Eugene Braunwald

Bio: Eugene Braunwald is an academic researcher from Brigham and Women's Hospital. The author has contributed to research in topics: Myocardial infarction & TIMI. The author has an hindex of 230, co-authored 1711 publications receiving 264576 citations. Previous affiliations of Eugene Braunwald include Boston University & University of California, San Francisco.

Determinants of the duration of the refractory period of the atrioventricular nodal system in man.

Abstract: One of the fundamental characteristics of nervous tissue, skeletal muscle, and myocardium is their refractoriness for short periods following depolarization (1). This period, during which a propagated action potential cannot be evoked by a stimulus, has been designated the \"effective refractory period\" (2), and the effective refractory period thus limits the maximal rate at which depolarizations can occur. When normal atrioventricular (AV) conduction takes place, the ventricular contraction rate is limited by the AV nodal system, which has been shown in experimental animals to have a longer effective refractory period than atrial or ventricular tissue (3). In spite of the fundamental importance of the refractory period of the AV nodal conduction system, this interval has heretofore been estimated only from electrocardiograms obtained from patients with spontaneous cardiac arrhythmias (4). The presence of arrhythmias may be associated with abnormalities of conduction, and the analysis of such electrocardiograms does not allow systematic investigation of the factors that influence this period in normal subjects. In the present investigation a practical method for the measurement of the effective refractory period of the AV nodal system in conscious human subjects is described. With this method normal basal values for this period were established, and the effects of tachycardia, exercise, atropine, and of various sympathomimetic drugs on its duration are presented.

Estimating treatment effects from observational data: dissonant and resonant notes from the SYMPHONY trials.

Abstract: CAN OBSERVATIONAL DATA SUBSTITUTE FOR RANDOMized controlled trials for developing treatment recommendations and initiating public health interventions? This question arises from the article by Newby and colleagues on the early initiation of statins in patients with acute coronary syndromes (ACS), reported in this issue of THE JOURNAL. The authors present results from an observational cohort study that indicate no difference in mortality and cardiovascular outcomes among patients with ACS who initiated statin treatment prior to hospital discharge and patients who did not receive statins. Almost 2 million patients with ACS are discharged from US hospitals each year. Since these patients are at high risk for recurrent events, secondary prevention is an important medical challenge. Randomized clinical trials (RCTs) have shown the benefits of aspirin, -blockers, and clopidogrel in these patients. Furthermore, there is evidence that administration of these agents prior to hospital discharge reduces recurrent event rates. Large RCTs have indicated that initiation of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) months to years following an ACS event is effective for secondary prevention. Recently, attention has focused on the optimal time to commence statin therapy. Several observational studies, among them 2 large studies comprising some 40000 patients, found that early statin therapy was associated with lower rates of death. In addition, the results from 2 RCTs, although not definitive, yielded consistent results. Consequently, a strong momentum is building to recommend routine, early initiation of statin therapy in post-ACS patients. Indeed, such therapy is recommended in contemporary practice guidelines. The retrospective cohort study using data from the Sibrafiban vs Aspirin to Yield Maximum Protection From Ischemic Heart Events Post-acute Coronary Syndromes (SYMPHONY) ACS trials strikes a dissonant note. In contrast to the previous studies, the report by Newby et al indicates no benefit from early initiation of statin therapy for any clinical end point, except stroke, for which statins appeared protective. How should the results from the SYMPHONY populations be interpreted and how can the differences between this and the previously reported studies be explained? One possible reason for the surprising findings is that the fractions of patients in the 2 SYMPHONY trials for whom statins were started in the hospital as well as those for whom revascularization was performed were much larger than in the other 2 observational studies. Perhaps the analysis reported by Newby and colleagues signals that statins simply do not offer a significant additional benefit in the presence of revascularization therapy in relatively low-risk patients. Other possible explanations for the different results obtained by the various studies are measurement error and confounding. Any results, whether from observational studies or RCTs can be distorted by measurement error. Measurement error may have affected the ascertainment of statin use, the diagnosis of ACS, and all clinical covariates. Furthermore, observational studies are especially vulnerable to confounding. Although analytic techniques can address the control of measured confounders, unmeasured confounders remain an omnipresent threat to the validity of nonrandomized research. Mismeasurement of a confounder, such as low-density lipoprotein cholesterol (LDL-C) level, might not create a problem if the physician decided treatment based on the mismeasured variable. Nevertheless, any discrepancy between the value of a confounder used by the physician and that used in the analysis could lead to residual confounding. To overcome the lack of randomization in their cohort, Newby et al used propensity scores to account for imbalances in baseline characteristics. In the 2 other large observational studies on this issue available to date, propensity scores were also used. Propensity scores have become a popular tool in pharmacoepidemiology. Of particular con-

The Problem of Persistent Platelet Activation in Acute Coronary Syndromes and Following Percutaneous Coronary Intervention

Abstract: Platelets play a central role in the atherosclerotic inflammatory response, thrombotic vascular occlusion, microembolization, vasoconstriction, and plaque progression. Persistent platelet activation poses a serious problem among patients with acute coronary syndromes (ACS) and those who have undergone percutaneous coronary intervention (PCI), placing them at risk for ischemic events and subacute stent thrombosis. Patients undergoing PCI are at risk for further ischemic events because of procedure-related platelet activation as well as the inherent persistent platelet hyperreactivity and enhanced thrombin generation associated with ACS. Persistent platelet activation following an acute coronary event and/or PCI supports incorporating antiplatelet strategies into the standard medical management of such patients. In this clinical setting, antiplatelet therapies are capable of improving outcomes. Aspirin, thienopyridines, and glycoprotein IIb/IIIa inhibitors, the 3 major pharmacologic approaches to persistent platelet activation, target various levels of the hemostatic pathways and thrombus formation.

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.

Abstract: "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure" provides a new guideline for hypertension prevention and management. The following are the key messages(1) In persons older than 50 years, systolic blood pressure (BP) of more than 140 mm Hg is a much more important cardiovascular disease (CVD) risk factor than diastolic BP; (2) The risk of CVD, beginning at 115/75 mm Hg, doubles with each increment of 20/10 mm Hg; individuals who are normotensive at 55 years of age have a 90% lifetime risk for developing hypertension; (3) Individuals with a systolic BP of 120 to 139 mm Hg or a diastolic BP of 80 to 89 mm Hg should be considered as prehypertensive and require health-promoting lifestyle modifications to prevent CVD; (4) Thiazide-type diuretics should be used in drug treatment for most patients with uncomplicated hypertension, either alone or combined with drugs from other classes. Certain high-risk conditions are compelling indications for the initial use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, β-blockers, calcium channel blockers); (5) Most patients with hypertension will require 2 or more antihypertensive medications to achieve goal BP (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes or chronic kidney disease); (6) If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy with 2 agents, 1 of which usually should be a thiazide-type diuretic; and (7) The most effective therapy prescribed by the most careful clinician will control hypertension only if patients are motivated. Motivation improves when patients have positive experiences with and trust in the clinician. Empathy builds trust and is a potent motivator. Finally, in presenting these guidelines, the committee recognizes that the responsible physician's judgment remains paramount.

Cochrane Handbook for Systematic Reviews of Interventions

Abstract: The Cochrane Handbook for Systematic Reviews of Interventions is the official document that describes in detail the process of preparing and maintaining Cochrane systematic reviews on the effects of healthcare interventions.

Atherosclerosis — An Inflammatory Disease

Abstract: Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.4,5 In fact, the lesions of atherosclerosis represent . . .

Lifetime Prevalence and Age-of-Onset Distributions of DSM-IV Disorders in the National Comorbidity Survey Replication

Abstract: Context Little is known about lifetime prevalence or age of onset of DSM-IV disorders. Objective To estimate lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the recently completed National Comorbidity Survey Replication. Design and Setting Nationally representative face-to-face household survey conducted between February 2001 and April 2003 using the fully structured World Health Organization World Mental Health Survey version of the Composite International Diagnostic Interview. Participants Nine thousand two hundred eighty-two English-speaking respondents aged 18 years and older. Main Outcome Measures Lifetime DSM-IV anxiety, mood, impulse-control, and substance use disorders. Results Lifetime prevalence estimates are as follows: anxiety disorders, 28.8%; mood disorders, 20.8%; impulse-control disorders, 24.8%; substance use disorders, 14.6%; any disorder, 46.4%. Median age of onset is much earlier for anxiety (11 years) and impulse-control (11 years) disorders than for substance use (20 years) and mood (30 years) disorders. Half of all lifetime cases start by age 14 years and three fourths by age 24 years. Later onsets are mostly of comorbid conditions, with estimated lifetime risk of any disorder at age 75 years (50.8%) only slightly higher than observed lifetime prevalence (46.4%). Lifetime prevalence estimates are higher in recent cohorts than in earlier cohorts and have fairly stable intercohort differences across the life course that vary in substantively plausible ways among sociodemographic subgroups. Conclusions About half of Americans will meet the criteria for a DSM-IV disorder sometime in their life, with first onset usually in childhood or adolescence. Interventions aimed at prevention or early treatment need to focus on youth.

Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

Abstract: The National High Blood Pressure Education Program presents the complete Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Like its predecessors, the purpose is to provide an evidence-based approach to the prevention and management of hypertension. The key messages of this report are these: in those older than age 50, systolic blood pressure (BP) of greater than 140 mm Hg is a more important cardiovascular disease (CVD) risk factor than diastolic BP; beginning at 115/75 mm Hg, CVD risk doubles for each increment of 20/10 mm Hg; those who are normotensive at 55 years of age will have a 90% lifetime risk of developing hypertension; prehypertensive individuals (systolic BP 120-139 mm Hg or diastolic BP 80-89 mm Hg) require health-promoting lifestyle modifications to prevent the progressive rise in blood pressure and CVD; for uncomplicated hypertension, thiazide diuretic should be used in drug treatment for most, either alone or combined with drugs from other classes; this report delineates specific high-risk conditions that are compelling indications for the use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, calcium channel blockers); two or more antihypertensive medications will be required to achieve goal BP (<140/90 mm Hg, or <130/80 mm Hg) for patients with diabetes and chronic kidney disease; for patients whose BP is more than 20 mm Hg above the systolic BP goal or more than 10 mm Hg above the diastolic BP goal, initiation of therapy using two agents, one of which usually will be a thiazide diuretic, should be considered; regardless of therapy or care, hypertension will be controlled only if patients are motivated to stay on their treatment plan. Positive experiences, trust in the clinician, and empathy improve patient motivation and satisfaction. This report serves as a guide, and the committee continues to recognize that the responsible physician's judgment remains paramount.