The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

Background We compared the angiotensin receptor–neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients. Methods In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes. Results The trial was stopped early, according to prespecified rules, after a median followup of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P = 0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. Conclusions LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.)

/pdf/angiotensin-neprilysin-inhibition-versus-enalapril-in-heart-394udbl54o.pdf

Angiotensin-neprilysin inhibition versus enalapril in heart failure.

2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

/pdf/a-comprehensive-1000-genomes-based-genome-wide-association-4p4zlig8vc.pdf

A comprehensive 1000 Genomes–based genome-wide association meta-analysis of coronary artery disease

The Clinical Efficacy Assessment Subcommittee of the American College of Physicians–American Society of Internal Medicine acknowledges the scientific validity of this product as a background paper and as a review that captures the levels of evidence in the management of patients with chronic stable angina as of November 17, 2002





The American College of Cardiology (ACC)/American Heart Association (AHA) Task Force on Practice Guidelines regularly reviews existing guidelines to determine when an update or a full revision is needed This process gives priority to areas in which major changes in text, and particularly recommendations, are merited on the basis of new understanding or evidence Minor changes in verbiage and references are discouraged

The ACC/AHA/American College of Physicians–American Society of Internal Medicine (ACP-ASIM) Guidelines for the Management of Patients With Chronic Stable Angina, which were published in June 1999, have now been updated The full-text guideline incorporating the updated material is available on the Internet (wwwaccorg or wwwamericanheartorg) in both a track-changes version showing the changes in the 1999 guideline in strike-out (deleted text) and highlighting …

https://cdr.lib.unc.edu/downloads/bz60cz34d

ACC/AHA 2002 guideline update for the management of patients with chronic stable angina--summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina)

OBJECTIVE
Human brain natriuretic peptide-32 (BNP) (i.e. proBNP(77–108)), the mature form of BNP and secreted predominantly by the cardiac ventricle, is formed from a high molecular weight precursor, proBNP(1–108). We have recently identified the aminoterminal form proBNP(1–76) (NT-proBNP) in human plasma but its source, metabolism and production in circulatory disorders are unknown. We have investigated the relationship between immunoreactive (IR) NT-proBNP and BNP-32 in normal and hypertensive subjects and in patients with cardiac impairment, as well as the regional plasma concentrations in patients undergoing routine cardiac catheterization.

DESIGN AND PATIENTS
Plasma hormone measurements were made in 26 normal subjects, 20 subjects with untreated mild hypertension and 111 treated patients with a history of coronary heart disease and documented cardiac impairment (left ventricular ejection fraction (LVEF) < 45% (mean 29%); 25 NYHA Class I, 65 Class II and 21 Class III). Regional blood sampling from the femoral artery, femoral vein, renal vein and coronary sinus was undertaken in 14 patients presenting for left and right cardiac catheterization studies in the course of standard investigation for a range of cardiac disorders.

MEASUREMENTS
Plasma samples were assayed for IR NT-proBNP and IR BNP-32 (and atrial natriuretic peptide (ANP) in the regional blood samples). In the patients with cardiac impairment, LVEF was determined by gated radionuclide ventriculography, exercise capacity was measured using a modified Naughton multistage protocol and creatinine clearance was calculated from plasma creatinine, age and weight. In the regional study, extraction ratios across the kidney and lower limb (and step-ups across the heart) were calculated from plasma peptide concentrations.

RESULTS
In normal subjects mean IR NT-proBNP levels (10.8 ± 1.3 pmol/L) were similar to levels of IR BNP-32 (9.7 ± 0.5 pmol/L). In hypertensive patients the levels of IR NT-proBNP and IR BNP-32 tended to be higher than but were not significantly different from normal subjects. Both IR NT-proBNP and IR BNP-32 were raised in NYHA Classes I, II and III compared with normals (P < 0.001 for all) with higher levels of both BNP forms seen with increasing cardiac impairment. The levels of IR NT-proBNP were greater than IR BNP-32 in all NYHA Classes (P < 0.001) for all). Overall, the levels of IR NT-proBNP (129 ± 12 pmol/L) were 4-fold higher than concomitant BNP-32 levels (29 ± 2 pmol/L). Multivariate analysis showed that LVEF, exercise test time and creatinine clearance were independent predictors of IR NT-proBNP. In all study groups, the levels of IR NT-proBNP and IR BNP-32 levels were highly correlated. Regional plasma sampling showed similar step-ups in IR NT-proBNP and IR BNP-32 levels across the heart, together with similar extraction of both BNP forms across the kidney and lower limb. For both BNP forms, these changes across tissues were significantly less than for ANP.

CONCLUSIONS
Plasma levels of immunoreactive amino terminal-proBNP are raised in cardiac impairment, including NYHA Class I, and rise with increasing cardiac decompensation. Metabolism and tissue uptake of immunoreactive amino terminal-proBNP and immunoreactive BNP-32 appear similar. In cardiac impairment the proportional and absolute increment above normal levels of the aminoterminal BNP peptide exceeds that for BNP-32 and suggest that amino terminal-proBNP may be a more discerning marker of early cardiac dysfunction than BNP-32.

Immunoreactive amino‐terminal pro‐brain natriuretic peptide (NT‐PROBNP): a new marker of cardiac impairment

Renal, haemodynamic, and hormonal effects of human alpha atrial natriuretic peptide in healthy volunteers

Metabolic clearance rate and plasma half life of alpha-human atrial natriuretic peptide in man.

The Amino-Terminal Portion of Pro-Brain Natriuretic Peptide (Pro-BNP) Circulates in Human Plasma

Background—Plasma neurohormones were analyzed for prediction of adverse outcomes and response to treatment in 415 patients with ischemic left ventricular dysfunction randomly assigned to receive carvedilol or placebo. Methods and Results—Atrial natriuretic peptide, brain natriuretic peptide (BNP), or norepinephrine (NE) levels above the group median were associated with increased mortality rates and heart failure. On multivariate analysis, both BNP and NE interacted with treatment to predict death or heart failure independent of age, New York Heart Association class, and left ventricular ejection fraction. For placebo, supramedian levels of BNP were associated with 3-fold the mortality rate of inframedian levels (20/104; 19% vs 6/99; 6%; P<0.01). For carvedilol, mortality rate was comparable in these 2 subgroups (12/109; 11% vs 8/94; 9%; NS). Corresponding rates for heart failure were 29/104 (28%) versus 3/99 (3%; P<0.001) for placebo and 16/109 (15%) versus 7/94 (7%; NS) for carvedilol. High NE levels di...

Arthur Mark Richards

Papers

Immunoreactive amino‐terminal pro‐brain natriuretic peptide (NT‐PROBNP): a new marker of cardiac impairment

Renal, haemodynamic, and hormonal effects of human alpha atrial natriuretic peptide in healthy volunteers

Metabolic clearance rate and plasma half life of alpha-human atrial natriuretic peptide in man.

The Amino-Terminal Portion of Pro-Brain Natriuretic Peptide (Pro-BNP) Circulates in Human Plasma

Neurohumoral Prediction of Benefit From Carvedilol in Ischemic Left Ventricular Dysfunction