Heart Disease Eating Plan

Your Heart and Nutrition

Your Heart and Nutrition

Prevention is better than a cure. Learn how to cherish your heart by taking the necessary means to keep it pumping healthily and steadily through your life.

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Natural Secrets For Healing Your Heart

This eBook is devoted to exposing the secrets that cardiologists and surgeons don't want you to know, and how to take control of your own heart and heal yourself. Eight out of every ten coronary bypasses will not actually help the patient. So why risk being in the 80% that will get no benefit from a bypass? Learn to heal your own heart and keep yourself healthy with this eBook guide. Bob Livingston has poured years of research into his findings, and is now sharing the methods that he has developed from careful, methodical research that the medical industry would never allow. It would make them go bankrupt! You will learn what supernutrient doctors don't want you to know about, and how to make an all-natural, chemical and drug-free blood thinner And even more information that doctors don't want revealed to the public. You don't have to be one of the 70% of Americans diagnosed with heart disease. You can heal your heart!

Natural Secrets For Healing Your Heart Overview

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Adiponectin Deficiency and Cardiovascular Diseases

Adiponectin is inversely correlated with a panel of traditional cardiovascular risk factors, including blood pressure, heart rate, and total and low-density lipoprotein (LDL) cholesterol and triglyceride levels, and is positively related to high-density lipoprotein (HDL) cholesterol levels (80,81). Hypoadiponectinemia has been shown to be an independent risk factor for endothelial dysfunction and hypertension, regardless of insulin resistance (82,83). In addition, the association of hypoadiponectinemia with coronary heart disease (84), ischemic cerebrovascular disease (85), and coronary artery calcification (86) was also reported to be independent of classical cardiovascular risk factors, such as diabetes, dyslipidemia, and hypertension. A recent report by Kumada et al. showed that the prevalence of coronary artery disease in male subjects with hypoadiponectinemia (< 4 pg mL) was 2.05-fold higher than those with adiponectin concentrations of more than 7.0 pg mL, after adjustment for...

Implementation Of An Acute Stroke Team And Acute Stroke Protocols

The overwhelming prerogative, in thrombolysis for acute ischemic stroke, is the need for rapid, yet complete, evaluation of potential therapeutic candidates within the 3-hour treatment window. Time is the acute stroke clinician's worst enemy.33 The acute stroke protocol should begin at the first of point of contact with the healthcare system the call to an ambulance dispatcher. Stroke symptoms should be recognized and given high priority for dispatch. Emergency medical technicians (EMTs) should be trained to identify potential thrombolysis candidates in the field by recognizing signs of stroke,73,74 and several simple scales have been created for this purpose.75-78 Prenotification by the EMTs, before hospital arrival, allows time for notification of the acute stroke team and preparation of the CT scanner before patient arrival, and has been associated with fewer in-hospital delays in treatment.79,80 The initial evaluation, after arrival in the emergency department, should include a...

Cryothermia Induced Myocardial Infarction Model

A rat cryothermia-induced myocardial infarction model was used to study microvascularization and ventricular function after local alginate-encapsulated angiogenic growth factor treatment in rat model by Huwer et al. (21). After exposing the hearts of Sprague-Dawley rats through a left lateral thoracotomy, cryothermia was induced to the LV wall using a 5-mm cryoprobe cooled to -120 C, and 0.2 mL of calcium-algineate beads were injected into the cryoinjured tissue. The beads contained 0.4 g bFGF, 0.1 g vascular endothelial growth factor (VEGF), or 4.2 g epidermal growth factor (EGF). Four weeks later the chest was reopened and the formation of microvessels within the myocardial lesion, hemody-namics, and LV function were evaluated. The results of the study indicated that although the functional capillary density did not improve, there was a significant increase in the number of microvessels larger than capillaries. The increased number of microvessels within the infarcted tissue only...

Spontaneous Cardiovascular Disease in Animals

Cardiovascular disease occurs commonly in companion animals, particularly in domestic cats and dogs 1 . Myocardial disease represents a substantial portion of these disorders, many of which closely resemble cardiomyopathies in human patients 2 . Such disorders in cat, include hypertrophic 3,4 , dilated 5 , restrictive 6, 7 , and arrhythmogenic right ventricular cardiomyopathies (ARVC D) 8 . A heritable form of hy-pertrophic cardiomyopathy associated with a cardiac myosin binding protein C mutation has been recently reported in the Maine Coon cat breed 4 . In dogs, chronic myxomatous valve disease is the most prevalent cardiac disorder 9,10 , but cardiomyopathies occur frequently, particularly within certain medium and large-sized breeds 10 . Familial forms of dilated car-diomyopathy have been described in the Doberman Pinscher 11 , Irish wolfhound 12 , and Great Dane 13 , and a familial form of ARVC D has been reported in the boxer breed 14,15 . Dysplastic conditions of the right...

Previous Stroke Neuroprotective Trials

Over the past 15 years, over 85 phase II and phase III drug trials have been conducted to investigate the clinical efficacy of stroke neuroprotective drugs that target one or more pathways of cell death.5 These drugs were developed based on the promising results of over a thousand experimental studies in animal stroke models.6 Unfortunately, no drug has survived the challenge of clinical testing. The most notable failure is the SAINT-II trial of NXY-059, a free radical scavenger. Rodent and primate studies had shown remarkable efficacy with this drug, and the initial SAINT-I trial in Australasia and Europe showed that NXY-059 improved functional outcome after acute stroke and reduced the risk of thrombolytic-associated hemorrhage.7 The field of stroke neuroprotection was optimistic that SAINT-II, the largest ever acute stroke trial, would yield positive results. However, like numerous other trials of nonthrombolytic drugs, SAINT-II proved to be a negative trial and the company...

Are all abnormal ECGs indicative of heart disease

Just as some individuals are very tall, some individuals without real cardiac pathology have electrocardiogram (ECG) findings that deviate enough from the population mean to raise the question of heart disease. Careful history and physical examination may help identify individuals who truly have cardiac pathology. Noninvasive techniques such as echocardiography and cardiac magnetic resonance imaging may aid in separating patients with true structural heart disease from those with unusual variations who are abnormal only in a statistical sense. Other findings such as right bundle-branch block (RBBB), are present in patients with heart disease but also occur frequently in patients who have no evidence of heart disease by history, physical examination, or echocardiography.

Coronary Artery Disease

Coronary artery disease, also called simply heart disease, is a condition in which the coronary arteries (the blood vessels that supply blood to the heart muscle) become blocked, cutting off blood flow and, therefore, oxygen to the heart muscle. This damages the heart, causing it to malfunction. Coronary artery disease is the leading cause of death in the United States for both men and women. Nearly 20 percent of men aged 65 to 69 have had a heart attack, and nearly 30 percent of men aged 80 to 84 have had a heart attack. Nearly half of all men who die of coronary artery disease are not aware that they have the disease. The following risk factors increase your risk of developing heart disease Family history. Your chances of having coronary artery disease are much greater if either of your parents had heart disease before age 65. Smoking. Smokers have a 70 percent greater chance of developing coronary artery disease than nonsmokers. Diabetes. More than 80 percent of people with...

European Cooperative Acute Stroke Study I

The European Cooperative Acute Stroke Study (ECASS) I was the first large-scale prospective, multicenter, double-blinded, randomized clinical trial of rtPA in the treatment of acute ischemic stroke (13). Eligible patients were between 18 and 80 years of age and presented within 6 hr of onset of a moderate-to-severe acute ischemic stroke. Patients with strokes severe enough to cause an impaired level of consciousness or forced head and eye deviation were excluded. Patients with rapidly improving symptoms or mild strokes were also excluded. Importantly, patients with CT scans that showed ICH, hypoattenuation exceeding a third of the MCA territory, or diffuse sulcal effacement of one entire brain hemisphere were excluded. Eligible patients received either 1.1 mg kg of alteplase or placebo over 60 min (10 as a bolus).

Multicenter Acute Stroke Trial I and E

Conducted in Italy in 1995, the multicenter acute stroke trial (MAST)-I was a randomized, controlled, multicenter, open trial of 622 patients who had stroke onset within 6 hr (20). The subjects were randomized to 1 of 4 groups 1-hr IV infusion of 1.5 MU streptokinase, 300 mg day buffered aspirin for 10 days, both streptokinase and aspirin, or neither. Streptokinase (alone or with aspirin) was associated with numerous 10-day case fatalities (odds ratio 2.7 p < 0.001). Comparison of groups that received streptokinase with those who did not revealed increased rates of symptomatic ICH. Due to the above results, this trial was also stopped early. The following year, MAST-E was published (21). This was a double-blinded, controlled trial of 310 patients in France and England that assessed the efficacy and safety of administration of streptokinase within 6 hr of ischemic stroke. Noteworthily, the use of anticoagulants or antiplatelets was allowed during the first 24 hr. The primary outcome...

Intraarterial Thrombolytics In Acute Stroke Therapy

The trials discussed above demonstrated either a nonsignificant or negative effect of treatment of ischemic strokes beyond the 3-hr window. Relatively few patients were able to present to the emergency room, undergo a CT scan, and receive evaluation and treatment by a neurologist within 3 hr. In the NINDS rtPA trial, 16,000 patients were screened for the total study population of 624 patients (15). This time-constraint problem, along with the advent of more advanced radiographic technologies, warranted questioning whether the time window for treatment of acute stroke could be expanded by local application of IA thrombolytics to the causative clot. IA application theoretically would increase the effectiveness of thrombolytics by increasing the local concentration at the site of the clot while decreasing the total amount used, thereby decreasing the hemorrhagic complication rate. This methodology appeared especially enticing for large strokes that were caused by occlusion of major...

Other Thrombolytics For Acute Stroke Ancrod

Ancrod, a purified venom extract from the Malaysian pit viper, induces rapid defibrinogenation, which, in turn, may increase local thrombolysis by stimulating plasminogen activators. In 1994, a study was undertaken in the United States and Germany to test the safety and efficacy of this treatment in ischemic stroke patients who present within 6 hr. A nonsignificant improvement in outcome was noted at 3 months, with no symptomatic hemorrhages in the ancrod group (31). The Stroke Treatment with Ancrod trial studied ancrod in acute stroke using a 3-hr window (32). Using the primary efficacy endpoint of Barthel Index > 95 at 90 days revealed a statistically significant difference in outcome between ancrod and placebo groups (42.2 vs. 34.4 p 0.01). This effect was proportional to the rate of defibrinogenation. A nonsignificant trend toward increased symptomatic hemorrhages in the ancrod group was also reported.

Key Points Ischemic Heart Diseases

Patients with excellent exercise capacity, even in the presence of ischemic heart disease, will be able to tolerate the stresses of noncardiac surgery. The ability to climb two-to-three flights of stairs without significant symptoms (angina, dyspnea) is usually an indication of adequate cardiac reserve.

What electrocardiogram findings support the diagnosis of ischemic heart disease

The resting 12-lead ECG remains a low-cost, effective screening tool in the detection of IHD. It should be evaluated for the presence of ST-segment depression or elevation, T-wave inversion, old MI as demonstrated by Q waves, disturbances in conduction and rhythm, and left ventricular hypertrophy. Ischemic changes in leads II, III, and aVF suggest right coronary artery disease, leads I, aVL, V5 and V6 monitor the circumflex artery distribution, and leads V1 to V4 look at the distribution of the left anterior descending artery.

Describe common findings of the history and physical examination in patients with valvular heart disease

A history of rheumatic fever, intravenous drug abuse, embolization in different organs, genetic diseases such as Marfan syndrome, heart surgery in childhood, or heart murmur should alert the examiner to the possibility of valvular heart disease. Exercise tolerance is frequently decreased patients may exhibit signs and symptoms of heart failure, including dyspnea, orthopnea, fatigue, pulmonary rales, jugular venous congestion, hepatic congestion, and dependent edema. Angina may occur in patients with a hypertrophied left ventricle, and atrial fibrillation frequently accompanies enlargement of the atria.

Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke

The second attempt to extend the time window of rtPA administration was the Alteplase Throm-bolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) study (45 ). Like ECASS II, ATLANTIS was originally designed to show if the benefits of systemic thrombolysis could extend up to 6 hr. After the publication of the NINDS study in 1995, the time window for enrollment was changed to encompass 3 to 5 hr. The primary endpoint for the modified study was good outcome, defined as an NIHSS score of 0 or 1 at 90 days. After 761 patients had been enrolled in ATLANTIS, the trial was terminated prematurely because of projected lack of benefit with active treatment. Again, no difference in mortality was observed between the 2 treatment groups, suggesting that delayed administration of rtPA was safe. The ATLANTIS investigators followed the precedent observed in ECASS II by concluding that the use of rtPA for acute ischemic stroke should not be undertaken after 3 hr.

Cigarette Smoking And Cardiovascular Disease

Cigarette smoking-related cardiovascular diseases have been described widely. However, the mechanisms of their effects on cardiovascular system were not totally clear. The effects of nicotine and carbon monoxide on blood vessel walls, unfavorable lipid profiles, increased myocardial work and the decreased oxygen carrying capacity of the blood of smokers contribute to the overall effect of cigarette smoking on cardiovascular disease 3J. Of the increased cardiovascular risk caused by smoking, it is estimated that approximately one-tenth of this is due to smoking-induced changes in serum lipid 4 , The majority of studies indicate elevations in serum cholesterol, phospholipids, triglycerides, low-density lipoprotein (LDL) and increased hepatic lipase activity in smokers, with decreased serum high-density lipoprotein (HDL) cholesterol 5 , In addition, cigarette smoking is associated with unhealthy eating patterns, including increased intakes of alcohol, total fat, cholesterol, saturated...

Alcohol Abuse And Cardiovascular Disease

Although there is considerable evidence that moderate drinking protects against mortality and morbidity from coronary heart disease 21,22 , heavy consumption is shown to have deleterious cardiovascular effects. It exerts its adverse effects by increasing the risks of cardiomyopathy, hypertension, and stroke 23 , Chronic ethanol consumption has been linked to the prevalence of hypertension, which contributes to an increased incidence of stroke. Heavy drinkers have alO mmHg higher systolic blood pressure than non-drinkers even though the relationship may differ between men and women 24 , Stroke is a leading cause of death and morbidity. Alcohol may increase the risk of stroke through various mechanisms that include hypertension, hypercoagulable states, cardiac arrhythmias, and cerebral blood flow reductions 25 , Hypertension, including borderline hypertension, is probably the most important stroke risk factor based on degree of risk and prevalence. Furthermore, cardiac morbidity,...

Trials of Heparin in Acute Ischemic Stroke

Placebo-Controlled Trials of UFH, LMWH, and Heparinoids The International Stroke Trial (1ST)8 was a randomized, placebo-controlled trial of UFH (5000 or 12,500 IU twice daily) and aspirin (300 mg) in 19,435 unselected patients with acute stroke within 48 hours of symptom onset. Because of limited availability of neuroimaging, 33 of participants were enrolled with suspected but not proven ischemic stroke, some of whom may have suffered primary intracerebral hemorrhage (ICH).

Pcos And Risk For Cardiovascular Disease

Evidence for Association Between Polycystic Ovary Syndrome, Cardiovascular Risk (CVR) Factors and Cardiovascular Disease (CVD) Recognized CVR factors Atherosclerosis coronary artery disease myocardial infarction athero Decreased sex hormone-binding globulin (SHBG), which is typical in PCOS and increases bioavailable testosterone, may be considered a surrogate marker of IR such that lower levels of SHBG are related to a greater degree of IR (18). Therefore, IR may in part indirectly contribute to CVR in PCOS by amplifying androgen excess. In addition to this possible selection bias, large-scale clinical trials evaluating the morbidity and mortality for CVD in women with PCOS are lacking. No long-term data of well-characterized women with PCOS are present in the literature, and the link of PCOS to primary cardiovascular events, such as stroke or myocardial infarction (MI), remains to be demonstrated. Epidemiological studies on isolated signs and stigmata of PCOS have produced mixed...

Trials Comparing Heparin to Aspirin in Acute Stroke

The Heparin in Acute Embolic Stroke Trial (HAEST) was a multicenter, randomized trial of the effect of LMWH (dalteparin 100 IU kg sc twice daily) or aspirin (160 mg once daily) for the acute treatment of 449 patients with ischemic stroke and atrial fibrillation (AF).13 The primary outcome was the rate of recurrent stroke within 14 days. No difference in rates of early recurrence (8.5 dalteparin treated vs. 7.5 aspirin treated) or good 3-month functional outcome was found. The frequency of early sICH was 2.7 on dalteparin versus 1.8 on aspirin. Tinzaparin in Acute Ischemic Stroke Trial (TAIST) was a randomized, doubleblind trial that compared high-dose tinzaparin (175 IU kg day), medium-dose tinza-parin (100 IU kg day), or aspirin (300mg day) started within 48 hours of acute ischemic stroke, given for up to 10 days.14 The proportion of patients independent at 6 months was similar in all the three groups (41.5 high-dose tinzaparin, 42.5 medium-dose tinzaparin, 42.5 aspirin). Rates of...

Combination Anticoagulant and Antiplatelet Therapy in Acute Stroke

The Cochrane group examined (a) whether the addition of UFH or LMWH to anti-platelet agents offers any net advantage over antiplatelet monotherapy for acute stroke, and (b) the effectiveness of anticoagulants compared to antiplatelets in acute ischemic stroke.17 They included 4 trials of 16,558 patients, each of which specified aspirin (160-333 mg daily) as the control, and all of which randomized patients within 14 days of stroke onset. The anticoagulants tested were UFH and LMWH. Almost 98 of the patients were followed up for 6 months. This was largely influenced by the high-dose UFH group in 1ST (OR 1.38, 95 CI 1.05-1.82). An interaction by UFH dose (p 0.01) on recurrent stroke risk with combination UFH-aspirin therapy compared to aspirin monotherapy was observed, with a trend toward increased risk of recurrent stroke with high-dose UFH + aspirin (OR 1.22, 95 CI 0.92-1.62) and a trend toward reduced risk with low-dose UFH + aspirin (OR 0.75, 95 CI 0.56-1.03), equivalent to 10 fewer...

Trials of GP IIbIIIa Antagonists in Acute Ischemic Stroke

The abciximab in Acute Ischemic Stroke trial was a randomized, placebo-controlled dose-escalation study to examine the safety of abciximab in acute stroke.23 It randomized 74 patients within 24 hours of stroke onset to receive one of four doses of abciximab (by bolus with or without additional infusion, 54 patients) or placebo (20 patients). The median baseline National Institute of Health Stroke Scale (NIHSS) score was 15. The rates of asymptomatic ICH were 19 in the intervention group compared to 5 in the placebo group (p 0.07). Most (9 of 11) of the asymptomatic ICH patients had more severe stroke (NIHSS > 14). No cases of symptomatic ICH or major systemic bleeding occurred. There was a trend toward a lower rate of stroke recurrence (2 vs. 5 ) and a higher rate of functional recovery at 3 months in the group treated with abciximab than with placebo. The Safety of Tirofiban in Acute Ischemic Stroke (SaTIS) trial examined 250 patients 6-22 hours after stroke onset treated with...

Lipids And Cardiovascular Disease

There are a substantial number of large epidemiological studies examining the relationship between dietary ATC intake and cardiovascular disease mortality (reviewed in 116-118 ). For example, studies carried out two decades ago showed a correlation between higher than expected mortality and very low dietary ATC intakes (as well as with very high ATC intakes 119 ). The basis of its cardioprotective effects is the ability of ATC to reduce damage caused by ROS in general, and specifically to inhibit the oxidation and MDA-modification of unsaturated lipids in low-density lipoprotein (LDL) particles 116,120,121 , These oxidized products ofLDL are highly damaging and initiate the formation of atherosclerotic plaques and lesions and are related to the course of myocardial infarction 116,122 . However, atherosclerotic plaque formation and the mechanisms for the ensuing increased morbidity and mortality are complex processes, which involve, for example, the production of superoxide by...

Antithrombotic Treatment of Acute Stroke Due to Large Artery Atherosclerosis

Early Recurrence Rates in Large Artery Disease Stroke due to LAA has been associated with a higher risk of early recurrence compared to cardioembolic, undetermined, and lacunar subtypes. A meta-analysis of population studies found a 4.5 recurrent stroke risk associated with LAA at 7 days and 9.4 recurrence at 1 month, a threefold increase in adjusted risk as compared to other subtypes.52 Patients with strokes caused by LAA appear to be at the greatest risk of worsening and recurrence in the early poststroke period. In the National Institute of Neurological Disorders and Stroke (NINDS) stroke database, patients with LAA had a 30 risk of worsening during acute hospitalization and a 7.9 risk of stroke recurrence within 30 days.

High SensitiveCRP and Other Proinflammatory Indices as Markers of Cardiovascular Diseases But Why and

It is evident from the preceding discussion that hs-CRP and other proin-flammatory indices could be used as independent risk factors for cardiovascular diseases and atherothrombosis. High levels of hs-CRP, IL-6, IL-18, TNF-a, amyloid A, MPO, fibrinogen, and leukocytosis appear to predict future cardiovascular risk in apparently healthy men and women. Despite these findings, the exact mechanism(s) involved in cardiovascular disease process remains unclear. It is likely that markers such as CRP and MPO are closely linked to the underlying pathophysiology, that is, low-grade systemic inflammation. High hs-CRP concentration may thus simply reflect the underlying inflammatory process ultimately responsible for the initiation and progression of atherosclerosis that finally results in CHD. Since atherosclerosis occurs as a result of failure of the antithrombotic properties of endothelium, it is possible that increased hs-CRP is an indication that endothelial cells are no longer able to...

The Impact of Cardiovascular Disease and Its Major Component Coronary Heart Disease on Human Health

Cardiovascular disease is the most prevalent threat to life and health in the United States.1,2 It is the major cause of mortality, with 44 of deaths, and it is a major cause of morbidity.3 A major cardiovascular disease develops in 1 3 of men and 1 10 of women before the age of 60.4 The incidence of major cardiovascular events in men increases dramatically with age, from 7 events 1,000 people at age 35-44 to 68 events 1,000 people at age 85-94 comparable rates occur for women about 10 years later in life, but the difference narrows with age.5 In the United States, the cost of medical care is higher for cardiovascular disease than for any other diagnostic group.3 This diagnostic group includes the major forms of cardiovascular disease, which are coronary heart disease, stroke, congestive heart failure, pulmonary embolism, cardiac dysrhythmias, hypertensive disease, and peripheral artery disease. Together, these diseases are a massive burden on our health care system. Coronary heart...

Cardiovascular Disease

Obesity is associated with an increased risk of coronary artery disease (CAD) and mortality from cardiac events including myocardial infarction, arrhythmias, and sudden cardiac death (46). Morbidity and mortality rates rise proportionally to the degree of obesity in men and women, and the impact of excess body fat is more significant in younger subjects than in older ones (47). Heart function is directly influenced by excess body fat (52). In addition to higher cardiac output in obese patients, left ventricular volume and filling pressures are higher than normal. This frequently results in the development of left ventricular strain, which leads to hypertrophy, often of the eccentric type (53). Left ventricular diastolic function is frequently impaired by this effect. Weight loss has a beneficial impact on the functional and the structural cardiac status. In a study of obese patients with a mean BMI of 32.7, weight loss of 8 kg over a period of 25 wk was associated with a significant...

Blood Lipids and Coronary Heart Disease

The major risk factors for coronary heart disease are well known and include smoking, high blood pressure, and blood cholesterol levels. In addition, obesity, diabetes, and family history are recognized as important factors. While each of these factors is important, the predominant factor may be blood cholesterol levels. Serum total cholesterol and lipoproteins are well-established risk factors for coronary artery disease. Numerous studies have confirmed the relationship between serum total cholesterol and coronary heart disease.1013 A rule of thumb from epidemiologic studies suggest that for every 1 increase in total cholesterol, the risk of CHD increases by 2 .14,15 The National Cholesterol Education Program defines three categories of serum total cholesterol. These are desirable (< 200 mg dL), borderline high (200-239 mg dL) and high (> 240 mg dL). These classifications have been used as a basis for prescribing preventive treatments including dietary changes and pharmaceutical...

The Pathogenesis of Coronary Heart Disease

The underlying cause of coronary heart disease is atherosclerosis, which from a clinical view leads to the formation of plaque, degeneration of vessel intima, thro-mobosis, and ultimately vessel occlusion and ischemia. An interesting aspect of atherosclerosis is that it occurs more frequently at certain locations than others in the vasculature, albeit throughout the body. Atherosclerosis is commonly located at bifurcations and areas of vessel stress. These areas often have a low oscillating shear stress. Presumably, this stress facilitates the accumulation of lipid and initiation of atherosclerosis.42 In recent years, oxidation and inflammation have been viewed as primary mechanisms in the initiation and progression of atherosclerosis. Oxidative damage and inflammation have been linked with the risk of coronary heart disease in several instances.43,44 Together, these observations suggest that factors other than hypercholesterolemia alone are important in the generation of Oxidative...

Hypothermia for Ischemic Stroke

Early clinical data have shown promise for induced hypothermia for the treatment of acute ischemic stroke. Hypothermia acts by decreasing the cerebral metabolic rate, stabilizing cell membranes, preserving the integrity of the BBB, reducing the release of destructive enzymes, reducing the inflammatory response, and decreasing the release of excitotoxic neurotransmitters, such as glutamate and dopamine. Early treatment with hypothermia may reduce total infarct volume, and may prevent the development of cerebral edema. However, its use is associated with several potential adverse side effects, including an increased risk of infection, coagulopathy, hypokalemia, hyperglycemia, and cardiovascular suppression. Furthermore, when hypothermia is discontinued, a rebound elevation of ICP has also been noted, which may be fatal. The timing, degree, and duration of hypothermia in ischemic stroke have not been fully worked out, nor has the safest rate of re-warming. Numerous small studies have...

What causes pulmonary hypertension in association with congenital heart disease

Pulmonary artery hypertension (PAH) is associated with a variety of disease states and can also be idiopathic. When associated with congenital heart disease, PAH is usually the result of high blood flow and pressure in the pulmonary vasculature caused by left-to-right intracardiac shunting at the ventricular level. This situation is typically present with ventricular or atrioventricular septal defects, in which blood flows along a pressure gradient from the high-pressure left ventricle to the lower-pressure right ventricle.

What effects do anesthetic agents have on shunting in patients with cyanotic congenital heart disease

Hypercyanotic spells by decreasing SVR, studies have demonstrated that right-to-left shunting usually does not change significantly as long as ventilation and oxygenation are maintained. Nevertheless, as with any patient with cardiovascular disease, it is wise to avoid great changes in hemodynamic parameters by careful dosing, combining anesthetic drugs to achieve a balanced technique, and using muscle relaxants to facilitate lower anesthetic doses.

What is the best anesthetic technique for patients with congenital heart disease

There is no simple recipe for anesthetic management of the patient with congenital heart disease, and many rational approaches can be used. Choices depend on a thorough assessment of the patient's condition, the type of surgical procedure to be performed, and postoperative goals (e.g., mechanical ventilation vs. extubation). Review of cardiac catheterization and echocardiographic data will provide information concerning shunts, valve function, pulmonary hypertension, and ventricular function. It is necessary to understand the anatomy and pathophysiology of the patient's cardiac lesion so shunt balance, ventricular function, and rhythm can be better maintained maintain good oxygenation and ventilation and be familiar with the cardiovascular effects of anesthetic drugs and avoid cardiovascular depressants. A balanced technique using more than one anesthetic can often ensure adequate anesthesia while minimizing side effects. Be careful

How is congenital heart disease managed during pregnancy

Pulmonary artery catheterization is rarely required for most patients with congenital heart disease. Intrathecal opioid injections are good choices for labor analgesia when patients will not tolerate decreased systemic vascular resistance and decreased venous return. Epidural anesthesia is contraindicated in few, if any cardiac lesions, provided that the induction of anesthesia is slow and hemodynamic changes are treated promptly. Single-injection spinals for cesarean delivery are contraindicated in many patients with congenital heart disease.

Cardiac Complications In Ischemic Stroke Patients

Acute stroke patients are at high risk for cardiac events, including myocardial infarction (MI) and dysrhythmias from autonomic derangement, particularly with strokes involving the insular cortex. Although the precise mechanisms and triggers for this have yet to be elucidated, it appears that there is a predominance of sympathetic activity associated with strokes involving the right hemisphere.115 Seizures that originate from the left temporal lobe may be more commonly associated with bradycardia and even cardiac asystole.116'117 In stroke patients, however, involvement of the right hemisphere appears to correlate most strongly with cardiac autonomic derangements. Colivicci et al.118 evaluated 103 patients with 24-hours Holter monitoring, and found a significantly higher rate of complex arrhythmias in patients with infarction of the right insular cortex. Meyer et al.119 assessed sympathetic function in acute stroke patients by measuring plasma epinephrine and norepine-phrine levels....

Atherosclerosis and Coronary Artery Disease

Obesity may be an independent risk factor for ischemic heart disease. However, numerous studies have been unable to confirm this association because of the short time period of observation. Indeed, the association between obesity and ischemic heart disease seems evident only after two decades of follow-up (76). The Manitoba Heart Study reported that a high BMI was significantly associated with development of myocardial infarction, coronary insufficiency, and sudden death (76). A cross-sectional study by Takami et al. (88) of 849 Japanese men aged 20 to 78 yr investigated the relationship between body fatness (particularly abdominal fat) and carotid atherosclerosis. They found that general adiposity (as measured by BMI), WC, waist-to-hip ratio (WHR), abdominal subcutaneous fat, and intra-abdominal fat were all correlated with carotid IMT after adjustment for age and smoking habits. Adjustment for BMI eliminated all other associations except those of WHR with IMT, suggesting that in...

Transient Ischemic Attack Vs Stroke

Transient ischemic attack (TIA) and acute ischemic stroke are often difficult to differentiate in the emergency room if patients are seen acutely within minutes or hours of symptom onset. In fact, TIA and stroke may represent a spectrum of ischemic stroke. Recent evidence suggests that TIA is a medical emergency. When focal cerebral ischemic symptoms completely resolve within 24 hours, the event has been considered a TIA, not a stroke. However, the majority of TIAs resolve within minutes, and advanced neuroimaging studies demonstrate that events with longer-lasting symptoms are likely to be strokes (3). TIAs have a more serious prognostic implication than previously appreciated. After a TIA occurs, approximately 10 of patients will have a stroke in the next three months, and almost half of these strokes will develop within the first two days of the initial symptoms (4). Simple symptom duration risk factor scales (4,5) can be used with imaging to identify patients at high risk for TIA....

Therapeutic Applications In Acute Ischemic Stroke

IV rtPA is currently the only Food and Drug Administration (FDA)-approved therapy for ischemic stroke within 3 hours of symptom onset (8). Noncontrast CT is the first-line imaging test for differentiating hemorrhagic from ischemic events. Based on the time of onset and clinical and CT examinations, rtPA can be given without confirmation of the presence of an arterial occlusion (8) . Thrombolytic treatment without confirmation of arterial occlusion has been criticized (69). More centers are now attempting to employ vascular imaging to determine the presence, or persistence, of occlusion or reocclusion that has been linked to poor prognosis and that may necessitate further (currently experimental) intra-arterial interventions (70,71). Various tests can be used for this purpose, including invasive digital subtraction angiography, magnetic resonance angiography, CT angiography, and ultrasound (72,73). Ultrasound has the advantage of being a quick and inexpensive method for the real-time...

Neurogenesis After Stroke

Although it was learned from studies performed on macaque monkeys in the mid-1960s that neurons can be formed within the adult brain (1,2), the dogma until recently has been that brain tissue could not be regenerated in the adult. It is now known that neural stem cells (NSCs) and neural progenitor cells (NPCs) are present in at least two regions in normal adult mammalian brain the subventricular zone (SVZ) and the subgranular zone (SGZ) in hippocampal dentate gyrus. These cells might promote recovery of neural functions that were lost due to stroke. The proliferation and recruitment of endogenous NSCs and NPCs present after stroke give rise to many, if not all, types of cells found in the adult brain (3-6). The proliferation, migration, and maturation of these cells can be controlled by growth and trophic factors and other signaling molecules, and are affected by ischemia (7,8). Induction of these new neurons, if functional, may provide a novel therapeutic strategy for the treatment...

Clinical Trials of Aspirin in Acute Ischemic Stroke

Fewer recurrent ischemic strokes at 2 weeks among the aspirin-treated group (2.8 vs. 3.9 , 2p < 0.001), which was not offset by any significant excess of hemorrhagic strokes (0.9 vs. 0.8 ). The Chinese Acute Stroke Trial (CAST) compared 160 mg aspirin to placebo given for 4 weeks to 21,106 patients with acute ischemic stroke19 treated within 48 hours. Eighty-seven percent of patients had a brain computed tomography (CT) scan. The mortality rate after 1 month in the aspirin group was lower than in the placebo group (3.3 vs. 3.9 , 2p 0.04) with areduction in the rate of recurrent ischemic stroke at 1 month(1.6 vs.2.1 , p 0.01). A small (nonsignificant) increase in hemorrhagic stroke in the aspirin-treated group was observed (0.21 , p > 0.1). In the Multicenter Acute Stroke Trial Italy (MAST-I) study, 622 patients were randomized in a 2 x 2 factorial design to receive either a 1-hour infusion of 1.5 IU streptokinase or 300 mg aspirin or both, or neither.20 Streptokinase (alone or...

Alcohol and nonfatal myocardial infarction or incidence of CHD

Data on the incidence of myocardial infarction or CHD were available for about 40 of the cited cohorts. It is no longer disputed that drinkers as a group have a lower incidence of Table 1.1 Large population studies examining alcohol intake and cardiovascular disease 10 Puerto Rico Heart Health Program 11 Yugoslavia Cardiovascular Disease Study *Length of follow-up (years) +Number of incidence cases unless otherwise indicated CHD coronary heart disease CVD cardiovascular disease NHANES I the First National Health and Nutrition Examination Survey. *Length of follow-up (years) +Number of incidence cases unless otherwise indicated CHD coronary heart disease CVD cardiovascular disease NHANES I the First National Health and Nutrition Examination Survey. acute myocardial infarction or CHD than do non-drinkers. However, it is unresolved as to whether there is a dose-response relation between increasing alcohol intake and decreasing incidence and whether there is an increase in risk at the...

Establishing The Diagnosis Of Ischemic Stroke

Subinsular White Matter

Recent years have seen the emergence of successful treatment strategies for ischemic stroke, but these are most effective only when initiated within several hours after stroke onset. Therefore, extremely rapid diagnosis and initiation of treatment are critical in avoiding death or severe disability. Unfortunately, there are a variety of other clinical conditions that may mimic the presentation of acute ischemic stroke. These include intracranial hemorrhage, seizure, sepsis, cardiogenic syncope, complicated migraine, dementia, nonischemic spinal cord lesion, peripheral neuropathy, transient global amnesia, and brain tumor, among others. One recent study found that, of patients presenting to a hospital with stroke-like symptoms, the diagnosis of stroke or transient ischemic attack was never established confidently in 31 , and alternative diagnoses were ultimately made in 19 . Modern imaging techniques are capable of establishing the diagnosis with a high degree of certainty, and of...

Current Barriers In Acute Stroke Care Pre Hospital Delays

Fewer than half of all patients with acute stroke are seen in the emergency department (ED) within 3 hours of symptom onset.4 Patients in remote locations or in hospitals without available stroke expertise may have even more limited access to thrombolysis. In a study of non-urban East Texas communities in the United States, only 1.4 of patients with ischemic stroke received IV rt-PA,5 versus 14.7 at a university hospital in Houston, the nearest major city.6 Other studies have linked racial, ethnic, geographic, or socioeconomic differences to low rates of rt-PA utili-zation,4,6 suggesting that populations most underserved by stroke expertise may have the lowest rates of rt-PA delivery.

Susceptibility To Ischemic Heart Disease

In a cohort study of ischemic heart disease among residents in the BFD-endemic area, a significant biological gradient was observed between the incidence of ischemic heart disease and the cumulative arsenic exposure (Chen et al., 1996). There was also an increased incidence of ischemic heart disease for patients affected with BFD as compared with the unaffected. The status of BFD may be considered an indicator of long-term arsenic exposure, systemic atherosclerosis and or susceptibility to arseniasis. The association between BFD and ischemic heart disease remained significant after adjustment for cumulative arsenic exposure and other risk factors, showing a multivariate-adjusted relative risk of 2.5. In a recent case-control study on ischemic heart disease in arseniasis-hyperendemic villages (Hsueh et al., 1998), serum samples of 74 patients and 193 matched healthy controls were tested for serum levels of micronutrients by HPLC. A significant reverse dose-response relationship with...

Inflammation And Cardiovascular Risk

Inflammation is an intrinsic part of the pathogenesis of atherosclerosis and cardiovascular disease (CVD)1. Accumulation of inflammatory cells in the vessel wall and predominantly in so-called vulnerable plaques suggests that the most vulnerable sites in the vessel wall have the most intense inflammatory activity2'3. Inflammatory cells whether in the vessel wall or the circulation produce a number of inflammatory proteins called cytokines which are central to the proinflammatory response of the vessel wall and the systemic acute phase response. Inflammatory cytokines such as interleukin-1 (IL-1) and interleukin-6 (IL-6) stimulate the production of C-reactive protein (CRP) predominantly by the liver, but also by endothelial and smooth muscle cells in the vessel wall (Figure 6.1).

European Cooperative Acute Stroke Study II

In the wake of the NINDS rtPA Stroke Study, ECASS II was undertaken to determine if rtPA could be effective even when administered more than 3 hr after the onset of stroke symptoms. ECASS II is the largest randomized trial of thrombolytic therapy that has been conducted in acute stroke to date, enrolling 800 patients in 108 centers throughout Europe, Australia, and New Zealand, randomly assigning them to rtPA, using the NINDS Stroke Study dosing regimen versus placebo (43). To prevent the large number of protocol violations observed in ECASS I, the steering committee for ECASS II undertook more rigorous training of investigators to improve interpretation of CT scans and treat hypertension appropriately. The primary endpoint was a favorable outcome on the mRS, using the dichotomized method of analysis employed in the NINDS study. Only 158 (19.8 ) of the 800 patients were enrolled, randomized, and treated within 3 hr of stroke symptom onset. A favorable outcome of no more than 1 point...

Lipids Oxidation and Cardiovascular Disease

Abstract Blood cholesterol and LDL levels are well-established risk factors for cardiovascular disease and, in particular, coronary heart disease. In recent years, the role of LDL in the pathogenesis of atherosclerosis, the underlying cause of coronary heart disease, has been studied extensively. These studies have highlighted the complexity of atherosclerotic processes and identified oxidative damage and inflammation as important components of the process. In addition, the formation and possible involvement of various oxidized lipids in atherosclerosis have been identified by the studies. The oxidized lipids include the products of oxidative enzymes, located in the vasculature, as well as nonspecific oxidation products. Many of these lipids have been found in atherosclerotic plaque and have potent bioactivities. Moreover, these oxidation products and, reactive oxygen and nitrogen species, have been linked with cellular signaling pathways that can influence the development of...

Monitoring Of Intracranial Pressure In Ischemic Stroke Patients

Able for stroke patients at risk for herniation, each with advantages and disadvantages. Unfortunately, noninvasive techniques have not proven to be sufficiently reliable for detecting elevations in ICP, and thus clinicians are left with a host of invasive techniques. EEG monitoring may be useful in acute stroke patients. Seizures are not uncommon following stroke, occurring in 6-9 of patients in the acute setting.112 The possibility of seizures in the patient with a massive stroke with cerebral edema is concerning, given that it could contribute to ICP elevations and worsen herniation effects. In one study of two groups of stroke patients, with (n 110) and without (n 275) seizures, the patients with seizures were significantly more likely to exhibit periodic lateralized epileptiform discharges (PLEDs) and frontal intermittent rhythmic delta activity (FIRDA).113 Some endorse the use of continuous EEG monitoring in patients with acute ischemic stroke, perhaps adding value to outcome...

Ischemic Stroke

Transient hypertension is observed frequently following acute ischemic stroke and might be the result of a combination of factors, including anxiety, pain, neuroendocrine factors, stroke location, or a compensatory response to increased ICP (41-44). Acutely elevated BP is associated with increased early mortality after stroke, although whether this represents the consequence of stroke severity or its cause is presently unknown (1,2,45). Interestingly, low SBP and DBP, as well as elevated SBP, DBP, and MABP have been associated with poor stroke outcome, producing a U-shaped relationship between SBP and outcome (46-50). Analysis of a single SBP measurement prior to randomization in the International Stroke Trial in 17,398 patients with confirmed ischemic stroke also found a U-shaped relationship between baseline SBP and both early death and late death or dependency (50). In addition, patients with admission SBP greater than 200 mmHg had more than a 50 greater risk of recurrent stroke,...

Stroke Historical Perspectives And Future Directions

The modern period in the history of stroke began in the 1960s when C. Miller Fisher described detailed clinical and pathological observations on the features of lacunar strokes, carotid artery disease, transient ischemic attacks, and intracerebral hemorrhage. His student Louis Caplan established one of the first stroke registry Acute Ischemic Stroke An Evidence-based Approach, Edited by David M. Greer. Copyright 2007 John Wiley & Sons, Inc. databases to collect and analyze important epidemiological, clinical, radiological, and pathological data. Stroke treatment was rudimentary and often nihilistic. Stroke victims might have been treated with maggots or leeches in order to improve blood supply to the brain in hopes of restoring its functions. In 1961, Thomas Dawbe introduced the term ''risk factors'' to describe the contribution of specific conditions to cardiovascular disease. Shortly thereafter, the Framingham heart study highlighted the link between cardiovascular risk factors...

Identifying The Vascular Lesion

Ischemic stroke occurs because of impairments in microvascular perfusion of affected brain tissue. However, the vascular event that results in impaired perfusion often occurs in a macroscopically visible vessel. Imaging studies that can study these vessels provide several kinds of important information to the stroke neurologist. First, by definitively demonstrating a vascular lesion that could be responsible for ischemic symptoms, vascular imaging can help to cement the diagnosis of an acute ischemic stroke, especially when DWI is not available and other studies are equivocal or negative. Second, the location of the vascular lesion conveys important prognostic information. In general, vascular lesions that involve larger, more proximal arteries that serve larger volumes of tissues cause infarcts that result in more severe neurologic deficits and a greater likelihood of hemorrhagic transformation. Finally, vascular imaging can be essential in guiding therapy. Intra-arterial...

Observational Study Results

The Healthy Ageing Longitudinal study in Europe (HALE), examined singly the effects of consumption of the Mediterranean diet, and in combination with being physically active, moderate alcohol use, and nonsmoking on 10 year all-cause and CHD mortality in 2,339 men and women ages 70-90 from 11 European countries.13 Adherence to the Mediterranean diet was associated with a significant reduction in all-cause mortality (HR 0.77, 95 CI, 0.68-0.88). Adherence to the Mediterranean diet combined with additional diet and lifestyle factors lowered the all-cause mortality rate (HR 0.35, 95 CI, 0.28-0.44). In total, lack of adherence to this low risk pattern was associated with a population attributable risk of 60 for all deaths, 64 for deaths from coronary heart disease, and 61 from cardiovascular diseases.

Acute Vs Chronic Aneurysms Cocainerelated Bleed Sites

The exact mechanism by which berry aneurysms form remains undetermined, but research indicates that propagation and rupture of the aneurysm are aggravated by hypertension and tachycardia (132). The drug most often associated with acute cerebrovascular events is cocaine. Intracerebral hemorrhages or SAHs are the most frequently observed cerebrovascular complications of this drug (123). Several mechanisms might be responsible for the cerebrovascular complications. Traditional teaching is that hypertension is the likely precursive factor in cocaine-induced aneurysmal rupture, and a sudden rise in systemic arterial pressure might cause hemorrhages, frequently in association with an underlying aneurysm or AVM. Recent reports have indicated that these patients might have underlying vascular malformations (133,134). Rupture of aneurysms and AVMs has been detected in up to half of the patients with hemorrhagic stroke due to cocaine abuse. In addition to stroke, cocaine seems to provoke...

BP Components and Risk

To make matters more confusing, higher MAP and higher PP are each independently associated with increased cardiovascular disease risk. The contrasting effects of MAP and PP on diastolic DBP contribute to the frequently described and often misunderstood non-linear (U- or J-shaped) relation between diastolic BP and cardiovascular events. For example, low diastolic BP and wide PP are associated with increased risk of mortality 21 yet high diastolic BP independently increases risk 22 . The problem is in the confounding caused by the use of diastolic BP as a risk surrogate. The situation becomes much clearer if risk is attributed to either elevated MAP or elevated PP. Hypertension as a clinical condition is thus intrinsically heterogeneous, and is perhaps best considered as an admixture of disordered large artery function (generating systolic hypertension) and disordered microcirculatory function (generating diastolic hypertension). Understanding which form of hypertension to treat and how...

Rationale For Therapy

Cerebral infarction may result from large artery atherosclerosis, cardiac embolism, small artery lipohyalinosis, cryptogenic embolism, or, more rarely, from other diverse conditions such as arterial dissection, infective endocarditis, and sickle cell disease.2 Arterial occlusion is the cause of at least 80 of acute cerebral infarctions.3,4 Acute Ischemic Stroke An Evidence-based Approach, Edited by David M. Greer. Copyright 2007 John Wiley & Sons, Inc.

Intravenous Thrombolytics

Thrombolytic agents cause the breakdown or dissolution of thrombi. Many of these agents work by converting inactive plasminogen into plasmin, a serine protease, which then cleaves fibrin within the thrombus (Fig. 3.1). Agents that have been studied in acute ischemic stroke include human rt-PA, urokinase, streptokinase, and desmoteplase. Systemic administration of these agents may also cause systemic fibrinogen degradation, reduction in circulating plasminogen and a2-antiplasmin, inactivation of factors V and VIII, platelet disaggregation, and possibly platelet This section will review the phase III clinical trials of IV thrombolytic agents for acute ischemic stroke, organized by the type of agent and the time window from stroke onset to study drug delivery (Table 3.1). The 1995 National Institute of Neurological Disorders and Stroke (NINDS) rt-PA trial is presented first because it showed that IV rt-PA, given within 3 hours of stroke onset, reduced stroke-related disability. This...

Indo Mediterranean Diet Heart Study

A recently completed trial conducted in India, the Indo-Mediterranean Diet Heart Study,25 complements findings from the Lyon Diet Heart Study. The study population consisted primarily of men ( 90 ) who were at high-risk for either a first myocardial infarction or a recurrence approximately 60 had a history of myocardial infarction at baseline, and 35 had a recent (< 4 weeks) myocardial infarction. In contrast to the Lyon Diet Heart Study, two-thirds of participants were vegetarian at baseline. All participants were given advice to reduce their intake of fat, saturated fat, and cholesterol (< 30 kcal from fat, < 10 kcal from saturated fat, and < 300 mg cholesterol day). Those participants in the intervention arm were also advised to increase their consumption of fruits, vegetables, and nuts and to use mustard seed and soybean oil (3-4 servings day), both of which are rich in ALA. After 2years of follow-up, there was a 50 reduction in total cardiovascular endpoints (fatal...

Initial Stabilization

Cardiac abnormalities are common in the first 24 to 48 hr following SAH, and they are almost always completely reversible. Electrocardiographic alterations, including tall-peaked T-waves (cerebral T-waves), QT segment prolongation, and ST segment elevation depression, are frequent they have been linked to excessive levels of circulating catecholamines (19). Cardiac enzymes may be elevated in up to one-third of patients and are variably associated with echocardiographic abnormalities. These disturbances may occur in the absence of coronary artery disease. Myocardial lesions (mainly contraction band necrosis) that have been reported in cases of SAH are pathologically distinct from ischemic lesions (20). Arrhythmias are frequently seen however, life-threatening arrhythmias such as ventricular tachycardia have been only rarely noted (21). Cardiac wall motion abnormalities have also been detected in up to one-third of patients (22). In rare cases, a picture of a stunned myocardium...

Small Arteries and Arterioles

Aging and disease modify vascular structure and function. Hypertension is associated with vasoconstriction, VSM hypertrophy and rarefaction in the microcirculation. Pulse volume, pressure, and velocity are important physiological variables that may function as biologic signals to the endothelium and VSM of the microcirculation. The capillary pulse volume modifies and in turn is modified by microcirculatory structure and function. For example, both MAP and PP affect glomerular filtration rate independently, presumably through direct effects on glomerular filtration pressure 61 . Increased systolic BP or PP is associated with a variety of disorders related to aging, including atherosclerotic cardiovascular disease 62, 63 , heart failure 64 , stroke 65, 66 , cognitive disorders 67-69 , white matter lesions 70, 71 , macular degeneration 72 , renal dysfunction 73 , osteoporosis 74 , and glucose intolerance 75-77 . Abnormal microcirculatory pulsation may participate in the pathogenesis of...

Vulnerable Plaque Description and Pathophysiology

I nvestigators, working in the field of identification and treatment of high-risk vulnerable atherosclerotic plaques and patients, have recognized that an increased understanding of the pathophysiology of coronary thrombosis and onset of acute coronary syndromes has created the need for agreement on nomenclature 1 . This chapter gives a summary of that agreement. The terms in figure 1 are proposed for use on a conceptual basis. The progression from asymptomatic atherosclerosis, to a high-risk vulnerable plaque, to a thrombosed plaque, and to clinical events is presented. It is of note that the later stages of the progression may be repeated in a relatively short time interval as documented by the high short-term risk of a recurrent event in patients with acute coronary syndromes. This may be caused by rethrombosis of the lesion causing the index event, and or the simultaneous occurrence of multiple high-risk vulnerable plaques and or thrombosed plaques that have not previously caused...

Anterior Circulation Thrombolysis

Internal Carotid Artery Occlusion Acute stroke due to a distal ICA T (T terminus) occlusion carry a much worse prognosis than MCA occlusions. In a recent analysis of 24 consecutive patients (median NIHSS 19) presenting with T occlusions of the ICA who were treated by IAT using urokinase at an average of 237 minutes from symptom onset, only four patients (16.6 ) had a favorable outcome at 3 months. Partial recanalization of the intracranial ICA was achieved in 15 (63 ), of the MCA in 4 (17 ), and of the ACA in 8 patients (33 ). Complete reca-nalization did not occur. The presence of good leptomeningeal collaterals and age < 60 years were the only predictors of a favorable clinical outcome.26 New treatment strategies, such as the combination of IV rt-PA and IAT27, or the use of new mechanical devices13 may improve the outcome in these patients.

Summary and Conclusion

The Mediterranean dietary patterns are associated with lower CHD rates and with improved CHD risk factors. In the interpretation of observational data, it is often difficult to separate the effects of diet from other factors, e.g., smoking and physical inactivity, that likely account, in part, for observed differences in CHD risk. Nonetheless, the totality of evidence documenting a beneficial impact of Mediterranean dietary patterns on CHD risk is remarkable and consistent in both the original Seven Countries Study and in recent studies of populations with Western variants of the original diet. Cardiovascular disease risk reduction by consumption of the Mediterranean diet may be mediated through demonstrated effects on traditional CVD risk factors of through effects of factors which reduce oxidative stress.

Hierarchy Of Clinical And Functional Outcomes After aSAH

As mortality rates have fallen over the years, stroke research has increasingly focused on patient-centered outcomes that assess functional disability and health-related quality of life (QOL) among survivors (12-14). Outcome assessment after stroke is conceptualized in terms of global outcome (the entire spectrum from death to complete recovery), impairment (loss of neurologic function), disability (loss of independence in activities of daily livings, ADLs), handicap (limitation of social or societal role function), and health-related QOL (a multidimensional

Combined Intravenous and Intra Arterial Thrombolysis

Some studies have evaluated the feasibility, safety, and efficacy of combined IV rt-PA at a dose of 0.6 mg kg with IAT in patients presenting with acute strokes within 3 hours of symptom onset.31-34 This approach has the potential of combining the advantages of IV rt-PA (fast and easy to use) with the advantages of IAT (directed therapy, titrated dosing, mechanical aids to recanalization, and higher rates of recanalization), thus improving the speed and frequency of recanalization. The IMS II objective was to continue investigating the feasibility of the combined IV and IA approach to restore cerebral blood flow in acute stroke patients.37 The difference between IMS I and IMS II is that IMS II used the EKOS microcath-eter to deliver the rt-PA into the clot, using microcatheter ultrasound technology. The rationale is that the ultrasound energy delivered in the clot loosens the fibrin strands, increasing the permeability and penetration of the thrombolytic agents. In IMS II, patients...

Neurologic Impairment After aSAH

Assessment of impairment is critical for detection of a positive treatment effect in clinical trials, because it is the measure of outcome that most directly reflects neurologic injury. Unfortunately, scales used to evaluate impairment after ischemic stroke, such as the NIHSS,

Basic Laboratory Research

Oxidative processes may play an important role in the pathogenesis of many chronic diseases, including atherosclerosis, cancer, arthritis, eye disease, and reperfusion injury during myocardial infarction (MI). Data from in vitro and in vivo studies suggest that oxidative damage to low-density lipoprotein (LDL) promotes several steps in atherogenesis,7 including endothelial cell damage,8,9 foam cell accumulation,1012 and growth13,14 and synthesis of autoantibodies.15 In addition, animal studies suggest that free radicals may directly damage arterial

Endothelial Function Mechanical Stress and Atherosclerosis

Atherosclerosis and its complications represent the leading cause of morbidity and mortality in the industrialized as well as in the developing countries. Classical cardiovascular risk factors have been identified over the past decades leading to recommendations for life style modifications and to the development of efficient and well-tolerated drug regimens aimed at reducing the occurrence of cardiovascular complications. The endo-thelium due to its position in the circulation is the first organ being exposed to circulating noxious elements and solutes as well as to the mechanical aggressions generated by heartbeats and pulsating blood flow. This review addresses the relevance of the combined effects of the mechanical stress and cardiovascular risk factors on the early phases of atherosclerosis. It is now well established that endothelial dysfunction is a very early event if not the earliest in the process of atherogenesis and therefore, testing endo-thelial function may serve as a...

Observational Epidemiology

While molecular mechanisms exist to explain potential benefits of antioxidants, clinical outcomes are needed to evaluate the benefit in humans. Observational studies can use information about diet and vitamin intake to identify potential protective effects of antioxidants. Results from cross-sectional, case-control, and cohort studies suggest that antioxidant consumption reduces the risk of developing heart disease and stroke19 with the strongest data in favor of vitamin E.20

Role Of Matrix Metalloproteinases

Tissue inhibitor of metalloproteinases (TIMP), especially (TIMP-2), which is found in the brain parenchyma, can be administered in experimental ICH to decrease perihematoma edema by protecting the BBB (80). In humans, a high blood concentration of MMP-9 detected within the first 24 hr of ICH (81) was associated with early edema and edema progression in the subsequent days, whereas high MMP-3 concentration correlated with mortality and residual scar volume (82). MMP-9 concentration was also found to serve as a biologic marker for predicting ICH complications after thrombolytic therapy in human ischemic stroke (83) and hematoma expansion (23) , which would suggest that MMPs are predisposing factors for hemorrhage. Interestingly, activation of MMPs was observed in heart transplant recipients when donors died following spontaneous ICH. These heart transplant recipients demonstrated upregulation of MMP-2 and MMP-9, which was associated with cardiac remodeling and subsequent development of...

Etiologic Factors For Intracerebral Hemorrhage

An ICH, classified as either primary or secondary, can be caused by a variety of factors (Table 1). Primary ICH refers to spontaneous hemorrhage from systemic hypertension. Hypertensive ICH usually occurs in middle-aged to older patients, and the hemorrhage might be attributed to small aneurysmal dilatations on the small, perforating cerebral arteries. These aneurysms are usually multiple, tend to occur in arteries < 25 pm in diameter, and might attain a diameter of up to 2 mm. These microaneurysms are usually seen in hypertensive patients and are occasionally seen in normotensive patients and in those over 65 years of age. Secondary ICH can occur due to a variety of underlying structural abnormalities, including a ruptured cerebral aneu-rysm, arteriovenous malformation, other vascular malformation, cerebral amyloid angiopathy, tumors, trauma, and vasculitis. ICH can also occur secondary to coagulopathy that results from thrombocytopenia and anticoagulant therapy. Thrombolytic...

Vitamin E Primary Prevention Trials

Table 3.2 Completed and ongoing randomized clinical trials of vitamin E supplementation in the primary prevention of cardiovascular disease (CVD) Table 3.2 Completed and ongoing randomized clinical trials of vitamin E supplementation in the primary prevention of cardiovascular disease (CVD) Fatal ischemic heart disease Fatal ischemic stroke Fatal hemorrhagic stroke The Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study was the first large-scale randomized trial of antioxidant vitamins in a well-nourished population. This 2 x 2 factorial trial tested the effect of synthetic vitamin E (50 mg d) and beta-carotene (20 mg d) in the prevention of lung cancer among 29,133 Finnish male smokers aged 50-69 years.29 After a median of 6.1 years, vitamin E supplementation did not reduce the risk of lung cancer (the primary endpoint). There was also no clear reduction in risk of death due to ischemic heart disease (RR 0.95 95 CI, 0.85-1.05) or ischemic stroke (RR 0.84 95 CI, 0.59-1.19)...

Endovascular Thrombectomy

The Concentric Retriever (Concentric Medical Inc., Mountain View, CA), a flexible, nitinol wire with helical tapering coil loops (X5 and X6) that is used in conjunction with a balloon guide catheter (8 or 9 French) and a microcatheter, is the only device currently approved by the FDA for the endovascular treatment of stroke patients (Fig. 4.3).13 The second-generation devices (L5 and L6) differ from the X devices by the inclusion of a system of arcading filaments attached to a nontapering

Vitamin E Secondary Prevention Trials

Table 3.3 Completed and ongoing randomized clinical trials of vitamin E supplementation in the secondary prevention of cardiovascular disease (CVD) Secondary Prevention with Antioxidants of Cardiovascular disease in Endstage renal disease (SPACE) Women's Antioxidant Cardiovascular Study (WACS) MI + ischemic stroke + 0.46 (0.27-0.78) peripheral vascular disease + unstable angina Because antioxidants may have an earlier and more pronounced effect in patients with high oxidative stress, the Secondary Prevention with Antioxidants of Cardiovascular Disease in Endstage Renal Disease (SPACE) trial randomized 196 hemodialysis patients with CVD to large doses of vitamin E (800 IU daily) or placebo.47 After a median follow-up of 519 days, vitamin E was associated with significant reductions in the combined endpoint of MI (fatal and nonfatal), ischemic stroke, peripheral vascular disease, and unstable angina (RR 0.46 95 CI, 0.270.78). Those in the vitamin E group were less likely to have an MI...

Computerized Tomography and Magnetic Resonance Imaging

Distinguishing between ICH and ischemic stroke becomes a daunting task if only clinical criteria are used, though the presence of headache, nausea, and vomiting significantly elevated blood pressure, and an early reduction in the patient's level of consciousness favor the diagnosis of ICH. Brain computerized tomography (CT) is essential for making the diagnosis of ICH and for guiding patient-risk allocation and management based on the location of the bleed. An ICH > 30 cc is usually an indicator of poor prognosis, with mortality rates increasing significantly

Blood Pressure Management

The accurate assessment of the hemodynamic state in ICH patients is of primary importance during their early management. The vast majority of acute stroke patients present with elevated blood pressure as clinical manifestation of a long-standing premorbid condition, as a physiologic response to the acute neurologic insult, or as a combination of both. In the unusual situation in which hypotension occurs, etiologic causes, such as hypovolemia, neuro cardio-genic cardiac dysfunction, or significant bleeding at a remote site, must be investigated and treated aggressively, once demonstrated. Vascular access must be adequate for all diagnostic and therapeutic interventions. Central venous access should be considered for patients who require administration of vasoactive drugs or who have inadequate peripheral vein caliber to accommodate the large-bore catheters that are necessary for resuscitation. Insertion of an arterial catheter should be considered in patients in whom measurement of...

Blood Pressure Large Arteries and Atherosclerosis

It is generally accepted that the increased cardiovascular morbidity and mortality in hypertension are related to target organ damage. Classically, the target organs are heart, brain, and kidneys. This brief report examines whether high arterial pressure may also affect other organs, such as aorta and large arteries. An attempt was also made to elucidate the relationship between disorders of the aorta and large arteries and other cardiovascular risk factors to the pathophysiology and treatment of patients with hypertension and its severe comorbid disease, atherosclerosis. The positive correlation between arterial pressure and adverse cardiovascular events is certainly well documented. It was Sir George Pickering who vigorously opposed the idea of dividing blood pressure into normotension and hypertension stating that ' the various complications, like myocardial infarction and stroke, are also quantitatively related to arterial pressure ' 1 . Furthermore, current therapeutic approaches...

Betacarotene Primary Prevention Trials

Results from large-scale randomized trials of beta-carotene in the primary prevention of CVD have been disappointing. These trials are summarized in Table 3.4. In the previously described ATBC trial among Finnish male smokers, participants assigned to 20 mg d of beta-carotene had an increased risk of ischemic heart disease mortality (RR 1.12 95 CI, 1.00-1.25) and no reduction in the risk of angina (RR 1.06 95 CI, 0.97-1.16). For the primary endpoint of lung cancer, an increased risk was noted after 4 years (RR 1.18 95 CI 1.03-1.36), but this association disappeared after 6 years of post-trial follow-up (RR 1.06 95 CI 0.94-1.20).31 There were no late preventive effects of beta-carotene. Table 3.4 Completed and ongoing randomized clinical trials of beta-carotene alone in the primary prevention of cardiovascular disease (CVD) CVD mortality Fatal ischemic heart disease Fatal ischemic stroke Fatal hemorrhagic stroke CVD mortality

Arterial Stiffness and Coronary Ischemic Disease

Large artery stiffening may be both a cause and a consequence of atherosclerosis and is independently related to coronary outcome. This relationship is likely to be causal given the unfavourable effect of large artery stiffening on coronary hemodynamics. There is clear experimental and clinical evidence that large artery stiffening promotes myocar-dial ischemia secondary to central pulse pressure elevation. Many agents commonly used to treat ischemic heart disease symptoms also reduce large artery stiffness, through both functional and structural mechanisms. Such effects likely contribute to the anti-ischemic actions of these drugs. However, it remains to be elucidated whether agents specifically targeted to reduce large artery stiffness provide ischemic protection in the setting of coronary disease. Stiff large arteries are associated with coronary artery disease 1-7 , myocardial ischemia 8, 9 and coronary mortality 10 . The inter-relationships between large artery stiffness and...

Betacarotene Secondary Prevention Trials

Table 3.5 Completed and ongoing randomized clinical trials of beta-carotene alone in the secondary prevention of cardiovascular disease (CVD) Table 3.5 Completed and ongoing randomized clinical trials of beta-carotene alone in the secondary prevention of cardiovascular disease (CVD)

Pharmaceutical Drug Trials Antioxidants Free Radical Scavengers

A trial of Ebselen PZ51, a selenoorganic compound with glutathione peroxidase-like action, is currently in phase III of clinical trial. A small, randomized, double-blind, placebo-controlled trial of Ebselen initiated within 48 hours after stroke suggested protective efficacy as measured by the Glascow Outcome Scale (GOS) and Barthel Index (BI) at 1 month (p 0.023), but not at 3 months (p 0.056). Better clinical outcomes were observed if Ebselen administration was initiated less than 24 hours after symptom onset, but not greater than 24 hours.19 The Edaravone Acute Infarction Study (EAIS), a double-blind, randomized, placebo-controlled study looking at the effect of Edaravone (MCI-186) administered within 72 hours after ischemic stroke onset, yielded promising results (modified Rankin Scale mRS score significantly improved p 0.0382).20 The agent has been clinically available in Japan since 2001 however, it has not been followed up with either further study or clinical usage in the...

Combination Antioxidant Primary Prevention Trials

Table 3.6 Completed and ongoing randomized clinical trials of combinations of antioxidants in the primary prevention of cardiovascular disease (CVD) Table 3.6 Completed and ongoing randomized clinical trials of combinations of antioxidants in the primary prevention of cardiovascular disease (CVD)

Anticoagulant Related Hemorrhage

Chronic anticoagulation, often for the purpose of preventing ischemic stroke, is a risk factor for ICH. It also appears to be associated with an increased likelihood of a poor outcome in patients who suffer an ICH. Two early reports focused on prognosis in anticoagulant-related hemorrhage. One reported that 20 of 40 patients did not survive, but 18 of 20 survivors recovered completely. Five patients suffered concomitant subdural hematomas, but no patients had multiple ICHs (59). The second report found that 28 of a series of 200 patients with ICH had been taking warfarin at the time of the hemorrhage (57). The mortality of the entire group was 30 , but 57 of those with anticoagulant-related hemorrhages died. The anticoagulant-related hemorrhages were also larger on average (57). A 2004 study attempted to quantify the independent effect, on ICH prognosis, of anticoagulation with warfarin by assessing 435 consecutive ICH patients over age 55, of whom 102 were taking warfarin at the time...

Does Arterial Stiffness Predict Atherosclerotic Coronary Events

Coronary heart disease is a major cause of death and morbidity. Due to the increased longevity of most developed societies, there is an increasing overlap between arteriosclerosis associated with normal vascular ageing and atherosclerosis associated with cardiovascular risk factors. There is therefore a need for improvements, both in the early identification of individuals at risk, and in cardiovascular risk stratification. Arterial stiffness is an important determinant of cardiovascular risk and can now be measured simply and non-invasively in large populations. This review will therefore focus on the current evidence as to the predictive value of arterial stiffness in relation to coronary events and also on the possible pathophysiological mechanisms linking arterial stiffness and atherosclerosis. Atherosclerotic coronary heart disease (CHD) is one of the leading causes of death worldwide. Therefore, the early detection of occult atheroma, or those individuals who are at...

Combination Antioxidant Secondary Prevention Trials

Table 3.7 Completed and ongoing randomized clinical trials of combinations of antioxidants in the secondary prevention of cardiovascular disease (CVD) 20,536 men and women aged 40-80 years, with CHD, diabetes or treated hypertension United Kingdom 423 postmenopausal women with coronary artery disease 8,171 female health professionals aged > 45 years, with CVD or > 3 coronary risk factors United States In the Women's Angiographic Vitamin and Estrogen (WAVE) trial, 423 post-menopausal women with coronary artery disease were randomized to a combination of vitamin E (400 IU twice daily) and vitamin C (500 mg twice daily) or placebo.67 After a mean follow-up of 2.8 years, those assigned to the high-dose antioxidant combination had the suggestion of an increased risk of death, stroke, or nonfatal MI (RR 1.5 95 CI, 0.80-2.9), but the confidence intervals were wide. This study suggested that there may be an increased risk associated with antioxi-dant combination supplements.

Mechanisms of Ischemic Cell Death

Ischemic stroke compromises blood flow and energy supply to the brain, which triggers at least five fundamental mechanisms that lead to cell death excito-toxicity and ionic imbalance, oxidative nitrative stress, inflammation, apoptosis, and peri-infarct depolarization (Fig. 1.1). These pathophysiological processes evolve in a series of complex spatial and temporal events spread out over hours or even days

Nonpharmaceutical Approaches Albumin

Ginsberg's pioneering animal research has shown that albumin infusions enhance red cell perfusion and suppress thrombosis and leukocyte adhesion in the microcirculation, particularly during the early reperfusion phase.54 Albumin also improves microcirculatory flow, plasma viscosity, red cell deformability, and oxygen transport capacity. In addition, albumin has potent antioxidant and antiapoptotic effects. In experimental stroke, albumin has been shown to reduce infarct size, improve neurofunction scores, and reduce brain edema.55 In the Albumin in Acute Stroke (ALIAS) phase II trial, an open-labeled, dose-escalation, nonrandomized pilot clinical trial conducted at two centers in North America, albumin was found to be safe and effective in reducing stroke-related brain injury.56,57 Eighty-two subjects with an NIHSS> 6 received 25 albumin within 16hours of stroke onset in two doses, 0.34-1.03 and 1.37-2.05 g kg. Nearly half of the patients (42) also received rt-PA. The probability of...

Excitatory Amino Acids

The NMDA receptor-channel complex is thought to facilitate calcium entry into the cell after stimulation by glutamate or NMDA. At rest, the NMDA channel is blocked by magnesium, which can be removed by a depolarizing stimulus. In addition to its ligand-binding site, the complex contains glycine, polyamine, and zinc domains, of which a variety of modulators have been studied in the laboratory as potential neuroprotectants (13). Unfortunately, none of the therapeutic strategies aimed at these targets have yielded positive results at the clinical level for treatment of acute stroke (14). Other work in this area suggests that modulation of NMDA subunits during ischemia and related insults might have an important role in their function. NMDA receptors consist of several subunits, including NR1 and NR2. NR1 might facilitate neurotoxicity, as NR1 knockout mice were resistant to glutamate-induced excitotoxicity (15) and rats treated with antisense oligodeoxynucleotides to inhibit the...

Immediate Early Genes

Members of the IEG families, such as c-fos, c-jun, and zinc finger (zif), were among the first genes observed after ischemia onset and are known to be highly upregulated within minutes (72). Mitochondrial membrane depolarization, calcium uptake, and release of factors (e.g., cytochrome c) can ultimately activate activator protein-1 (AP-1) to induce gene expression (73). The induction of IEGs includes several consecutive steps. Ischemia-associated increases in extracellular glutamate and intracellular calcium can lead to the activation of protein kinases (e.g., protein kinase A and protein kinase C), which can phosphorylate DNA binding proteins. DNA binding proteins recognize specific binding domains, which then initiate transcription of the downstream target genes (74). The c-fos gene, an IEG that encodes the Fos protein, was found to be upregulated within 30 min after stroke onset (72). Fos protein contains several important structural features, such as a DNA binding region and a...

Physiological Strategies Hypothermia

As with all molecular and biochemical pathways, the major mechanisms of cell death are temperature-dependent. Hypothermia can protect against multiple deleterious processes, including oxidative stress, inflammation, lipid peroxidation, and activation of cysteine or serine proteases.88-94 Each degree of temperature decline reduces the rate of cellular respiration, oxygen demand, carbon dioxide production by 10 .95 Preclinical and clinical results have been encouraging, making hypothermia an attractive physiological therapy that targets multiple injury mechanisms. However, the therapeutic time window for hypothermia is narrow.96 In one study, hypothermia proved beneficial if initiated 30 minutes before stroke onset, but not 10 minutes after stroke onset.97 Based on these results, additional controlled trials are now underway to test the therapeutic impact of hypothermia combined with thrombolysis. The results of a recent trial (Cooling for Acute Ischemic Brain Damage COOL-AID )105...

Conclusions And Future Directions

Ischemic stroke triggers a diversity of signaling pathways related to altered gene expression, inflammation, oxidative stress, mitochondrial function, and programmed cell death. The outcome of ischemic stroke depends on how early the blood flow can be restored and how early the related treatments can be provided. Although no one animal model can completely model the human disease, recent work has taken advantage of the many advances in molecular and cellular biology as tools to better understand the pathogenesis of stroke. Over the past 2 decades, only one treatment (thrombolytic therapy with rtPA) has been available in the United States for patients with acute stroke. However, a better understanding of the involved mechanisms should certainly lead to the identification of appropriate treatments.

Excitotoxicity and Ionic Imbalance

Ischemic stroke results in impaired cellular energy metabolism and failure of energy-dependent processes such as the sodium-potassium ATPase. Loss of energy stores results in ionic imbalance, neurotrans-mitter release, and inhibition of the reuptake of excitatory neurotransmitters such as glutamate. Glutamate binding to ionotropic N-methyl-D-aspartate (NMDA) and acid (AMPA) receptors promotes excessive calcium influx that triggers a wide array of downstream phospholipases and proteases, which in turn degrade membranes and proteins essential for cellular integrity. In experimental models of stroke, extracellular glutamate levels increase in the micro-dialysate 2, 3 , and glutamate receptor blockade attenuates stroke lesion volumes. NMDA receptor antagonists prevent the expansion of stroke lesions in part by blocking spontaneous and spreading depolarizations of neurons and glia (cortical spreading depression) 4 . More recently, activation of the metabotropic subfamily of receptors has...

Mri In Stroke Research

New imaging techniques, especially MRI, can provide a translational link between experimental advances in acute stroke research and clinical applications (33). MRI can identify markers of tissue at risk (to link therapy to tissue pathobiology) demonstrate the effects of cerebral reperfusion on the underlying vascular pathology, cerebral blood flow, and blood-brain barrier (BBB) integrity and establish parameters for dose, duration, and time window to optimize drug delivery to the ischemic area. New knowledge in these areas and the use of MRI in therapeutic studies can lead to improved patient selection and evaluation of drug activity in clinical trials.

MRI to Study Stroke Pathophysiology

The use of DWI and PWI to make prognoses in individual patients is an active area of research (11,16,35,36). Data from natural history studies and clinical trials show significant correlations between the volume of abnormality on acute DWI and clinical severity they also show that a combination of clinical factors (NIHSS score and time in hours from stroke onset to DWI) and DWI volume measurements is a better predictor of stroke outcome than the use of a single factor at acute or chronic times (11,12,16,17,19,37). Several studies have analyzed early MR characteristics that, in untreated stroke patients, predict the final infarct volume. We previously used a logistic regression model to differentiate regions of ultimate infarction versus noninfarction, based on baseline perfusion measures, and to operationally define the ischemic penumbra (36). Other groups have employed a variety of statistical and empirical approaches, such as generalized linear model algorithms, multiparametric...

MRI in Clinical Trials

Clinical trials must enroll a sufficiently homogeneous sample to reduce the statistical variance of the data and optimize the sensitivity of the design to detect a therapeutic response, while remaining representative of the population of interest. Ischemic stroke trials have traditionally limited the range of disease studied to one or more clinical dimensions (severity, duration, or prognosis of the clinical deficits) and relied on noncontrast CT scan for exclusion of cerebral hemorrhage or other nonischemic pathology. Reliance on clinical criteria, however, can be misleading, and CT scanning has poor sensitivity for the diagnosis of early ischemic changes (75). Because MRI can detect early ischemic pathology, rule out ICH, and visualize the vasculature, it can identify the pathologic subtype and allow the appropriate use of treatment-congruent criteria for patient selection (76). Using MRI-based pathologic criteria rather than clinical assessment In experimental models, reduction of...

National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study

The NINDS rtPA Stroke Study was conducted at the same time as ECASS I. The NINDS trial was the first large, randomized, double-blinded trial to show benefit of a thrombolytic in acute stroke (15). Patients were enrolled if they presented within 3 hr of an acute ischemic stroke and had a deficit as measured by the National Institute of Health (NIH) Stroke Scale, (NIHSS) , and a CT scan that showed no evidence of hemorrhage. Noteworthily, no patients were excluded due to Table 1 Intravenous Tissue Plasminogen Activator Administration Inclusion Exclusion Criteria for Ischemic Stroke 1. Clinical diagnosis of ischemic stroke with measurable deficit 7. Clinical presentation suggesting pericarditis or myocardial infarction group (21 p 0.30). Although certain rtPA-treated subgroups had worse clinical outcomes than the overall treatment group, all subgroups responded favorably to rtPA therapy when compared to their matched placebo groups (16). This trial was also the first large randomized...

Combined Intravenous and Intraarterial Therapies

The median time from stroke onset to treatment for the PROACT trials was approximately 5.5 hr, highlighting the problem with IA management of acute stroke. The time needed to assemble all of the components required to perform the procedure is substantial. Based on data from the NINDS trial, it would be unethical to withhold IV rtPA therapy in qualified patients presenting within 3 hr of stroke onset. However, certain subgroups of patients (hyperdense artery signs, more severe deficit, and older age) benefit from IV thrombolytics to a lesser degree than the general target population. No randomized, controlled study has compared the rates of recanalization of IV versus IA thrombolysis. Wolpert et al. reported that 32 out of 93 (34 ) patients had recanalization of their MCAs after the administration of IV rtPA, with most recan-alizations taking place in distal occlusions (28). In PROACT I and II, the recanalization rate was between 57.7 and 66 .

Emergency Management of Stroke EMSBridging Trial

Based on the results cited and other anecdotal evidence (and before publication of the NINDS stroke trial), the EMS-bridging trial was initiated to combine the purported advantages of both IV rtPA (timeliness and relative ease of administration) and IA administration (higher recanalization rates and decreased dose) (29). This was a Phase 1 pilot study of IV rtPA or placebo followed by immediate cerebral arteriography and local IA administration of rtPA. The goal was to test the feasibility, efficacy, and safety of this combined therapy in acute stroke within 3 hr of onset. Thirty-five patients were enrolled. The 17 patients who received IV rtPA were given a dose of 0.6 mg kg (maximum of 60 mg), 10 bolus, with remainder administered over 30 min. Of the 35 patients enrolled, 34 were taken for cerebral angiography. If an occlusion was found, a very specific protocol was followed for attempted recanalization 1 mg of rtPA was administered beyond the thrombus and then 1 mg was infused...

Manual Clot Retrieval

Due to the well-documented risks of thrombolytic therapy in stroke patients who present outside of the 3-hr time window, or other exclusions from standard therapy, manual thrombolectomy devices are being tested. One of the more promising of these is the concentric clot retriever device. Data was published in December 2004 from a Phase 1 trial that used this device specifically designed for intracranial embolectomy (39). Twenty-eight patients who presented within 8 hr, with a median NIHSS of 22, were treated. Successful recanalization with mechanical embolec-tomy was achieved in 12 (43 ) patients. With the addition of IA rtPA, a total of 18 (64 ) patients were recanalized. No symptomatic ICH occurred. At 1 month, 9 of 18 revascularized patients and none of the nonrevascularized patients had achieved significant recovery. However, a 7 complication rate, caused from either the device or the procedure, was reported. The mortality rate at 90 days was 39 . At present, there is presently...

Patients Outside the 3hr Window

Although little controversy exists over the care of stroke patients presenting within 3 hr of symptom onset, patients beyond this window have increased rates of complications that bring into question the benefit of thrombolytics. Desmoteplase is the only intravenously administered thrombolytic to show improved functional outcome in patients who present > 3 hr after onset of symptoms. The failure of the ECASS and ATLANTIS trials to show benefit has been largely attributed to the > 3-hr time limit to administer thrombolytics. These findings beg the question Should the 3-hr window be an absolute ceiling for administration of IV thrombolysis A pooled analysis of ECASS I and II, the NINDS, and ATLANTIS trials, which addresses this issue, was recently published (45). Results of this analysis again clearly verified the safety and efficacy of thrombolysis within 3 hr from onset of symptoms and, in fact, showed possible efficacy up to 4.5 hr (Fig. 1), in addition to demonstrating a strong...

Blood Pressure And Stroke

The most important risk factor for stroke is hypertension, and aggressive treatment of hypertension can significantly reduce the risk of stroke (2-4). In the setting of acute ischemic stroke, however, interventions that reduce blood pressure (BP) can be detrimental (5-7). Spontaneous BP fluctuations are also predictive of outcome both extreme hypotension and extreme hypertension after stroke onset are associated with worse outcome (8-14). Marked hypertension is associated with severe stroke, and appears to contribute to the development of cerebral edema (13,14). Whether treatment of extreme hypertension will improve outcome or limit the formation of cerebral edema has not been rigorously studied in prospective randomized, controlled trials. Given the tight regulation of CBF, the relationship between BP and stroke outcome might seem difficult to reconcile. Blood flow to the brain is independent of mean arterial blood pressure and cerebral perfusion pressure (CPP) within the normal...