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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.amjmed.2008.11.004 Byline: Vineet Chopra (a), Benjamin Plaisance (a), Erdal Cavusoglu (b), Scott A. Flanders (a), Kim A. Eagle (c) Keywords: Beta-blockers; Noncardiac surgery; Perioperative risk reduction; POISE Abstract: Recent studies have called into question the benefit of perioperative beta blockade, especially in patients at low to moderate risk of cardiac events. Once considered standard of care, the role of beta-blocker therapy now lies mired in conflicting data that are difficult to apply to the at-risk patient. We provide an overview of the evolution of perioperative beta blockade, beginning with the physiology of the adrenergic system, with emphasis on the biologic rationale for the perioperative implementation of beta-blockers. Although initial studies were small in size and statistically limited, early data showed cardiac benefit with the use of perioperative beta-blockers. However, larger, more recent studies now suggest a lack of benefit and potential harm from this practice. This paradigm holds true especially in those at low-to-moderate cardiovascular risk profiles. Potential explanations for these paradoxical results are discussed, stressing the key differences between earlier and current studies that may explain these divergent outcomes. We conclude by commenting on performance measures as they relate to perioperative beta-blockers and make recommendations for the continued safe implementation of this practice. Author Affiliation: (a) Division of General Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (b) Division of Cardiology, Department of Medicine, State University of New York Downstate Medical Center, Brooklyn (c) Division of Cardiovascular Medicine, Department of Medicine, University of Michigan Health System, Ann Arbor Article Note: (footnote) Funding: None; no funding received., Conflicts of Interest: There are no conflicts of interest for any of the authors., Authorship: All authors had access to the data and a role in writing the manuscript.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.amjmed.2005.10.039 Byline: Kenneth R. McQuaid (a)(b), Loren Laine (c) Keywords: Aspirin; Clopidogrel; Meta-analysis; Systematic review; Cardiovascular diseases Abstract: We performed a systematic review to define the relative and absolute risk of clinically relevant adverse events with the antiplatelet agents, aspirin and clopidogrel. Author Affiliation: (a) Veterans Affairs Medical Center, San Francisco, Ca (b) Department of Medicine, University of California San Francisco (c) Department of Medicine, University of Southern California, Los Angeles Article Note: (footnote) Supported by a grant from Bayer Healthcare LLC, Morristown, NJ.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.amjmed.2005.09.035 Byline: Bruce Ettinger Keywords: Hormone therapy; Low dosage; Side effects; Vasomotor symptoms Abstract: Recent clinical trials show that low-dose estrogen reduces the number of moderate to severe vasomotor episodes by 65%. This reduction is about midway between the 35% to 40% reduction observed with placebo and the 75% to 80% reduction observed with standard dosage. Compared with standard dosages whose effects are substantial by 4 weeks, relief with lower dosages is not maximal until 8 to 12 weeks. Women using lower dosages of estrogen experience 50% lower rates of irregular bleeding or breast tenderness compared with individuals taking standard dosages. Despite several lower dosage hormone therapy (HT) formulations being approved by the US Food and Drug Administration (FDA) and brought to market, their uptake by healthcare providers has been slow. Most women who have continued HT after reports of the Women's Health Initiative (WHI) were published take estrogen at the standard dosage; only a minority of these individuals report receiving guidance about switching to a lower dosage. The purpose of this review is to summarize the clinical trial data showing, on one hand, effects of various dosages of estrogen on vasomotor symptoms and, on the other hand, the effects of these same doses on troublesome adverse events, particularly vaginal bleeding or breast tenderness. It is time to reconsider the current estrogen dosage recommendation on the basis of symptom benefit versus symptom nuisance. Furthermore, healthcare providers need to learn how and when to prescribe lower dosages of HT to optimize patient acceptance and continuation. Article Note: (footnote) The opinions offered at the National Institutes of Health (NIH) State-of-the-Science Conference on Management of Menopause-Related Symptoms and published herein are not necessarily those of the National Institute on Aging (NIA) and the Office of Medical Applications of Research (OMAR) or any of the cosponsoring institutes, offices, or centers of the NIH. Although the NIA and OMAR organized this meeting, this article is not intended as a statement of Federal guidelines or policy. Publication of the online supplement was made possible by funding from the NIA and the National Center for Complementary and Alternative Medicine of the NIH, US Department of Health & Human Services.

Amlodipine is an intrinsically long-acting, vaso-selective calcium antagonist structurally related to nifedipine, but with unique binding and pharmacologic properties that distinguish it from other agents of this class. Pharmacokinatic studies in animal models demonstrate a more prolonged half-life, high volume of distribution, and gradual elimination of amlodipine compared with that of other calcium antagonists. The presence of a basic side chain at the 2-position of the dihydropyridine ring renders the molecule >90% ionized at physiologic pH and is believed to be primarily responsible for its markedly different pharmacologic and pharmacokinetic properties. Amlodipine has slow receptor binding kinetics that result in a gradual onset of action and may allow for less dependence on instantaneous plasma levels. Although amlodipine appears to bind to additional calcium channel recognition sites blocked by diltiazem and verapamil, it does not significantly depress heart rate nor does it produce significant negative inotropic effects or electrophysiologic disturbances. Preclinical studies indicate that amlodipine is a potent antihypertensive agent with natriuretic and diuretic properties that may enhance its ability to reduce blood pressure without attendant fluid retention. (Am J Cardiol 1994;73:2A-9A)

Withdrawal of [Beta]-blocker therapy has been associated with the development of adrenergic hypersensitivity and adverse clinical effects in patients with coronary artery disease and hypertension. The aim of this study was to establish the occurrence and clinical significance of adrenergic hypersensitivity after abrupt withdrawal of long-term [Beta] blockade in hypertrophic cardiomyopathy. Beta-adrenergic sensitivity was measured using the isoprenaline chronotropic [dose.sub.25] Symptom assessment chronotropic [dose.sub.25] calculation, bicycle exercise, echocardiography and Holter monitoring were performed while the patient received [beta]-blocker therapy and repeated on days 2, 4, 6, 8 (acute withdrawal period) and on day 21 after abrupt withdrawal. The study was terminated after 7 patients had been studied because all patients experienced a marked deterioration in symptoms and several clinical events had occurred. The chronotropic [dose.sub.25] (mean [+ or -] standard deviation) demonstrated [beta]1-adrenergic hypersensitivity with a minimal value of 1.6 [+ or -] 0.8 [microgram] during the acute withdrawal period compared with 3.8 [+ or -] 1.7 [microgram] on day 21 (p = 0.003). Heart rates during rest and exercise showed an overshoot increase during the acute withdrawal period. The maximal 24-hour ventricular ectopic count was higher during the acute withdrawal period than during day 21 (p = 0.04). Of 3 patients with inducible outflow tract gradients, 2 developed resting gradients > 30 mm Hg during the acute withdrawal period. There was an increase in peak late filling velocity of mitral inflow after [beta]-blocker withdrawal. In conclusion, transient [Beta]-adrenergic hypersensitivity occurs after [Beta]-blocker withdrawal in hypertrophic cardiomyopathy and is associated with significant physiologic changes and adverse clinical consequences., Beta adrenergic blocking agents (beta blockers) are a class of drugs that have widespread use in the treatment of cardiovascular disorders, particularly coronary artery disease (blockage of the arteries supplying blood to the heart) and hypertension (high blood pressure). Adverse effects have been reported in patients who received long-term administration of beta blockers when the treatment regimen was abruptly halted. Hypersensitivity to the effects of neurotransmitters, whose actions had been inhibited by the beta blockers, has been reported to produce a variety of symptoms, including irregular heartbeat, hypertension above pretreatment levels, and extreme anxiety. In severe cases, chest pain, heart attack, and death have occurred. This so-called beta-blocker withdrawal syndrome may result from an increase in the number or sensitivity of cell surface beta adrenergic receptor molecules during drug treatment. To assess the frequency and clinical significance of adrenergic hypersensitivity following withdrawal from chronic beta blocker treatment, a study was carried out involving a group of patients diagnosed as having hypertrophic cardiomyopathy (a complication of hypertension) who were to be taken off of beta blocker therapy for a variety of reasons. Physiological evaluations were conducted on this group of patients 2, 4, 6, 8, and 21 days following beta blocker withdrawal. The study was terminated after seven patients were evaluated because all patients experienced a deterioration in symptoms. Sensitivity to the cardiovascular effects of isoprenaline (a beta-receptor stimulating drug) was significantly increased during the acute withdrawal period (days two to eight), compared with day 21. Heart rate during rest and exercise showed a significant increase during the acute withdrawal period. Several patients experienced other significant adverse effects during this period (fainting, chest pain, partial paralysis); six of the seven resumed beta blocker treatment to alleviate these symptoms. (Consumer Summary produced by Reliance Medical Information, Inc.)

Previous studies have shown that long-term survival after acute myocardial infarction (AMI) is improved by Beta-adrenergic blockade and anterograde flow in the infarct artery. This study was done to assess the influence of Beta blockade on mortality in survivers of AMI without anterograde flow. Over 9.5 years, 113 subjects (87 men and 26 women, aged 26 to 66 years) with AMI and no anterograde flow in the infarct artery and no disease of the other arteries were medically treated for 48 +/- 28 (mean +/- standard deviation) months. Forty-six patients received long-term P blockade (group 1), whereas 67 did not (group 11). The groups were similar in age, sex, cardioactive medications, left ventricular performance and infarct artery. Of the 46 group 1 subject, 1 (2%) died of cardiac causes; in contrast, 20 30%) of the group 11 patients died of cardiac causes (p = 0.007 compared with group 1). Thus, in survivors of AMI without anterograde flow in the infarct artery, mortality is markedly reduced by long-term Beta blockade. (Am J Cardiol 1991;68:150-154), Acute myocardial infarction (AMI; heart attack) occurs when one or more of the coronary arteries, which supply blood to the heart, become blocked. The subsequent myocardial ischemia (diminished cardiac blood flow) can cause death or permanent cardiac damage. Among AMI survivors, ischemia-induced cardiac arrhythmias, or abnormal heart rhythms, appear to be a significant contributor to cardiovascular mortality. Some studies have reported that arrhythmias are more prevalent among AMI patients in whom there is no anterograde flow in the infarct artery. (That is, abnormal heart rhythms occur more often in AMI patients when blood flow is not reestablished in the occluded artery). Beta adrenergic receptor blockers (beta blockers), a class of drugs with blood pressure-lowering and anti-arrhythmic properties, have been reported effective in reducing mortality among AMI survivors. To test the hypothesis that one mechanism of action through which this is accomplished is suppression of cardiac arrhythmias, a study was done involving 113 subjects (87 men and 26 women between the ages of 26 and 66) who were recovering from AMI, and in whom there was no anterograde flow in the infarct-related coronary artery. Researchers theorized that since these patients are more prone to cardiac arrhythmias, they should be more susceptible to any beneficial effects of beta blocker treatment. Patients were randomly assigned to one of two groups and received either standard medical treatment or the same treatment plus beta blockers. Among the beta blocker-treated patients, only one person (2 percent) died during the course of the 48-month treatment period; 20 patients (30 percent) who did not receive beta blocker treatment died during the same period. Hence, long-term beta blockade therapy significantly reduced mortality in AMI survivors who are prone to cardiac arrhythmias. (Consumer Summary produced by Reliance Medical Information, Inc.)

Effective blood pressure control with traditional high-dose diuretic therapy has led to a distinct decrease in cerebrovascular morbidity and mortality, but failed to achieve a satisfactory reduction of coronary complications and sudden death. The same applies also for [beta] blockers, although they have been shown to be effective in secondary prevention of myocardial infarction. it is suspected that conventional antihypertensive treatment has an unfavorable effect on coronary risk factors other than hypertension : For instance, thiazide-type diuretics can impair glucose tolerance and increase the potentially atherogenic serum low-density lipoprotein (LDL) cholesterol fraction and triglycerides. Beta blockers without partial intrinsic sympathomimetic activity increase serum triglycerides and tend to lower the potentially antiatherogenic high-density lipoprotein (HDL) cholesterol. Certain [beta] blockers may also impair glucose tolerance, particularly when they are combined with diuretics. Calcium channel [beta] blockers, angiotensin converting-enzyme inhibitors and al-receptor blockers do not adversely affect lipoprotein or carbohydrate profiles. The latter two drug classes may even increase insulin sensitivity, and al blockers may also slightly improve lipid metabolism. The prognostic relevance of drug-induced dyslipidemia and/or glucose intolerance awaits further clarification. in the meantime, it is of clinical interest that several of the generally available antihypertensive drugs seem to be metabolically neutral or sometimes perhaps even potentially beneficial with regard to the lipoprotein and carbohydrate metabolism. (Am J Cardiol 1991;67:26B-3SB), Hypertension, or persistent high blood pressure, is often treated with adrenergic blocking agents (beta blockers) and diuretics (drugs that increase urine out-put). This treatment generally results in a long-term reduction in blood pressure, with a concomitant decrease in cerebrovascular disease and mortality, but it has not been shown to reduce the development (and, in fact, may increase the prevalence) of complications and sudden death resulting from coronary artery disease. This may result from the adverse effects that beta blockers and diuretics have on coronary risk factors other than hypertension, that is, these drugs may increase the risk for coronary artery disease independent of hypertension. Many beta blockers are known to increase the levels of blood triglycerides (fats) and reduce high-density lipoprotein cholesterol (so-called good cholesterol). Some beta blockers also have adverse effects on carbohydrate (sugar) metabolism, and are known to decrease insulin sensitivity, resulting in poorly controlled changes in blood sugar levels following the ingestion of carbohydrate-rich foods. These side effects tend to promote the development of fatty atherosclerotic deposits in the coronary arteries, resulting in an unfavorable long-term prognosis. More recently developed antihypertensive agents such as calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors and alpha-one adrenergic receptor blockers do not share this undesirable side effect profile; some may actually improve insulin sensitivity and blood lipid profiles. (Consumer Summary produced by Reliance Medical Information, Inc.)

Casual blood pressure, or the blood pressure reading obtained during visits to the doctor, is used as the standard for diagnosing hypertension (high blood pressure). However, in many cases, casual blood pressure readings differ significantly from average 24-hour blood pressure values, and are often not at all predictive of blood pressure levels during sleep. Studies have reported that older patients (over the age of 60) who are not taking antihypertensive medication suffer a higher incidence of myocardial infarction (MI; heart attack) during waking hours, whereas older patients who are taking antihypertensives have a higher reported incidence of MI during sleep. This finding suggests that some antihypertensive agents fail to adequately regulate cardiovascular function in these patients during the night. To further characterize the effects of antihypertensive medication on blood pressure reduction during sleep, a study was carried out in which hemodynamic variables (factors pertaining to blood flow) were measured in 68 hypertensive patients during waking and sleep. Twenty-five patients were over the age of 60 (older group); 43 patients were 59 years or younger (younger group). Baseline hemodynamic values were determined, and the effects of a variety of antihypertensive medications were determined. Thirty-six percent of the older group had high waking baseline blood pressures, with marked downward excursions during sleep. In this group, cardiac output (the volume of blood pumped from the heart during contraction) was low during waking hours, and dropped even further during sleep. Among older patients, but not younger ones, changes in blood pressure were correlated with vascular resistance (the degree of constriction of blood vessels, which affects resistance to blood flow). The antihypertensive effects of various medications during sleep were quite variable; calcium antagonists caused the greatest reduction in sleeping blood pressure, followed by (in descending order) angiotensin-converting enzyme (ACE) inhibitors, nonspecific adrenergic blockers, beta blockers, and centrally acting adrenergic blockers. (Consumer Summary produced by Reliance Medical Information, Inc.)

Blood pressure reduction in hypertensive patients is a surrogate for the real therapeutic goal of reducing the risks consequent to hypertension. This surrogate is convenient but its use may have important therapeutic implications. Results of treatment with new antihypertensive agents, data from clinical trials, and insights into underlying mechanisms are reviewed. The overall success of antihypertensive therapy has been undeniable, but has reduced minimally the frequency of atherosclerosis and coronary events; metabolic disarray resulting from the agents used, especially thiazides and beta blockers, may have contributed to this. Electrolyte abnormalities predispose to malignant arrhythmias and sudden death during myocardial infarction. Left ventricular hypertrophy, a chief risk factor for coronary events, arrhythmias, and heart failure, responds selectively to antihypertensive agents. Similarly, progression of renal injury may be sensitive to the agents used. Obesity and hypertension frequently coexist. Evidence is growing that atherogenic abnormalities common in obese patients, such as insulin resistance, also occur in the nonobese patient and are sensitive to the antihypertensive agent selected., Individuals with hypertension (high blood pressure) are at high risk of developing other types of cardiovascular disease, particularly atherosclerosis (fatty occlusive plaques within the coronary arteries) and acute myocardial infarction (heart attack). In the past 25 years antihypertensive therapy has been aggressively pursued, and treatments have brought about a dramatic reduction in the incidence of hypertension. However, many complications, such as other cardiovascular diseases, have proven to be resistant to antihypertensive therapy. One likely reason for this disappointing outcome may be the metabolic consequences of drugs used to treat hypertension. Diuretics lower blood pressure by increasing urinary fluid excretion and subsequently reducing blood volume, but this class of drugs also has detrimental effects on electrolyte balance (the concentration of various salts in body fluids), and the particular changes wrought by diuretics (decreased levels of potassium and magnesium) have been linked to the development of a variety of heart diseases. Beta blockers, a class of antihypertensive drugs that acts by interfering with the actions of the hormone epinephrine (adrenaline), have adverse effects on lipid (fat) metabolism and thus promote the formation of atherosclerotic deposits. Finally, left ventricular hypertrophy (enlargement of the ventricular chamber of the heart from which blood is pumped to most of the body), a condition that results from hypertension and obesity, among other conditions, does not respond to some antihypertensive therapy, notably diuretics and beta blockers. The newer classes of antihypertensive agents, such as calcium antagonists and angiotensin-converting enzyme (ACE) inhibitors, appear to be much more promising from the standpoint of these issues. More data need to be acquired concerning the effects of long-term hypertension management with ACE inhibitors and calcium antagonists on other forms of heart disease. (Consumer Summary produced by Reliance Medical Information, Inc.)

Nonfatal myocardial infarction (MI, heart attack) occurs more frequently in the late morning, suggesting that sudden cardiac death might also exhibit a circadian, or 24-hour pattern. Mortality data were examined for 1983 from the Massachusetts Department of Public Health yielding 2,203 individuals who met the criteria, and the Framingham Heart Study, in which there were 429 other definite or probable sudden cardiac deaths. The study was complicated because diagnosis of sudden cardiac death is difficult because it can seldom be confirmed objectively, and because about one third of sudden cardiac deaths are caused by acute MI. Time of death is often unknown because many deaths are unwitnessed, especially at night. Also, the sleep-wake cycle is a better measure of circadian variation than absolute time of day. Sudden cardiac death is not uniformly coded in the International Classification of Disease system, so it was defined as death occurring within one hour of onset of symptoms. There was a pronounced circadian peak from 6 a.m. to 9 a.m., and an almost equal distribution over the other 21 hours. The variation was similar for men and women, and for all age groups. Increased physical and mental activity may play a role. It also suggests that sudden cardiac death may be a consequence of myocardial ischemia (decreased blood flow to the heart muscle) caused by blood clots, or it may be caused by a disturbance of the heart rhythm. Both are more likely to happen in the morning when systemic arterial blood pressure is at its highest, and clotting is rapid and natural clotting dissolving function low. Increased catecholamines, naturally occurring chemicals which stimulate the heart muscle, may also contribute to abnormal heart rhythms that could result in sudden cardiac death. (Consumer Summary produced by Reliance Medical Information, Inc.)

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajo.2006.11.058 Byline: Ronald Klein (a), Yingzi Deng (b), Barbara E.K. Klein (a), Leslie Hyman (c), Johanna Seddon (d), Robert N. Frank (e), Robert B. Wallace (f), Susan L. Hendrix (g), Baruch D. Kuppermann (h), Robert D. Langer (i), Lewis Kuller (j), Robert Brunner (k), Karen C. Johnson (l), Asha M. Thomas (m), Mary Haan (b) Abstract: To examine the association of cardiovascular disease (CVD), CVD risk factors, and CVD treatment with age-related macular degeneration (AMD). Author Affiliation: (a) Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin (b) Department of Epidemiology, University of Michigan, Ann Arbor, Michigan (c) Division of Epidemiology, Department of Preventive Medicine, Stony Brook University, Stony Brook, New York, New York (d) Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts (e) Kresge Eye Institute, Wayne State University, Detroit, Michigan (f) Department of Epidemiology, The University of Iowa, Iowa City, Iowa (g) Department of Obstetrics and Gynecology, Wayne State University Medical School, Hutzel Hospital, Detroit, Michigan (h) Department of Ophthalmology, University of California, Irvine, Irvine, California (i) Outcomes Research Institute, Center for Health Research, Geisinger Health System, Danville, Pennsylvania (j) Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania (k) University of Nevada School of Medicine, Reno, Nevada (l) Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee (m) MedStar Research Institute, Washington, DC Article History: Accepted 22 November 2006