After a long winter, particularly for those on the East Coast, spring is finally in the air. I hope everyone had a nice spring break with their family and is eager to do some insightful cardiology reading.

We touch on several clinical conundrums in this issue that I am sure our readers will find illuminating. Dr Navin Nanda discusses genetic characteristics and their associations with aortic valve calcification evaluated by standard CT scans. He reports that a specific SNP, rs10455872, has been identified that is associated with aortic valve calcification and aortic valve stenosis; research also implicates elevated plasma Lp(a) levels in the development of aortic valve disease.

Dr. German Hernandez delves into the association between obesity’s links to hypertension and suggests that that higher weight in young adulthood and weight gain through middle age both increase the risk of subsequently developing hypertension. He goes on to say that this knowledge provides an important contribution to the impact of body weight gain on the risk of developing hypertension throughout the life course.

Dr. Saurav Chatterjee discusses blood transfusion in myocardial infarction and informs us that a liberal blood transfusion strategy compared with no blood transfusion or a restricted blood transfusion strategy appears to be associated with higher all-cause mortality, as well myocardial infarction rates in patients with myocardial infarction. One should use caution and careful risk-benefit analysis prior to transfusing these patients.

Dr. Sucheta Gosavi talks about the effect of ramipril on walking times and quality of life in patients with peripheral arterial disease, and reports that there was some improvement in the median physical component summary score with ramipril.

She suggests that with few FDA-approved drugs available for alleviation of PAD symptoms, the addition of ramipril therapy would be highly desirable. Dr Samuel Mann dissects diuretic use in black patients with uncontrolled hypertension and asserts that although many drug classes provide very reasonable and metabolically neutral alternatives to diuretics as first-step drugs, and although a diuretic is not the right drug for everyone, the low rate of diuretic usage in a black population with uncontrolled hypertension is simply wrong, and hard to explain.

Dr. Hitinder Gurm looks at paclitaxel-eluting balloons, paclitaxel- eluting stents, and balloon angioplasty in patients with restenosis after implantation of a drug-eluting stent, and thinks that paclitaxel-eluting balloons have demonstrated remarkable efficacy and are a welcome addition to the catheterization laboratory armamentarium. Once clinically available, it will likely emerge as the preferred device for both DES and BMS restenosis.

Dr. Ragavendra Baliga assesses whether yoga has a beneficial effect on the burden of atrial fibrillation and patients’ quality of life, depression, and anxiety, and reports that although the study cohort was small, the findings suggest that yoga may be a useful adjunct, if not primary treatment, to reduce the burden of atrial fibrillation. He further states that the mind is able to perform inexplicable events that modern medical science is unable to explain, and we must not be quick to discount these effects merely because we do not comprehend them.

Ms. Jackie Syrop (our tireless and astute managing editor) has put together a succinct summary of several key late-breaking clinical trials presented at the recent American College of Cardiology meeting, which I am sure you will find useful reading. In our diabetes column, Dr Aparna Bhagavat provides an excellent review of ß-cell dedifferentiation and type 2 diabetes.

I hope that you will find these commentaries to be valuable and enjoyable. I encourage you to share your insights, thoughts, and personal experiences on the myriad topics touched upon in this issue. On a broader level, I would love to hear feedback on how we can make this journal the best cardiology journal that reviews contemporary literature. My goal continues to be to make you look forward to every issue of Cardiology Review.

Articles

Editor's Page

Spring Is In the Air

Vice Chairman, Department of Internal Medicine

Texas Tech University Health Sciences Center

Professor of Medicine and the Michael and

Clinical Pharmacy Specialist—Cardiology

Residency Program Director—PGY2 Cardiology

San Mateo Multispecialty Physicians Group

Director of Cardiac Intermediate Care Unit

Philip J. and Harriet L. Goodhart Professor of

Director of Cardiovascular Imaging Program

Zena and Michael A. Wiener Cardiovascular

Associate Professor of Medicine (Cardiology)

Editorial Advisory Board

Cardiology Review Editorial Advisory Board

The American College of Cardiology’s (ACC) 62nd Scientific Sessions featured over 2100 abstracts and 22 late-breaking clinical trials across 5 sessions. More than 22,000 people attended the 3-day conference, which focused on the transformation of cardiovascular care from discovery to delivery.

 is highlighting 8 study presentations from ACC 2013: PEITHO, ASTRONAUT, SELECT-ACS, REMINDER, CHAMPION-PHOENIX, ACRIN PA 4005, RED-HF, and RELAX.

Reduction of Events by Darbepoetin in Heart Failure

The Reduction of Events with Darbepoetin Alfa in Heart Failure (RED-HF) trial tested darbepoetin alfa (Aranesp) in heart failure (HF) patients with anemia. This phase 3 trial started in 2006 and enrolled 2278 patients with symptomatic systolic HF and anemia. Patients were randomized in a 1:1 ratio to darbepoetin alfa or placebo. The trial was designed to evaluate whether the treatment of anemia could improve morbidity and mortality in systolic HF patients.

Results showed no difference between the treatment and placebo arms in the composite end point of time to death from any cause or first hospital admission for worsening HF (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.90-1.13). The goal in the treatment group was a target hemoglobin of at least 13.0 g/dL. The primary end point was a composite of time to death from any cause or first hospitalization for worsening HF in subjects with HF and anemia.

No new safety issues emerged in RED-HF. In June 2011 the FDA advised tailored dosing for erythropoieisis-stimulating agents in patients with chronic kidney disease (CKD) because of an increased risk of cardiovascular events. This action followed reports of an increased risk of stroke for diabetic patients with CKD who were not yet on dialysis and were taking darbepoetin (see 2009 TREAT trial: 

http://www.nejm.org/doi/full/10.1056/NEJMoa0907845

Analysis of the Pulmonary Embolism Thrombolysis Study (PEITHO), the largest trial of thrombolysis for intermediate- risk pulmonary embolism (PE) ever done, shows that the addition of tenecteplase to standard treatment with heparin in patients with intermediate-risk PE significantly reduced the primary end point of death or hemodynamic collapse within 7 days of randomization. However, the benefit came with a significantly increased risk of major hemorrhage.

Study coauthor Stavros Konstantinides, MD, of the University of Mainz, Germany, said, “There is a price to pay, and we would not say that everybody in this group should receive thrombolysis.” He said that an analysis by age was performed, and showed that age might be an important factor. Patients less than 75 years of age had most of the benefit and a tendency toward fewer hemorrhagic strokes. Dr Konstantinides said the dose of drug that was used could be lowered in older patients, and alternative ways to deliver thrombolytics could be explored.

PEITHO was conducted in 1006 patients, mean age 70 years, in 13 countries (Europe and Israel) from 2007 to mid-2012. Patients were randomized to heparin plus placebo or heparin plus a weight-adapted bolus of tenecteplase.

The primary end point was reduced by 56% in patients treated with tenecteplase and heparin, compared with the heparin-only group (2.6% in the tenecteplase group vs 5.6% in the placebo group; 

 = 0.015). However, major bleeding was significantly increased with tenecteplase: 6.3% vs 1.5% in the placebo group (

<0.001). There were 10 hemorrhages in the tenecteplase group and 1 in the placebo group.

Tenecteplase is not FDA approved for acute PE. Dr. Konstantinides said further research is needed to better identify patients who will benefit most with less risk of bleeding.

PEITHO was sponsored by Assistance Publique-Hopitaux de Paris and funded by the French Ministry of Health, the German Ministry of Education and Research, and by a grant from Boehringer Ingelheim to the sponsor.

Safety and Efficacy of Early Eplerenone in Patients With Acute MI

Data from the REMINDER trial suggest that early use of eplerenone (Inspra) can improve the outlook of patients with acute ST-elevation myocardial infarction (STEMI). This double-blind, randomized, placebo-controlled trial evaluating the safety and efficacy of early treatment with eplerenone in patients with acute myocardial infarction (MI) involved patients identified during emergency department or ambulance evaluation and diagnosis of acute STEMI in the absence of HF. Those who agreed to participate were randomized and given an initial dose of either eplerenone or placebo within 12 to 24 hours of initial onset of symptoms of an acute MI.

REMINDER data were presented by Gilles Montalescot, MD, professor at the Institute of Cardiology, Centre Hospitalier Pitié- Salpêtrière, Paris. It is the first large study to examine the safety profile of eplerenone for early administration, with no prior potassium check.

Eplerenone’s once-daily dosing of 25 mg/d or 50 mg/d was based on serum potassium and eGFR levels. A total of 88.6% of patients received the 50-mg/d dose. Patients in both arms of the trial also received standard medical care for acute STEMI. A total of 1012 patients were randomized, 506 to each arm.

The primary end point was a composite of cardiovascular mortality, ventricular arrhythmia, clinical or subclinical heart failure as determined by left ventricle ejection fraction (LVEF) <40%, or elevated brain natriuretic peptide (BNP)/N terminal (NT)-proBNP 1 month or longer after enrollment.

A mean follow-up of 10.5 months found 93 patients (18.4%) in the eplerenone group had reached the primary end point versus 150 patients (29.6%) in the placebo group. Eplerenone had an overall hazard ratio (HR) of 0.57 (

 <0.0001) for the primary end point. A high BNP/NT-proBNP level was observed in 18 patients in the eplerenone group compared with 131 patients in the placebo group after the same follow-up period. The eplerenone HR for high BNP/NT-proBNP was 0.58 (

Adverse event rates were similar in both groups.

SELECT-ACS Results Pique Interest in More Research

A small phase 2 study of the P-selectin antagonist inclacumab suggests that it may be able to reduce myocardial damage in patients undergoing percutaneous coronary intervention (PCI) for non-ST-elevation myocardial infarction (NSTEMI). P-selectin is a cell-adhesion molecule expressed on endothelial cells and platelets, and is known to play a part in leukocyte and platelet rolling. Earlier research suggests that inhibiting P-selectin may limit macrophage accumulation and neointimal formation after injury by decreasing neutrophil and platelet adhesion.

Lead author Jean-Claude Tardif, MD, of the Montreal Heart Institute, presented the findings, which he said were early but nonetheless interesting, and should lead to additional studies in a phase 3 trial.

In SELECT-ACS, 544 NSTEMI patients scheduled for coronary angioplasty were randomized to placebo infusion of either a 5-mg/kg or 20-mg/kg infusion of inclacumab. Of these, 340 patients went on to have PCI; their peak troponin I (the primary end point for the 16- and 24-hour time points) and creatine kinase-myoglobin (CK-MB) values were measured at intervals after the procedure. Safety visits were also conducted with all patients at 30 and 120 days.

After 24 hours, peak troponin I was reduced in the 20-mg/kg dose—but not in the 5-mg/kg dose&mdash;compared with placebo. The 

 value was only marginally significant, however. At 16 hours a trend in the same direction did not reach statistical significance. CK-MB followed a similar pattern; the placebo-adjusted change also failed to reach statistical significance.

Few serious adverse events were reported, but there were more of them in the treatment groups (they were not statistically significant). No deaths occurred in the placebo group; there were 4 in the 5-mg/kg group and 2 in the 20-mg/kg group. Nonfatal MI rates were also more common in the treatment groups, but event rates were small. There was no increased bleeding or infection reported.

Study results were simultaneously published online in the

 Journal of the American College of Cardiology

Cangrelor Reduces Complications at PCI Versus Clopidogrel

The experimental IV antiplatelet agent cangrelor, administered at the time of PCI, reduces ischemic complications better than clopidogrel, according to results of the CHAMPION- PHOENIX trial. However, some kinds of bleeding were more common with cangrelor.

The trial included 11,145 patients getting urgent or elective PCI who were randomized to double-blind, double-dummy treatment with a bolus and infusion of cangrelor (30 μg/kg, then 4 μg/ kg/min) or a loading dose of 600 mg or 300 mg clopidogrel. All patients were to get dual antiplatelet therapy with aspirin and clopidogrel in the first 48 hours after the procedure.

CHAMPION-PHOENIX followed 2 earlier phase 3 studies of cangrelor (CHAMPION PCI and CHAMPION PLATFORM), in which the medication did not achieve its primary goals versus a control group given a clopidogrel 600-mg loading dose in the first trial and 60 mg after stenting in the second.

Co-lead researcher Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital and the Boston VA Healthcare System, said the composite rate of heart attack, death, or revascularization due to ischemia was 4.7% with cangrelor versus 5.9% with a standard loading dose of clopidogrel at 48 hours (

 = 0.005)—a 22% reduction in ischemic complications (number needed to treat [NNT] with cangrelor, 84). The risk of severe bleeding wasn’t significantly different between the groups. Need for glycoprotein IIb/IIIa inhibitors as rescue therapy during the procedure was less common with cangrelor (2.3% vs 3.5%, 

 <0.001). Cangrelor also had an advantage on the secondary end point of stent thrombosis at 48 hours, with a rate of 0.8% versus 1.4% in the clopidogrel group (odds ratio [OR], 0.6;

Like clopidogrel, prasugrel, and ticagrelor, cangrelor targets platelet activation by P2Y12 inhibition, but with immediate onset and a short half-life of just 3 to 5 minutes; platelet function resumes normal levels within 1 hour of stopping infusion. The researchers said that the reduction in the ischemic complication rate was driven by fewer periprocedural MIs.

CHAMPION-PHOENIX was simultaneously published in 

http://www.nejm.org/doi/full/10.1056/NEJMoa1300815

The trial was funded by the Medicines Company, the sponsor of cangrelor. Dr. Bhatt reported grant funds to his institutions from the Medicine Company; board membership with Medscape Cardiology, Boston VA Research Institute, and the Society of Chest Pain Centers; and payment for developing education presentations from WebMD. He also reported grants to his institution from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, and sanofi-aventis.

Aliskiren Trial on Acute Heart Failure Outcomes

The addition of aliskiren (Tekturna) to other heart failure (HF) medications beginning less than 1 week after discharge from hospitalization for low-left ventricular ejection fraction (LVEF) HF made no significant difference to cardiovascular death or hospitalization at 6 months and had no clinical benefit up through 1 year, according to results of the ASTRONAUT trial.

ASTRONAUT was conducted at 316 centers in North and South America, Europe, and Asia and randomized 1639 stable patients with HF, LVEF ≤40% (mean, 28%), and elevated natriuretic peptides who had been discharged from a HF hospitalization an average of 5 days before. Approximately 40% had diabetes and 21% had renal insufficiency. Patients received either aliskiren or placebo in addition to standard HF medications.

However, treatment with aliskiren led to significant and sustained reductions in natriuretic peptide levels, according to lead author Mihai Gheorghiade, MD, of Northwestern University, Chicago, IL. Dr. Gheorghiade and colleagues said reduced natriuretic peptide levels were an indirect sign of possible HF improvement even if it did not translate clinically. Favorable effects on HF progression may have been offset clinically by adverse effects associated with the drug, such as hyperkalemia, hypotension, and renal dysfunction.

It had been hoped that further inhibition of the renin-angiotensin- aldosterone system (RAAS) through a mechanism different from angiotensin-converting enzyme (ACE) inhibition, angiotensin receptor blockers (ARBs), or aldosterone antagonists would add clinical value in HF treatment. It was thought that aliskiren might fit that bill, as it blocks the RAAS at its nearest step and might suppress compensatory renin increases seen with RAAS inhibition later in the pathway.

More than 50% of patients in the ASTRONAUT trial were already taking an aldosterone antagonist, 84% were taking an ACE inhibitor or ARB, and more than 80% were taking betablockers. A subgroup analysis suggested that the drug may have increased the risk of death from any cause at 12 months in the 41% of patients with a history of diabetes; those without diabetes showed a significant benefit for that end point and cardiovascular death/HF rehospitalization.

“At the end of the day the message is that the study was neutral,” said Dr. Gheorghiade. “We’ve generated 2 hypotheses that remain to be tested, that patients with diabetes are harmed by the drug, and that patients without diabetes are benefiting from it.”

The study was simultaneously published online in JAMA (

http://jama.jamanetwork.com/article.aspx?articleid=1666394

ASTRONAUT was sponsored by Novartis. Dr. Gheorghiade disclosed consulting for Novartis, Bayer HealthCare, Abbott, Astellas, AstraZeneca, Corthera, Cytokinetics, Debiopharm, Errekappa Terapeutici, GlaxoSmithKline, Johnson & Johnson, Medtronic, Merck, Otsuka, Pericor Therapeutics, Protein Design Laboratories, Sanofi, Sigma Tau, Solvay, and Takeda.

RELAX Trial Did Not Show Benefit of PDE-5 Inhibitors in HF-PEF Patients

The Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic HF Trial (RELAX) was not able to show that sildenafil (Viagra/Revatio) might improve exercise capacity and improve clinical outcome in patients with heart failure (HF) with preserved ejection fraction (HF-PEF). The randomized trial, conducted at 26 centers in the United States and Canada, enrolled HF-PEF patients (LVEF ≥50%) in NYHA class 2-3. A total of 113 patients received sildenafil 20 mg 3 times daily for 3 months, followed by 60 mg 3 times daily for another 3 months, compared with the placebo control group (n = 103). The median patient age was 69 years.

Lead researcher Margaret Redfield, MD, of the Mayo Clinic (Rochester, MN) said there was no signal of benefit with the drug. “There was no increase in peak oxygen consumption, and none of the other plethora of data points that we collected—6-minute walk distance, echocardiographic structure, structure by cardiac MRI, hemodynamics by Doppler, and neurohormonal activation&mdash; were improved by the PDE-5 inhibitor.” Symptoms, clinical status, and quality of life indices also did not show improvement. RELAX showed no significant difference in the primary end point of change in peak oxygen consumption at 24 weeks.

While they didn’t reach significance, there were serious adverse events on sildenafil, Dr. Redfield said. “There was a signal that was quite unexpected of worsening renal function with sildenafil,” she noted. There were more (but not significantly more) patients in the sildenafil group who withdrew consent, died, or were too ill to perform the cardiopulmonary exercise test, and patients treated with sildenafil had a higher incidence of vascular adverse events.

The study was published simultaneously in JAMA (

http://jama.jamanetwork.com/article.aspx?articleid=1663257

RELAX was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Dr. Redfield disclosed financial support from NIH and royalties from Annexon. Pfizer provided sildenafil and matched placebo.

1-Year Results for Trial of CTCA versus Traditional Care in ED Assessment of ACS

According to 1-year results from the ACRIN PA 4005 study, coronary computed tomography angiography (CCTA) is better than traditional “rule out” approaches for identifying patients in the emergency department (ED) with chest pain who do not have significant coronary disease. ACTIN PA 4005 is a multicenter, randomized controlled trial of more than 1300 patients carried out by the American College of Radiology Imaging Network (ACRIN) Institutions and funded by the Pennsylvania Department of Health.

Judd E. Hollander, MD, Professor and Clinical Research Director in the Department of Emergency Medicine at the University of Pennsylvania in Philadelphia, presented the study’s findings, which showed that relying on CCTA for ED assessment of coronary disease is safe because the 1-year rate of death or myocardial infarction (MI) was found to be substantially below 1% in patients who were judged negative for coronary disease by CCTA. The findings confirmed preliminary data presented a year ago at the 2012 ACC Congress (

Dr. Hollander stressed that although the findings supported a routine use for CCTA to assess the kinds of patients enrolled in ACTIN PA 4005, CCTA is not needed for every patient in the ED with questionable chest pain and should be used as an exclusionary test for patients who need an exclusionary test. He noted that there is a risk from radiation and physicians must carefully weigh the need for the CCTA test.

Approximately two-thirds of patients were randomized to CCTA assessment and the remaining third underwent traditional assessment including exercise treadmill testing, stress test with imaging, and echocardiography. During the 1-year follow-up of 1368 patients who began in the ACRIN study, 1 cardiac death and 1 MI occurred among the 825 patients randomized to the CCTA group, a 0.2% rate that was well under the trial’s safety goal of less than 1%.

There was no increase in resource use compared with ED chest—pain patients assessed by conventional methods. Overall use of cardiac testing, revascularization, readmission to hospital, and ED visits were similar in the 2 study groups. Dr Hollander further said that the data show that CCTA shifted resources to where they are most needed, with more CAD identified and treated and more patients without disease not being treated.

Dr. Holland discloses that he has received research funding from Abbott, Alere, Brahms, and Siemens, and that he has been a consultant for Behring, Janssen, Luitpold, and Radiometer.

Meeting Report

Meeting Report: ACC 2013 Scientific Sessions

Warning About Risk of Potentially Fatal Heart Rhythms With Azithromycin

The FDA has issued a Drug Safety Communication concerning azithromycin (Zithromycin, Zmax) because it can cause abnormal changes in the heart’s electrical activity that can lead to a potentially fatal irregular heart rhythm. The FDA is advising health care professionals to consider the risk of torsades de pointes and fatal arrhythmia when considering treatment options with azithromycin or alternative antibacterial drugs.

• Patients with known prolongation of the QT interval, a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure.

• Patients on drugs known to prolong the QT interval.

• Patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents.

• Elderly patients and patients with cardiac disease may be more susceptible to the effects of arrhythmogenic drugs on the QT interval.

• The potential risk of QT prolongation should be placed in appropriate context when choosing an antibacterial drug: Alternative drugs in the macrolide or fluoroquinolone drug classes also have the potential for QT prolongation or other significant side effects that should be considered when choosing an antibacterial drug.

Reports of adverse events involving azithromycin should be made to the FDA MedWatch program using the information in the “Contact FDA” box on the FDA’s website: 

www.fda.gov/ drugs/drugsafety/ucm341822.htm

Pilot Study Unveils Breath Test for Heart Failure

A prospective study of a test that uses a single puff of exhaled air to diagnose heart failure (HF) was published online in a research letter in the April 2013 Journal of the American College of Cardiology.* The study was conducted by Michael Samara, MD, and colleagues at the Cleveland Clinic.

The study tested the breath test technique they developed in 25 consecutive patients versus 16 controls, using ion-flow tube mass-spectrometry (SIFT-MS), to detect significantly higher levels of acetone in the exhaled breath of patients (811 parts per billion [ppb] versus 187 ppb; 

 = 0.01). All samples were evaluated within 2 hours of collection.

There was also a significant difference in the median amount of detected pentane (40 ppb vs 22 ppb;

The authors wrote that their findings demonstrate the feasibility of single exhaled breath analysis in acute decompensated HF, and provided pilot evidence to support SIFT-MS technology. “Exhaled breath constitutes a complex mixture of hundreds of volatile organic compounds that could potentially be used as a safe and noninvasive method of diagnostic and therapeutic monitoring,” they conclude.

The researchers said there were significant differences in baseline hypertension and baseline estimated glomerular filtration rate in the HF patients versus controls, but there were no significant differences in the age, body mass index, comorbidities, and active smoking that could compromise the exhaled metabolites. All of the patients tolerated the act of giving the breath sample, even those in intensive care or those being monitored invasively. Larger, prospective studies of the technique are needed to further evaluate the promise of this technology, the authors conclude.

*J Am Coll Cardiol. 2013;61(13):1463-1464. doi:10.1016/j.jacc.2012. 12.033.

Medscape’s 2013 survey of US physicians focused on the links between physician burnout and their lives outside of practice. Burnout was described as a loss of enthusiasm for work, feelings of cynicism, and a low sense of personal accomplishment.

The survey found that 39.8% of respondents said they were burned out; 60.2% said they were not. Among the 24 physician specialties ranked, the 2 with the highest percentage of burnout were emergency medicine (52%) and critical care (50%). Generalists were among the top 10 most burned out physicians—family physicians, ob/gyns, internists, and general surgeons. The least burned out specialties were pediatricians, rheumatologists, psychiatrists, and pathologists. Cardiologists were ranked 16th out of 24, with about 36% reporting burnout.

The reasons cited as causing burnout among the physicians surveyed include excessive workload, loss of control, too many bureaucratic tasks, too many hours at work, and the impact of the Affordable Care Act. On a scale of 1 to 7 (1 = not at all important and 7 = extremely important), these factors averaged a rating of over 4, as did insufficient income. The least important stress factors (but still scoring >3) were relationships with colleagues and patients.

More female physicians reported burnout (45%) than did male physicians (27%), likely attributable to women tending to enter the generalist professions rather than the lower-stress subspecialties. Burnout peaks at midlife (46-55 years of age), and then decreases thereafter.

When asked to rate happiness at work, burned-out physicians give low scores compared with their more satisfied colleagues. Although they are much happier at home than at work, they were still less happy than non-burned-out peers. Dermatologists and pediatricians rated themselves at the low end of the severity scale, while surgeons and ob/gyns rated themselves at the high end.

The survey also examined physicians’ assessments of their favorite pastimes, vacation habits, volunteering, lifestyle habits, health, financial condition, spirituality/religious involvement, political affiliations, marriage, children, and citizenship.

News & Trends

CME Instructions

CME Test

Insulin resistance and dysfunction of the pancreatic beta cells play a central role in patients with pre-diabetes, type 2 diabetes mellitus, and the metabolic syndrome. Although hyperinsulinemia is a primary feature of pre-diabetes, with the development of overt diabetes, insulin secretion starts declining. As this column has previously discussed weight loss as a crucial step in the treatment of type 2 diabetes mellitus, it is now time to examine the beta cells of the islets of Langerhans at the molecular level, to review the spectrum of hyperinsulinemia and eventual decreasing insulin levels. In addition to decreasing insulin level in overt diabetes, hyperglucagonemia is also a feature of type 2 diabetes mellitus.

Recent research has introduced new insights about beta cell function. Previous studies by Chang-Chen et al

 have attributed beta cell failure or decreasing insulin secretion in overt diabetes to programmed cell death as a result of the body’s increasing requirement for insulin. In their article, Weir et al

 clearly depict the 5 stages of the evolution of diabetes. In stage 1, there is increased insulin secretion with increase in beta cell mass to maintain normoglycemia, with preservation of acute glucose-stimulated insulin secretion (GSIS). In stage 2, there is an increase in glucose level with loss of beta cell mass, with decreased GSIS. Stages 3 and 4 are stages in which glucose levels keep rising, with gradually decreasing insulin secretion and decreasing beta cell mass. Stage 5 consists of a significant decrease in beta cell mass with progression to ketosis. Paradoxically, however, another study

 has shown little or no significant change in beta cell mass, not enough to explain the insulin deficiency, thus suggesting some other probable mechanism for decreasing insulin levels.

 has proposed a different theory. Animal studies have demonstrated the role of a key transcription factor that differentiates the beta cells from other cells in the islets of Langerhans. This is a specific transcription factor: Forkhead transcription factor O1 (FoxO1) of the O subclass.

 FoxO1 has little role to play; however, with increasing glucose and free fatty acid levels in the pre-diabetic stage, FoxO1 becomes active. FoxO1 moves from the cytoplasm to the nucleus

 to produce more insulin to meet the body’s demand. However, as this phase of hyperglycemia continues to full-blown diabetes, it has been shown that FoxO1 disappears altogether from the beta cells. Thus, Fox O1 is a marker of beta cell identity; loss of this transcription factor changes the very existence of beta cells, converting them into more of a progenitor/ stem cell capable of performing functions of other cells in the islets of Langerhans, such as producing glucagon, thus explaining the hyperglucagonemia noted in diabetes. These changed beta cells also lose their insulin encoding genes like glucose transporter 2, glucokinase, and major transcription factors. Studies in hyperglycemic stress-induced mice

 have also shown that there is a decrease in the pro-insulin-processing enzyme Pcsk 1 (proprotein convertase subtilisin/kexin type1). This leads to a vicious cycle of hyperglycemia, increased secretion of biologically inactive proinsulin, and reduced insulin secretion. With the disappearance of the Fox O1 factor, other markers of the endocrine progenitor cells like Neurogenin3, Oct4, Nanog, and L-Myc expression have been noted to increase.

 have also noted an inverse relation of FoxO1 and Neurogenin 3.

However, these beta cells that have lost their identity marker or transcription factor (FoxO1) do not die; in fact, they regress to their original or progenitor form, now capable of producing a variety of functions. This phenomenon of beta cell dedifferentiation has been labeled by Talchai et al

 as a “selfish” beta cell, thus also suggesting that the homeostatic mechanism of the endocrine islet cells is not perfect.

 showed that FoxO1 has also been found in human fetal pancreas during 8 to 12 weeks of fetal life. When exposed to exogenous insulin, the fetal islet cells showed disappearance of the FoxO1 from the nucleus, suggesting that this factor has an important role to play in the development of beta cells during fetal life.

This basic science research in animal models has brought up several intriguing questions.

 Is this process true for humans as well, and if so, in what manner will it affect treatment strategy? Other questions may arise, such as, is FOXO1 activity reversible, once this transcription factor disappears from the beta cells; and does it reappear if euglycemia is restored? Or does it mean that once FOXO1 disappears, it cannot return—or that, once lost, beta cell identity is lost forever? Is there some other transcription factor that replaces FOXO1? It is known that with gastric bypass surgery or an intensive diet, exercise, and drug regimen, there is regression from stage 4 diabetes to stage 1 diabetes.

Some other clinically relevant questions arise:

• Is there a window of opportunity prior to complete dedifferentiation and partial dysfunction or activation of the beta cells?

• How is exogenous insulin affecting these transcription factors, and how are our current treatment strategies affecting these transcription factors?

• Should our goal to correct hyperglycemia be targeted to reviving these dedifferentiated beta cells?

It would be interesting to monitor the studies that follow this exceptional article by Talchai et al.

1. Unger RH, Cherrington AD. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. 

2. Chang-Chen KJ, Mullur R, Bernal-Mizrachi E. 

3. Weir GC, Bonner-Weir S. Five stages of evolving beta cell dysfunction during progression to diabetes. Diabetes. 2004;53(suppl 3): S16-S21. 4. Rahier J, Goebbels RM, Henquin JC. Cellular composition of the human diabetic pancreas. 

5. Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. 

6. Buteau J, Accili D. Regulation of pancreatic beta cell function by the forkhead protein FoxO1. 

7. Thorel F, Nepote V, Avril I, et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. 

8. Accilli D, Ahrin B, Boitard C, Cerasi E, Henquin JC, Seino S. What ails the beta cell? 

9. Al-Masri M, Krishnamurthy J, Li J, et al. Effect of forkhead box O1 (FOX01) on beta cell development in the human fetal pancreas.

10. Dor Y, Glaser B. Beta-cell dedifferentiation and type 2 diabetes. 

Diabetes

Diabetes: Going the Distance

Study Suggests Bald Men Are at Higher Risk for Heart Disease

 suggests that male pattern baldness is strongly linked to increased risk of coronary heart disease (CHD) (

Japanese researchers analyzed 6 rigorously conducted studies (3 cohort and 3 case-control) of nearly 40,000 men published between 1993 and 2008; all of the studies controlled for complicating factors like age and smoking.

They found that mostly bald men in the cohort studies were 32% more likely to develop CHD over the follow-up period than those who weren’t balding (

 = 0.08). The association remained for men under the age of 60 years. In the case-control studies, the adjusted relative risk for baldness was 1.70 for all participants (

 = 0.0001). An assessment of results from 3 studies that assessed the degree of baldness using the modified Hamilton scale showed that only vertex baldness, but not frontal baldness, was significantly associated with an increased risk of CHD—and the link was dependent on the severity of baldness.

Extensive vertex baldness increased the risk of CHD by 48%, moderate vertex baldness increased it by 36%, and mild vertex baldness by 18%. There was no significant association between frontal baldness and CHD.

How is losing hair on the head associated with heart disease? “It has been suggested that classical coronary risk factors (eg, age, hypertension, dyslipidemia, and smoking) might influence both conditions, so that baldness is a marker of atherosclerosis,” the authors wrote. “It has also been postulated that baldness is linked to CHD by mechanisms such as hyperinsulinemia, chronic inflammation, and increased peripheral sensitivity to androgen.”

The theories, says American Heart Association spokesperson Nieca Goldberg, MD, are worth exploring. While it could be that baldness is just a sign of aging, she said, it makes sense to screen previously untested men who present with vertex baldness for CHD risk factors.

A New Culprit in Heart Disease: Gut Bacteria?

There is a new explanation of why red meat may contribute to heart disease. Cleveland Clinic researchers led by Stanley Hazen, MD, found that when carnitine, a chemical in red meat, is digested, a chemical called trimethylamine N-oxide (TMAO) is produced in the gut, and it increases plaque buildup in arteries (

, April 7, 2013). Carnitine is found in small amounts in fish and chicken and dairy products, but red meat is the major source. The study appears in the April 7 edition of 

The researchers said TMAO levels predicted heart attack risk in humans, and that meat eaters normally had more TMAO in their blood and readily made TMAO after taking supplements with carnitine in them. They found that TMAO actually caused heart disease in mice. The findings also call into question the safety of energy drinks and supplements used in body building, which both contain carnitine.

Dr. Hazen’s research used more than 2500 blood samples from patients he was following because they were all at risk for heart disease. The researchers also tested the carnitine and TMAO levels of omnivores, vegetarians, and vegans to see if there were differences in the levels of these chemicals that varied with diet in these subjects. The investigators were surprised to see what a large impact vegan and vegetarian diets had on the formation of TMAO from carnitine. Subjects who did not eat red meat did not make TMAO in their gut 

even when they ate a steak or took carnitine supplements

. Regular red meat eaters had a spike in TMAO levels within hours of eating. Hazen and colleagues did not expect to see such a dramatic difference.

The researchers gave meat eaters doses of antibiotics to wipe out almost all of their gut bacteria, after which they no longer had TMAO in their blood after eating red meat or taking carnitine pills.

The findings may lead to new treatments for heart disease and a test assessing heart disease risk by testing TMAO blood levels.

What Your Patients Are Reading

	Blood transfusions are often a preferred strategy to minimize cardiovascular events in anemic patients with myocardial infarction (MI),

 in spite of data from observational studies suggesting that blood transfusion is futile, and may even present the real possibility of harm.

 Until recently, randomized data have been lacking, and have not been definitive because of their small sample size and the nature of pilot trials,

 and their conflicting results have not contributed to clarifying the questions still remaining about the riskbenefit of blood transfusion in patients with MI.

 attempted to answer questions about the impact of blood transfusion on hard, clinically relevant outcomes in anemic patients with MI and as such has important implications for the treatment of these patients.

A search was carried out on MEDLINE, EMBASE, CINAHL, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) for relevant studies published in English between January 1966 and March 2012 containing the search terms “transfusion,” “myocardial infarction,” and “mortality.” The references of relevant studies and review articles were scanned. ClinicalTrials.gov and proceedings from major international cardiology meetings were also searched for relevant trials. Studies that compared blood transfusion with no blood transfusion or a liberal versus restricted blood transfusion strategy in patients with MI were eligible for inclusion. To be considered eligible for analysis, studies had to report on mortality and mean baseline hemoglobin/ hematocrit levels for both groups and confounding factors had to be adjusted between the groups by means of statistically acceptable methods such as regression analysis or propensity matching. Studies that assessed the effect of transfusion of components other than whole blood or red blood cells were excluded. Patient mean age ranged from 67 to 77.8 years; 45.9% to 99% of patients were male. Baseline hemoglobin level ranged from 8.91 g/dL to 13.9 g/dL.

	Two reviewers independently selected studies for the review; disagreements were resolved by consensus. Study quality was assessed using the Newcastle- Ottawa Scale, which covered adequacy of selection, comparability of groups, and outcomes assessment. Publication bias was assessed with a funnel plot, the Egger’s regression test, and the trim-andfill method (Duval-Tweedie). Number needed to harm (NNH) was calculated. Subgroup analyses were planned for patients with STEMI and for patients with a hematocrit less than 30%. The study sequential analysis of diversity-adjusted information size for the outcome of allcause mortality was calculated. Sensitivity analyses excluded 1 study at a time. Multivariate meta-regression was used to assess the influence of the variables: follow- up period, history of bleeding, baseline creatinine level, baseline hemoglobin level, nadir of hemoglobin level, change in hemoglobin level during the hospital stay, and use of glycoprotein IIb or IIIa, thrombolytics, or antiplatelets.

	Ten studies (1 randomized trial and 9 observational studies) met all criteria for review. A total of 203,655 patients were included for the analysis of events. Most studies were considered to have an intermediate risk of bias. Follow-up ranged from 1 month to 12 months where reported. There was no evidence of publication bias. Meta-analyses showed that blood transfusion/liberal blood transfusion increased all-cause mortality compared with no blood transfusion/restricted blood transfusion in anemic patients with MI (relative risk [RR], 2.91; 95% confidence interval [CI], 2.46-3.44; Ι² [quantitative measure of heterogeneity among included studies] = 92%; NNH = 8; 10 studies). Similar results were found when using adjusted mortality instead of the actual number of events (hazard ratio [HR], 2.25; 95% CI, 1.68-3.02; Ι² = 98%; 9 studies). Blood transfusion/ liberal blood transfusion was also associated with a higher risk of subsequent MI (RR 2.04; 95% CI, 1.06-3.93; Ι² = 98%; 7 studies). In summary, while 18% of the people died in the liberal transfusion arm, the mortality in the restricted transfusion arm was 10%. Subgroups of patients with STEMI and patients with a hematocrit of less than 30% showed no significant difference in mortality between liberal blood transfusion and comparator. Meta-regression showed that blood transfusion was associated with higher mortality after adjustment for different variables. Sensitivity analysis confirmed that no single study was the source of heterogeneity. Study sequential analysis

 of studies on all-cause mortality suggested firm evidence for a 20% increase in relative risk with blood transfusion or a liberal blood transfusion strategy, compared with no blood transfusion or a restricted blood transfusion strategy. The authors concluded that blood transfusion or a liberal blood transfusion strategy compared with no blood transfusion or a restricted blood transfusion strategy was associated with higher all-cause mortality, as well as higher subsequent MI rates in patients with MI.

	1. Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. 

	2. Jani SM, Smith DE, Share D, et al. Blood transfusion and in-hospital outcomes in anemic patients with myocardial infarction undergoing percutaneous coronary intervention. 

	3. Yang X, Alexander KP, Chen AY, et al; CRUSADE Investigators. The implications of blood transfusions for patients with non-STsegment elevation acute coronary syndromes: results from the CRUSADE National Quality Improvement Initiative. 

	4. Cooper HA, Rao SV, Greenberg MD, et al. Conservative versus liberal red cell transfusion in acute myocardial infarction (the CRIT Randomized Pilot Study). 

	5. Chatterjee S, Wetterslev J, Sharma A, et al. Association of blood transfusion with increased mortality in myocardial infarction: a meta-analysis and diversity-adjusted study sequential analysis. (published online December 24, 2012) 

. 2013;173:132- 139. doi:10.1001/2013.jamainternmed.1001.

	6. Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. 

	7. Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative metaanalysis. 

	8. Carson JL, Hébert PC. Here we go again— blood transfusion kills patients? comment on “Association of blood transfusion with increased mortality in myocardial infarction: a meta-analysis and diversity-adjusted study sequential analysis.” (published online December 24, 2012.) Arch Intern Med. 2013;173:139- 140. doi:10.1001/2013.jamainternmed.1001.

	9. Middelburg RA, van de Watering LM, van der Bom JG. Blood transfusions: good or bad? Confounding by indication, an underestimated problem in clinical transfusion research. 

	10. Myocardial Ischemia and Transfusion (MINT). ClinicalTrials.gov Identifier: NCT01167582. 

http://clinicaltrials.gov/ct2/ show/NCT01167582

	A Significant Mortality Risk Associated With Transfusion

	The authors attempted to address a direct and relevant question and identified studies using documented inclusion criteria. Several relevant data sources were searched. The search was restricted to studies in English, so language bias remains a possibility. Suitable methods were employed in an attempt to reduce the risks of reviewer error and bias throughout the review process. Study quality was assessed using appropriate criteria. Information about individual studies was provided as available in the referenced publications. Well-accepted methods were used to pool data and assess heterogeneity. The authors acknowledged some limitations due to observational study designs, diverse patient characteristics, and the restriction to studies in English.

	Despite significant heterogeneity (which the authors tried to explore by using sensitivity analysis and multivariate meta-regression), the pooled data consistently showed a significantly less harmful effect with no blood transfusion, and the directionality of the outcomes assessed consistently pointed to favorable outcomes with a restrictive transfusion strategy. An accompanying invited commentary

 suggests “confounding by indication”

 as a limitation. This remains a possibility, as the authors themselves acknowledge. However, it should be noted that an attempt was made to account for bleeding as an indication by including baseline hematocrit and nadir hematocrit, as well as drop in hematocrit from baseline in the multivariable model adopted for the adjusted risk estimates. The authors state that randomized controlled trials with adequate sample size and with low risk for bias were needed for more definitive conclusions. However, ongoing clinical trials continue to have inadequate sample size and thus are unlikely to be definitive.

 A less harmful effect was found with blood transfusion in a subgroup of patients with STEMI and with hematocrit of less than 30%, so future research should identify specific subgroups that may benefit from blood transfusion.

	Saurav Chatterjee, MD, is Clinical and Research Fellow in Preventive Cardiology and Outcomes Research at Brown University and Providence VAMC in Providence, RI, and will pursue a clinical cardiology fellowship at St Luke’s-Roosevelt Hospital of Columbia University beginning in July 2013. He graduated from Calcutta National Medical College with honors and was a resident in cardiology in Mercy Hospital, Kolkata, India, as well as trial coordinator of the CRESCENDO trial in Kolkata, India. He recently completed his residency in Internal Medicine from Maimonides Medical Center in Brooklyn, NY. Dr Chatterjee is the recipient of the 2012 Young Investigator Award for Health Outcomes and Population Genetics at the Annual Scientific Sessions of the American College of Cardiology 2012 in Chicago, and also the 2011 American Association of Cardiologists of Indian Origin (AACIO) Young Investigator Award for Interventional Cardiology and Electrophysiology.

Chatterjee S, Wetterslev J, Sharma A, Lichstein E, Mukherjee D. Association of blood transfusion with increased mortality in myocardial infarction: a meta-analysis and diversity-adjusted study sequential analysis. 

. 2013;173:132-139. Published online December 24, 2012. doi:10.1001/2013. jamainternmed.1001.

April 2013

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