 0.25 to 0.5 mcg/kg per minute. This can be increased as necessary to a maximum dose of 8 to 10 mcg/kg per minute, although use of these higher doses should generally be avoided or limited to a maximum duration of 10 minutes [9].

Toxicities and limitations of nitroprusside include:

Nitroprusside is metabolized to cyanide, possibly leading to the development of cyanide (or, rarely, thiocyanate) toxicity that may be fatal [9]. This problem, which can manifest in as little as four hours, presents with altered mental status and lactic acidosis. Risk factors for nitroprusside-induced cyanide poisoning include a prolonged treatment period (>24 to 48 hours), underlying renal impairment, and the use of doses that exceed the capacity of the body to detoxify cyanide (ie, more than 2 mcg/kg per minute). The risk of toxicity can be minimized by using the lowest possible dose, avoiding prolonged use (ie, no more than two or three days), and by careful patient monitoring (with special attention to unexplained acidemia or decreasing serum bicarbonate concentrations).

In addition, doses of 10 mcg/kg per minute should never be given for more than 10 minutes. An infusion of sodium thiosulfate can be used in affected patients to provide a sulfur donor to detoxify cyanide into thiocyanate [9].

Nitroprusside can result in dose-related declines in coronary, renal, and cerebral perfusion.

Nitroprusside should not be given to pregnant women, patients with Leber’s optic atrophy, or patients with tobacco amblyopia. In addition, nitroprusside should be avoided, if possible, in patients with impaired renal function. (See ‘Fenoldopam’ below.)

The high cost of nitroprusside may limit its availability in some settings (see Nitroprusside: Drug information, section Pricing: US).

Nitroglycerin — Nitroglycerin is also administered by intravenous infusion and is similar in action and pharmacokinetics to nitroprusside except that it produces relatively greater venodilation than arteriolar dilation. It has less antihypertensive efficacy compared with other drugs used to treat hypertensive emergencies, and its effects on blood pressure are variable from person to person and, potentially, from minute to minute. However, it may be useful in patients with symptomatic coronary disease and in those with hypertension following coronary bypass.

The initial dose of nitroglycerin is 5 mcg/min, which can be increased as necessary to a maximum of 100 mcg/min. The onset of action is 2 to 5 minutes, while the duration of action is 5 to 10 minutes. Headache (due to direct vasodilation) and tachycardia (resulting from reflex sympathetic activation) are the primary adverse effects. Cyanide accumulation does not occur. Methemoglobinemia has been reported in patients receiving this agent for more than 24 hours.

Calcium channel blockers

Clevidipine — Clevidipine is an ultra short-acting dihydropyridine calcium channel blocker that is approved for intravenous use to treat severe hypertension. The drug is hydrolyzed by serum esterases and has a serum elimination half-life of 5 to 15 minutes. It reduces blood pressure without affecting cardiac filling pressures but can cause reflex tachycardia [1,10]. Clevidipine is contraindicated in patients with severe aortic stenosis (because it increases the risk of severe hypotension), disordered lipid metabolism (because it is administered in a lipid-laden emulsion), or known allergies to soy or eggs (because these are used to produce the emulsion). It has not been compared with other short-acting drugs, such as nitroprusside and nitroglycerin. The initial dose is 1 mg/hour, which can be increased as necessary to a maximum of 21 mg/hour.

Nicardipine — Nicardipine is a dihydropyridine calcium channel blocker (like nifedipine) that can be given as an intravenous infusion. The initial dose is 5 mg/hour and can be increased to a maximum of 15 mg/hour. Nicardipine has a better safety profile and a similar antihypertensive effect when compared with nitroprusside [11]. The major limitations are a longer onset of action, which precludes rapid titration, and a longer serum elimination half-life (three to six hours).

Dopamine-1 agonist

Fenoldopam — Fenoldopam is a peripheral dopamine-1 receptor agonist which, unlike other parenteral antihypertensive agents, maintains or increases renal perfusion while it lowers blood pressure [12]. Fenoldopam may be particularly beneficial in patients with renal impairment. After starting at 0.1 mcg/kg per minute, the dose can be titrated at 15-minute intervals to 1.6 mcg/kg per minute, depending upon the blood pressure response. Some experts have used doses as high as 2.0 mcg/kg per minute or higher without inducing toxicity.

Fenoldopam should be used cautiously or not at all in patients with glaucoma [12]. In addition, because this agent is premixed in a solution containing sodium metabisulfite, caution is recommended for patients with sulfite sensitivity.

Adrenergic-blocking agents

Labetalol — Labetalol is a combined beta-adrenergic and alpha-adrenergic blocker. Its rapid onset of action (five minutes or less) makes it a useful intravenous medication for the treatment of hypertensive emergencies. However, one trial found that labetalol has less antihypertensive efficacy as compared with nicardipine [13].

Labetalol is safe in patients with active coronary disease since it does not increase heart rate. However, labetalol should be avoided in patients with asthma, chronic obstructive lung disease, heart failure, bradycardia, or greater than first-degree heart block. In addition, labetalol should not be used without prior adequate alpha blockade in patients with hyperadrenergic states, such as pheochromocytoma or cocaine or methamphetamine overdose, since unopposed, inadequately blocked alpha-adrenergic activity can increase blood pressure if beta blockade is not complete. (See “Cocaine: Acute intoxication”.)

Labetalol can be given as a series of intravenous bolus injections or as a constant-dose infusion. The bolus dose is 20 mg initially, followed by 20 to 80 mg every 10 minutes to a total dose of 300 mg. The infusion rate is 0.5 to 2 mg/min.

Esmolol — Esmolol, a relatively cardioselective beta blocker, is rapidly metabolized by blood esterases. Its effects begin almost immediately, and it has both a short half-life (about 9 minutes) and a short total duration of action (about 30 minutes), permitting rapid titration. Esmolol is often used during anesthesia to prevent postintubation hemodynamic perturbations.

Other agents

Hydralazine — Hydralazine is a direct arteriolar vasodilator with little or no effect on the venous circulation. Thus, precautions are needed in patients with underlying coronary disease or aortic dissection, and a beta blocker should be given concurrently to minimize reflex sympathetic stimulation. The hypotensive response to hydralazine is less predictable than that seen with other parenteral agents. The use of parenteral hydralazine is primarily limited to pregnant women, although a reduction in the utero-placental blood flow has been reported in such patients. (See “Management of hypertension in pregnant and postpartum women”.)

Hydralazine can be given as an intravenous bolus. The initial dose is 10 mg, with the maximum dose being 20 mg. The fall in blood pressure can be sudden and begins within 10 to 30 minutes and lasts two to four hours.

Enalaprilat — Enalaprilat is the intravenously active, des-ethyl ester of the angiotensin-converting enzyme (ACE) inhibitor, enalapril. The hypotensive response to enalaprilat is unpredictable and depends upon the plasma volume and plasma renin activity in individual patients with a hypertensive emergency [14]. Typically, hypovolemic patients with a high plasma renin activity are most likely to have an excessive hypotensive response. In addition, ACE inhibitors are contraindicated in pregnancy, severe renal artery stenosis with global ischemia, and severe hyperkalemia. (See “Adverse effects of angiotensin converting enzyme inhibitors and receptor blockers in pregnancy”.)

The usual initial dose is 1.25 mg. As much as 5 mg may be given every six hours as necessary [14]. The onset of action begins in 15 minutes, but the peak effect may not be seen for four hours. The duration of action ranges from 12 to 24 hours.

Phentolamine — Phentolamine is a nonselective alpha-adrenergic blocker, the use of which is limited to the treatment of severe hypertension due to increased catecholamine activity. Examples include pheochromocytoma or tyramine ingestion in a patient being treated with a monoamine oxidase inhibitor. (See “Clinical presentation and diagnosis of pheochromocytoma” and “Treatment of pheochromocytoma in adults”.)

Phentolamine is given as an intravenous bolus. The usual dose is 10 to 15 mg every 5 to 15 minutes as necessary. Patients receiving this agent who do not require intravenous therapy can be converted to oral phenoxybenzamine.

ORAL DRUGS — Oral antihypertensive agents usually lower the blood pressure more slowly than parenteral drugs. Thus, they are primarily used when parenteral agents are not available or when there is severe hypertension without serious acute end-organ damage; see Management of severe asymptomatic hypertension (hypertensive urgencies) in adults for a discussion of this issue, and see Moderate to severe hypertensive retinopathy and hypertensive encephalopathy in adults.

• Discuss the long-term management of this patient

A 26-year-old primigravida presents for her routine 6-week postpartum evaluation. Other than fatigue, which she attributes to doting on her newborn, she has no complaints. The pregnancy was complicated by pregnancy-induced hypertension, which required induction at 34 + 2 weeks and culminated in an abdominal delivery due to a protracted latent phase. The physical examination was significant for a BP of 210/130 mmHg. Of note, the pre-pregnancy BP was 110/72 mmHg and the BP was 118/84 mmHg on methyldopa (500 mg bid) at the time of discharge from the postpartum ward.

The next times she gets pregnant…tell her doc…and have meds ready. Monitor during pregnancy? There is no indication she is obese… and her pre-pregnancy BP was ok…on methyldopa.

Methyldopa, sold under the brand name Aldomet among others, is a medication used for high blood pressure. It is one of the preferred treatments for high blood pressure in pregnancy.

 

 


Vasovagal Syncope
A 32-year-old chief boatswain mate, generally known among his shipmates to be fearless and intimidating, was noted to be pale and diaphoretic as the ship’s corpsman readied him for venipuncture during shipwide HIV screening. Fortunately, 4 of his shipmates slowly lowered his 250-pound frame to the ground when he lost consciousness.

• Discuss the different causes of syncope

There are several different types of syncope. The type you have depends on what causes the problem.

Vasovagal syncope (also called cardio-neurogenic syncope)

Vasovagal syncope is the most common type of syncope. It is caused by a sudden drop in blood pressure, which causes a drop in blood flow to the brain. When you stand up, gravity causes blood to settle in the lower part of your body, below your diaphragm. When that happens, the heart and autonomic nervous system (ANS) work to keep your blood pressure stable.

Some patients with vasovagal syncope have a condition called orthostatic hypotension. This condition keeps the blood vessels from getting smaller (as they should) when the patient stands. This causes blood to collect in the legs and leads to a quick drop in blood pressure.

Situational syncope

Situational syncope is a type of vasovagal syncope. It happens only during certain situations that affect the nervous system and lead to syncope. Some of these situations are:

  • Dehydration
  • Intense emotional stress
  • Anxiety
  • Fear
  • Pain
  • Hunger
  • Use of alcohol or drugs
  • Hyperventilation (breathing in too much oxygen and getting rid of too much carbon dioxide too quickly)
  • Coughing forcefully, turning the neck, or wearing a tight collar (carotid sinus hypersensitivity)
  • Urinating (miturition syncope)

Postural syncope (also called postural hypotension)

Postural syncope is caused by a sudden drop in blood pressure due to a quick change in position, such as from lying down to standing. Certain medications and dehydration can lead to this condition. Patients with this type of syncope usually have changes in their blood pressure that cause it to drop by at least 20 mmHg (systolic/top number) and at least 10 mmHg (diastolic/bottom number) when they stand.

Cardiac syncope is caused by a heart or blood vessel condition that affects blood flow to the brain. These conditions can include an abnormal heart rhythm (arrhythmia), obstructed blood flow in the heart due to structural heart disease (the way the heart is formed), blockage in the cardiac blood vessels (myocardial ischemia), valve disease, aortic stenosis, blood clot, or heart failure. If you have cardiac syncope, it is important to see a cardiologist for proper treatment.

Neurologic syncope

Neurologic syncope is caused by a neurological condition such as seizure, stroke or transient ischemic attack (TIA). Other less common conditions that lead to neurologic syncope include migraines and normal pressure hydrocephalus

Postural Orthostatic Tachycardia Syndrome (POTS)

Postural-Orthostatic Tachycardia Syndrome is caused by a very fast heart rate (tachycardia) that happens when a person stands after sitting or lying down. The heart rate can speed up by 30 beats per minute or more. The increase usually happens within 10 minutes of standing. The condition is most common in women, but it can also occur in men.

Unknown Causes of Syncope

The cause of syncope is unknown In about one-third of patients. However, an increased risk of syncope is a side effect for some medications.
• Discuss the alterations in autonomic activation that characterize syncope

How is the autonomic nervous system involved in the onset of syncope? It is primarily responsible for sympathetic responses toward environmental challenges. The most frequent challenge triggering syncope might be a postural change (Figure  (Figure1).1). Syncope or fainting associated with orthostatic challenge includes vasovagal syncope (or in a wider sense, neurally mediated syncope) and orthostatic syncope (or orthostatic intolerance). The symptoms of these two situations seem to be the same, but the pathophysiology is different; they involve opposite directions of pathways of the autonomic nervous system.

So—The autonomic nervous system plays a central role in the maintenance of hemodynamic stability. Dysfunction of this complex regulatory system can lead to the development of loss of consciousness.

The pronunciation of “syncope” can differ from person to person; however, [síηkəpi] seems to be generally accepted, meaning “strike” or “cut-off” in ancient Greek.

The human autonomic nervous system regulates the systemic arterial pressure to maintain constant cerebral perfusion under conditions of uneven fluid shift caused by postural change. Syncope is the state of failure of this regulating function.

Many forms of syncope are preceded by a prodromal state that often includes dizziness and loss of vision, loss of hearing, loss of pain and feeling, nausea and abdominal discomfort, weakness, cold sweating, a feeling of hotness, palpitations and other phenomena, which are often called “presyncope” (Reeves and Swenson, ).

• Discuss baroreceptor reflexes

Baroreceptors are integral to the body’s function: Pressure changes in the blood vessels would not be detected as quickly in the absence of baroreceptors. When baroreceptors are not working, blood pressure continues to increase, but, within an hour, the blood pressure returns to normal as other blood pressure regulatory systems take over.[9]

Baroreceptors can also become oversensitive in some people (usually the carotid baroreceptors in older males). This can lead to bradycardia, dizziness and fainting (syncope) from touching the neck (often whilst shaving). This is an important cause to exclude in men having pre-syncope or syncope symptoms.

Baroreceptors are situated at the carotid sinus and the aortic arch; they monitor the arterial pressure and transmit information on this pressure to the central nervous system (Mathias and Bannister, ). Upon extension of the arterial wall by the raising of the blood pressure, the baroreceptors (stretch receptors) generate an impulse depending on the arterial pressure via the glossopharyngeal nerve (CN IX) from the carotid sinus and via the vagus nerve (CN X) from the aortic arch, and transmit the signals to the nucleus tractus solitarius (NTS) in the medulla.
• Discuss the carotid sinus reflex

Carotid sinus reflex death[edit]

Carotid sinus reflex death is a potential etiology[10] of sudden death in which manual stimulation of the carotid sinus allegedly causes strong glossopharyngeal nerve (Vagus nerve is for aortic arch baroreceptors) impulses leading to terminal cardiac arrest. Carotid sinus reflex death has been pointed out as a possible cause of death in cases of strangulationhanging and autoerotic strangulation, but such deductions remain controversial. Studies[citation needed] have also suggested that the carotid sinus reflex can be a contributing factor in other mechanisms of death by reducing blood pressure and heart rate, especially in the elderly or in people suffering from carotid sinus hypersensitivity. A carotid massage can also possibly dislodge a thrombus, or some plaque. This could lead to any number of life-threatening effects, including stroke.[11]
• Discuss the symptoms which characterize syncope

The sign of fainting is a sudden loss of consciousness.

The following signs and symptoms may happen before a fainting episode:

  • a feeling of heaviness in the legs
  • blurred or “tunnel” vision
  • confusion
  • feeling warm or hot
  • lightheadedness, dizziness, a floating feeling
  • nausea
  • sweating
  • vomiting
  • yawning.

When a person faints, they may:

  • fall over or slump
  • appear unusually pale
  • experience a drop in blood pressure and a weak pulse

• What are the elements of the medical history for a patient with syncope?

Syncope versus seizure

Every year, many patients experiencing syncope are wrongly diagnosed with epilepsy and vice versa, with long term consequences. It is very important to distinguish these two classically similar events. In addition to the three characteristics above, it is helpful to think in terms of what happened before, during and after the event.

Before

Was there a trigger?

This is an extremely useful piece of information for any presenting complaint but particular so in a loss of consciousness history. Syncope often includes an immediate preceding trigger such as emotion, pain or exercise.

Was there a prodrome?

Syncope often involves an immediate warning (called ‘pre-syncope’), consisting of symptoms such as feeling faint, dizzy, sick, visual disturbances and a ringing in the ears (tinnitus). The presence of palpitations or other cardiac symptoms suggests a cardiac cause of syncope.

 

Did the patient change colour?

Pallor occurs from systemic hypotension, thus indicating syncope. A blue colour (cyanosis) occurs from transient loss of respiratory muscle action in any seizure beginning with a tonic phase (e.g. generalised tonic-clonic seizure).

 

During

How long did the unconsciousness last?

Typically seconds in syncope (often longer in seizures).

 

Was there a convulsion?

Convulsions may occur in both and thus do NOT distinguish between the two. However specific patterns (e.g. tonic-clonic) may be recognisable if the eye witness provides a detailed, reliable account.

 

Was there tongue biting?

Although this can rarely happen in syncope, this is more strongly associated with seizures.

 

Was there urinary incontinence?

Urinary and faecal incontinence are more strongly associated with seizures and not a typical feature of syncope (although not impossible).

 

After

How long did it take for full recovery?

Seizures are followed by a postictal fatigue lasting hours, in contrast syncope is usually followed by near immediate complete recovery with no lasting effects.
• What specialized testing is appropriate for patients with syncope?

The history, examination, and initial ECG are the most important steps in the assessment of syncope. From the initial clinical assessment the direction of investigation can be constructed. The older patient with ischaemic heart disease and a low ejection fraction should be directed towards those investigations looking for ventricular arrhythmias.

  • Laboratory testing: Blood work to check for anemia or metabolic changes.
  • Electrocardiogram (EKG or ECG): A test that records the electrical activity of your heart. Electrodes (small sticky patches) are applied to your skin to collect this information.
  • Exercise stress test: A test that uses an ECG to record your heart’s electrical activity while you are active. This is done on a treadmill or stationary bike, which helps you reach a target heart rate.
  • Ambulatory monitor: You will wear a monitor that uses electrodes to record information about your heart’s rate and rhythm.
  • Echocardiogram: A test that uses high-frequency sound waves to create an image of the heart structures.
  • Tilt table (head-up tilt test): A test that records your blood pressure and heart rate on a minute-by-minute or beat-by-beat basis while the table is tilted to different levels as you stay head-up. The test can show abnormal cardiovascular reflexes that cause syncope.
  • Blood volume determination: A test to see if you have the right amount of blood in your body, based on your gender, height and weight. A small amount of a radioactive substance (tracer) is injected through an intravenous (IV) line placed in a vein in your arm. Blood samples are then taken and analyzed. The blood volume analyzer system used at Cleveland Clinic can provide accurate test results within 35 minutes.
  • Hemodynamic testing: A test to check the blood flow and pressure inside your blood vessels when your heart muscle contracts and pumps blood throughout the body. A small amount of a radioactive substance (tracer) is injected through an intravenous (IV) line placed in a vein in your arm and three sets of images are taken.
  • Autonomic reflex testing: A series of different tests are done to monitor blood pressure, blood flow, heart rate, skin temperature and sweating in response to certain stimuli. These measurements can help your doctor determine if your autonomic nervous system is working normally or if there is nerve damage.

Vestibular function testing may be done to rule-out problems in the inner ear.
• What is the differential diagnosis for syncope?

A 32-year-old chief boatswain mate, generally known among his shipmates to be fearless and intimidating, was noted to be pale and diaphoretic as the ship’s corpsman readied him for venipuncture during shipwide HIV screening. Fortunately, 4 of his shipmates slowly lowered his 250-pound frame to the ground when he lost consciousness.

The differential diagnosis should include nontraumatic causes of transient loss of consciousness. Rare causes include subclavian steal syndrome, pulmonary embolism, acute myocardial infarction, acute aortic dissection, leaking aortic aneurysm, subarachnoid hemorrhage, and cardiac tamponade.2,

For this person, I would guess, dehydration…or heatstroke as a differential.
• Discuss the factors that affect cerebral perfusion

Cerebral metabolic rate (CMR), autoregulation, CO2 reactivity, and O2 reactivity are the main factors affecting cerebral blood flow (CBF). Temperature and anesthetic medications also each influence CBF.

The cerebral metabolic rate

The brain consumes O2 at a high rate. Although accounting for only about 2% of total body weight, the brain receives 12% to 15% of cardiac output. Increases in regional brain activity lead to local increases in CMR that, in turn, lead to proportional changes in CBF cerevral blood flow–. This relationship is carefully maintained and is called flow-metabolism coupling.

The CMR decreases during sleep, increases with increasing mental activity, and may reach an extremely high level with epileptic activity. The CMR is globally reduced in coma and may be only locally impaired after brain injury.

Autoregulation

Autoregulation is defined as the maintenance of CBF over a range of mean arterial pressure (MAP) (see Figure 42-1). Cerebral vascular resistance (CVR) is adjusted to maintain constant CBF. Cerebral perfusion pressure equals MAP minus intracranial pressure (ICP). Because ICP (and therefore cerebral perfusion pressure) is not commonly available, MAP is used as a surrogate of cerebral perfusion pressure.

Autoregulation occurs when MAP is between 70 and 150 mm Hg in the normal brain (see Figure 42-1). This is a conservative estimate, given that considerable interindividual variation occurs. The lower limit of autoregulation (LLA) is the point at which the autoregulation curve deflects downward and CBF begins to decrease in proportion to MAP.

CVR — Cerebral vascular resistance

— varies directly with blood pressure to maintain flow, taking 1 to 2 min for flow to adjust after an abrupt change in blood pressure. In hypertensive patients, the autoregulatory curve is shifted to the right (Figure 42-2). A hypertensive patient may be at risk for developing brain ischemia at a MAP of 70 mm Hg, for example, because the LLA will be higher than in a nonhypertensive patient. Several weeks of blood pressure control may return the curve to normal. Following significant hypotension (lower than the LLA), autoregulation is impaired, and hyperemia may occur when MAP returns to the normal range. CO2 reactivity remains intact, and inducing hypocapnia may attenuate hyperemia.

• What treatment should be implemented in patients with vasovagal syncope?

Treatment

In most cases of vasovagal syncope, treatment is unnecessary. Your doctor may help you identify your fainting triggers and discuss ways you might avoid them.

However, if you experience vasovagal syncope often enough to interfere with your quality of life, your doctor may suggest trying one or more of the following remedies.

Medications

Fludrocortisone acetate is normally used to treat low blood pressure may be helpful in preventing vasovagal syncope. Selective serotonin inhibitors may also be used.

Therapies

Your doctor may recommend ways to decrease the pooling of blood in your legs. These may include foot exercises, wearing compression stockings or tensing your leg muscles when standing.

You may need to increase salt in your diet if you don’t usually have high blood pressure. Avoid prolonged standing — especially in hot, crowded places — and drink plenty of fluids.

Surgery

Very rarely, inserting an electrical pacemaker to regulate the heartbeat may help some people with vasovagal syncope who haven’t been helped by other treatments.

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