Updated Guidelines: Coronary Artery Bypass Grafting and Percutaneous Coronary Intervention

Collaboration of the two guideline writing teams reflects a push for closer interdisciplinary cooperation in decision making about coronary revascularization.

Sponsoring Organizations: American College of Cardiology (ACC), American Heart Association (AHA), American Association for Thoracic Surgery, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons

Background and Purpose: These new coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) guidelines update versions from 2004 and 2007, respectively. Unique to the revisions is a joint set of recommendations produced collaboratively to address the question of which patients should undergo which procedure. Additional input was also provided by the authors of the ACC/AHA guidelines on management of stable ischemic heart disease; revision expected in 2012) and unstable angina/non-ST-segment-elevation myocardial infarction.

Key Points:
1. Because data from trial registries show lower mortality rates in patients referred for a specific procedure compared with patients in concurrent randomized cohorts, these guidelines contain a new Class I recommendation for a multidisciplinary heart team (MHT) to coordinate care of patients with left main or complex coronary artery disease (CAD). The MHT includes an interventional cardiologist and a cardiac surgeon who jointly develop a revascularization plan to present to the patient for a final decision. A new recommendation for the use of transesophageal echocardiography during CABG (Class IIa) supports the inclusion of a cardiac anesthesiologist on the MHT.

2. The authors encourage the use of the SYNTAX and STS scoring systems in formulating revascularization decisions (Class IIa). This recommendation reflects a trend away from simple angiographic criteria toward a more integrated approach that incorporates functional assessment of lesion severity with measures such as fractional flow reserve.

3. PCI is now recognized as a reasonable alternative to CABG for unprotected left main lesions (Class designation raised to IIa from IIb) when anatomy is favorable for PCI and surgical risk is high. CABG retains a Class I indication for unprotected left main lesions and is also preferred (Class IIa) for most patients with three-vessel disease.

4. In separating survival indications from symptom relief, the authors now recommend PCI for angina that persists despite “guideline-determined medical therapy” (Class I), on the basis of findings from the COURAGE trial (in which the term “optimal medical therapy” was used.

5. Many recommendations pertain to appropriate medical therapy before and after PCI and CABG:

  • High-dose statin therapy is recommended before PCI (Class IIa).
  • The recommended aspirin dose after PCI has been reduced to 81 mg per day (Class IIa).
  • Ticagrelor now carries a Class I recommendation as an alternative to clopidogrel or prasugrel for 12 months after stenting.
  • Aspirin and beta-blockers are recommended before CABG (Class I).
  • Clopidogrel and ticagrelor should be discontinued 5 days before elective CABG and 24 hours before emergency CABG (Class I).
  • After CABG, patients should receive beta-blockers, statins, and intravenous insulin to maintain a blood glucose of <180 mg/dL (Class I).

6. N-acetylcysteine is no longer recommended for PCI in patients at risk for acute kidney injury (Class III).

7. Hybrid revascularization, off-pump CABG, and use of robotic techniques are discussed. Hybrid revascularization is deemed reasonable in patients with aortic, target-vessel, or conduit constraints to traditional CABG (Class IIa).

Comment: These updated guidelines provide a wealth of new information and recommendations. Most interesting, and perhaps most controversial, is the formal endorsement of a multidisciplinary heart team approach to revascularization decisions for complex coronary artery disease. This model is similar to one recently recommended for consideration of transcatheter aortic valve replacement in patients with extremely high-risk aortic stenosis, but it will be new to many involved in the treatment of CAD. I hope that the MHT approach will begin to build a new relationship between interventional cardiologists and cardiac surgeons, discouraging competition and promoting collaboration to improve patient outcomes.

Source: Journal Watch Cardiology.






First-Trimester Malaria: Treatment and Outcomes

Symptomatic and asymptomatic malaria infections during the first trimester of pregnancy were associated with miscarriage; treatment appeared to be safe.

Malaria during pregnancy has adverse effects, including maternal mortality, miscarriage, and low birthweight. During early pregnancy, treatment options are limited, especially in regions with drug resistance. In a retrospective study covering a 25-year period (1986–2010), investigators compared outcomes between women with a single episode of malaria during the first trimester and women without malaria during pregnancy. The women came from a camp for displaced persons in a remote rural area near the Thai–Burmese border.

Among 17,613 pregnant women, 945 (5%) had a single episode of malaria during the first trimester. Risk for miscarriage was increased by 2.7-fold in women with asymptomatic malaria — and by nearly 4-fold in those with symptomatic malaria — compared with uninfected women. Risk was similar between vivax and falciparum infections and was higher in women with hyperparasitemic or severe malaria. Other risk factors for miscarriage included smoking, maternal age 26, previous miscarriage, and nonmalarial febrile illness. Miscarriage risk was similar whether the woman was treated with chloroquine, quinine, or artesunate. No excess or specific fetal abnormalities were associated with artesunate-containing therapies, but the numbers available for this group were small (44 deliveries to artesunate recipients).

Comment: These findings are reassuring with regard to the safety of artemisinin derivatives during the first trimester of pregnancy, despite animal studies suggesting potential embryo toxicity. Prospective studies in women are warranted. The present results clearly demonstrate the adverse consequences of malaria — whether asymptomatic or symptomatic — so testing and treatment during all stages of pregnancy should be part of malaria programs. Although both malarial and nonmalarial febrile illnesses are associated with increased risk for miscarriage during the first trimester, the pathological process underlying the increased miscarriage risk with asymptomatic malaria is unclear and likely malaria specific. As emphasized by editorialists, the risk from malaria clearly outweighs the theoretical risk from artemisinin treatment during early pregnancy.

Source: Journal Watch Infectious Diseases




Nanoparticles Help Deliver Steroids To The Retina

Research at Wayne State University, Mayo Clinic, and Johns Hopkins offers potential treatment for macular degeneration and retinitis pigmentosa

Hitching a ride into the retina on nanoparticles, called dendrimers, offers a new way to treat age-related macular degeneration and retinitis pigmentosa. A collaborative research study among investigators at Wayne State University, the Mayo Clinic and Johns Hopkins Medicine shows that steroids attached to the dendrimers targeted the damage-causing cells associated with neuroinflammation, leaving the rest of the eye unaffected and preserving vision.

The principal authors of the study, Raymond Iezzi, M.D. (Mayo Clinic ophthalmologist) and Rangaramanujam Kannan, Ph.D. (faculty of ophthalmology at The Wilmer Eye Institute of Johns Hopkins) have developed a clinically relevant, targeted, sustained-release drug delivery system using a simple nanodevice construct. The experimental work in rat models was initiated and substantially conducted at Wayne State University, and showed that one intravitreal administration of the nanodevice in microgram quantities could offer neuroprotection at least for a month, and appears in the journal, Biomaterials.

Both dry age-related macular degeneration and retinitis pigmentosa are caused by neuroinflammation, which progressively damages the retina and can lead to blindness. Macular degeneration is the primary cause of vision loss in older Americans, affecting more than 7 million people, according to the National Institutes of Health (NIH). Retinitis pigmentosa encompasses many genetic conditions affecting the retina and impacts 1 in 4,000 Americans, the NIH estimates.

“There is no cure for these diseases, said Iezzi. “An effective treatment could offer hope to hundreds of millions of patients worldwide. We tested the dendrimer delivery system in rats that develop neuroinflammation leading to retinal degeneration. The target was activated microglial cells, the immune cells in charge of cleaning up dead and dying material in the eye. When activated, these cells cause damage via neuroinflammation—a hallmark of each disease.”

“Dendrimers are tree-like, non-cytotoxic polymeric drug delivery vehicles (~ 4 nm). Surprisingly, the activated microglia in the degenerating retina appeared to eat the dendrimer selectively and retain them for at least a month. The drug is released from the dendrimer in a sustained fashion inside these cells, offering targeted neuroprotection to the retina,” said Kannan.

The treatment reduced neuroinflammation in the rat model and protected vision by preventing injury to photoreceptors in the retina. Although the steroid offers only temporary protection, the treatment as a whole provides sustained relief from neuroinflammation, the study found.  The researchers believe that this patent-pending technology with significant translational potential will be advanced further, through this multi-university collaboration among Johns Hopkins, Mayo Clinic and Wayne State.

 Source:  Macular degeneration.

Award Ceremony Speech for The Nobel Prize in Physiology or Medicine 2011.

The Nobel Prize in Physiology or Medicine 2011

Bruce A. Beutler, Jules A. Hoffmann, Ralph M. Steinman


Presentation Speech by Professor Göran K. Hansson, Secretary of the Nobel Assembly at Karolinska Institutet and of the Nobel Committee for Physiology or Medicine, 10 December 2011

Your Majesties, Your Royal Highnesses, Ladies and Gentlemen,

We live in a dangerous world. During the hour you spend here in the Concert Hall, you will be exchanging millions of bacteria and viruses with each other. Fortunately, you are equipped with a strong defence, and we do not expect that this hour will lead to any significant reduction of our guest list.

This defence constitutes our immunological protection against bacteria, viruses and other microorganisms. It consists of two lines of defence: the first one stops the invaders and the second one eliminates them.

Much research has been focused on the second line of defence with its antibodies and killer cells. But a major question remained unanswered: How can we survive an infection until antibodies have been formed? It can take several weeks before the antibody levels are sufficient, and by then we may already have recovered from our infected wound or our common cold. The first line of the immune defence, which is also called innate immunity, must have recognised and stopped the bacteria long before the antibodies had arrived on the scene.

Jules Hoffmann went on a quest to reveal the secrets of the first line of defence. He knew that insects lack the second line of defence, and therefore chose fruit flies as his research model. It turned out that flies with defects in a gene called Toll could not combat infections successfully. Hoffmann and his colleagues were able to unravel a detector system involving Toll that is activated by molecules derived from microorganisms, leading to mobilisation of the immune defence against the intruders. Thanks to Hoffmann’s discovery, the sensors of the first line of host defence were finally identified.

Bruce Beutler was searching for the solution to another problem. He wanted to understand how bacteria such as Salmonella can elicit a life-threatening septic shock – what used to be called blood poisoning. By comparing the genome of different mouse strains, he could demonstrate that a single gene initiated the shock reaction. This gene turned out to be the mammalian counterpart of Toll, and it encodes a receptor that serves as a sensor on the cell surface. When bacterial components bind to this receptor, the immune system is activated, and antibacterial defence mechanisms are mobilised.

Thanks to Beutler’s discovery, we understood how the sensors of the innate immune system operate to recognise infectious agents. Together, the two Nobel Laureates had clarified how the first line of defence is mobilised.

In parallel with these discoveries, Ralph Steinman was studying the activation of the second line of defence, which is also called adaptive immunity.  More than 30 years ago, he isolated a new cell type called the dendritic cell.  Through systematic research, he showed that dendritic cells patrol the organs searching for pathogens, and mobilise the second line of immune defence, with its antibodies and immunologic memory. The dendritic cells themselves are in fact activated by the Toll receptor that Beutler and Hoffmann had identified. This mechanism ties together the two lines of immune defence.

The three discoveries now awarded the Nobel Prize have identified the triggers for the innate and the adaptive immune system, and taught us how these two lines of defence are interconnected to protect us against infections. Today, knowledge about the sensors of innate immunity is exploited to improve vaccines and therapies, and dendritic cells are used to treat infections and cancer.

Dear Professor Beutler and Professor Hoffmann,

Your research has identified the gatekeepers of the immune system. Not only have your discoveries resolved a major enigma in immunology, they have offered new hope for mankind in its combat against infections, cancer, and inflammatory diseases. On behalf of the Nobel Assembly at Karolinska Institutet, I wish to convey to you our warmest congratulations.

Dear Mrs Steinman,

Your late husband’s research has taught us how adaptive immunity is initiated and provided us with new tools in the struggle against disease. We deeply regret that Professor Steinman is no longer with us but we are happy that you are here to accept his Nobel Prize.

Professor Beutler, Professor Hoffmann and Mrs Steinman,

May I now ask you to step forward to receive the Nobel Prize from the hands of His Majesty the King.


Source:Nobelprize.org ( the official Nobel Prize Site)

SenoBright* Contrast Enhanced Spectral Mammography (CESM) technology

ImageSenoBright* Contrast Enhanced Spectral Mammography (CESM) technology is GE’s newly FDA-cleared technology that aids physicians in breast cancer diagnosis by producing images that illuminate and highlight contrast-enhanced areas. It is designed to help localize a lesion and cut the critical patient wait time from detection to diagnosis.

With SenoBright already in use in several countries, GE estimates that by 2020 more than 1 million women worldwide will be examined using SenoBright, leading to more productive diagnosis paths for nearly 250,000 women.

 source:GE Imaging

Tau-Targeted Immunization Impedes Progression of Neurofibrillary Histopathology in Aged P301L Tau Transgenic Mice

In Alzheimer’s disease (AD) brains, the microtubule-associated protein tau and amyloid-β (Aβ) deposit as intracellular neurofibrillary tangles (NFTs) and extracellular plaques, respectively. Tau deposits are furthermore found in a significant number of frontotemporal dementia cases. These diseases are characterized by progressive neurodegeneration, the loss of intellectual capabilities and behavioral changes. Unfortunately, the currently available therapies are limited to symptomatic relief. While active immunization against Aβ has shown efficacy in both various AD mouse models and patients with AD, immunization against pathogenic tau has only recently been shown to prevent pathology in young tau transgenic mice. However, if translated to humans, diagnosis and treatment would be routinely done when symptoms are overt, meaning that the histopathological changes have already progressed. Therefore, we used active immunization to target pathogenic tau in 4, 8, and 18 months-old P301L tau transgenic pR5 mice that have an onset of NFT pathology at 6 months of age. In all age groups, NFT pathology was significantly reduced in treated compared to control pR5 mice. Similarly, phosphorylation of tau at pathological sites was reduced. In addition, increased astrocytosis was found in the oldest treated group. Taken together, our data suggests that tau-targeted immunization slows the progression of NFT pathology in mice, with practical implications for human patients.


Vaccine Against Alzheimer’s Protein Slows Disease Progression In Mice

Promise for future immunization in people targeting the tau protein

Researchers at the University of Sydney’s Brain and Mind Research Institute (BMRI) have developed a vaccine that slows the progression of Alzheimer’s disease and other types of dementia in mice designed to show features of these diseases, according to results of a study published December 9 in the scientific journal PLoS ONE.

The vaccine, which targets a protein known as tau, prevents the ongoing formation of neurofibrillary tangles in the brains of these mice. The tau protein also is involved in frontotemporal dementia.

“Most of the other vaccines targeting tau were tested only before or around the onset of the disease in animal models. Our study is the first to show that a vaccine targeting the tau protein can be effective once the disease has already set in,” Lars Ittner, a senior research fellow and BMRI group leader said.

Rather than clearing existing tangles, the vaccine appears to slow the development of further tangles, Ittner said. The exact mechanism involved is not yet understood, he said.

BMRI already has begun working with U.S.-based pharmaceutical firms to develop it for human use, Ittner added.

It is estimated that there were 35.6 million people living with dementia worldwide in 2010, and this will increase to 65.7 million by 2030 and 115.4 million by 2050.


source: Alzheimer’s Foundation.



Muscular Dystrophy Associated with Increased Risks for Some Cancers

Myotonic muscular dystrophy is associated with a doubling in the overall risk for cancer — and sharp increases in risks for specific cancers — according to a JAMA study of Danish and Swedish cohorts.

Researchers used national hospital-discharge and cancer registries to compare cancer rates among patients with myotonic muscular dystrophy, the most common form of muscle dystrophy, with rates in the general population. Patients with muscular dystrophy had an eightfold increased risk for endometrial cancer, fivefold increases in risks for brain and ovarian cancers, and a tripled risk for colon cancer.

The authors speculate that changes in tumor-suppressor genes or oncogene expression may serve as the mechanism for the effect. They say that the clinical implications of their findings include, “at a minimum,” use of routine validated cancer screening in patients with myotonic muscular dystrophy, particularly for colon cancer.




Catheter-Directed Thrombolysis Improves Outcomes in DVT

Patients with iliofemoral deep venous thrombosis (DVT) who undergo catheter-directed thrombolysis are at lower risk for post-thrombotic syndrome, according to a Lancet study.

Roughly 200 adults with a first acute iliofemoral DVT were randomized to receive conventional anticoagulation (low-molecular-weight heparin plus warfarin) either alone or with additional catheter-directed thrombolysis. At 2 years, post-thrombotic syndrome — characterized by pain, edema, and skin deterioration — was less common with catheter-directed thrombolysis than with anticoagulation alone (41% vs. 56%). Twenty bleeding complications occurred in the catheter group.

The authors calculated that seven patients would need to receive catheter-directed thrombolysis to prevent one case of post-thrombotic syndrome.

Commentators call the study a “tremendous contribution” that “serves as a powerful motivation to undertake [catheter-directed thrombolysis] for symptomatic acute lower extremity DVT.”




Sodium Excretion of >7 g or <3 g Daily Is Associated with Elevated Cardiovascular Morbidity

By comparison, higher potassium excretion was associated with lower stroke risk.

The WHO recommends daily sodium intake of less than 2 g, based on relatively short trials in which the effect of sodium intake on blood pressure was assessed. In this study, researchers analyzed data for 28,880 patients in two international clinical trials of an angiotensin-receptor blocker; most patients (mean age, 67; 70% men) had histories of myocardial infarction, stroke, hypertension, or diabetes. People with congestive heart failure (CHF), decreased renal function, or uncontrolled hypertension were excluded. Mean daily sodium excretion (a surrogate for sodium intake) was 4.77 g, and daily potassium excretion was 2.19 g.

At 5 years, a composite outcome of cardiovascular mortality, myocardial infarction, stroke, and hospitalization for CHF occurred in 4729 patients. Patients with urinary sodium excretion of 4 to 6 g daily had the lowest risk for the composite outcome. Risk was higher by 21%, 16%, 15%, and 49% for patients with daily excretion of <2 g, 2–3 g, 7–8 g, and >8 g, respectively. Compared with patients who had daily potassium excretion of <1.5 g, risk for stroke was 32% lower in those with excretion of >3 g. These analyses were adjusted for numerous clinical and demographic factors.

Comment: This J-shaped relation between sodium intake and cardiovascular outcomes conflicts with current recommendations to limit daily sodium intake to 2 g. However, an editorialist is unconvinced and believes that randomized trials are needed to account for confounding caused by preexisting disease and risk factors. The small number of patients with low sodium intake — 3% of the total sample had urinary excretion <2 g daily — also tempers the results. Consuming a diet high in natural foods and low in processed foods would result in a lower sodium–potassium ratio –– which could be more important than the actual intake levels.

Source: Journal Watch General Medicine