Dual antiplatelet therapy for primary and secondary prevention.

The concomitant use of aspirin and an ADP receptor (P2Y12) blocker, also known as dual antiplatelet therapy (DAPT), has been extensively investigated as a primary and secondary prevention strategy in an effort to reduce the risk of cardiovascular events. In this manuscript the authors review the current guideline recommendations for DAPT and discuss the scientific data that supports these recommendations. Reported are also the scientific knowledge gaps and how future studies are likely to delineate these issues. Incremental knowledge is not likely to be an alternative to individualized care provided by the astute clinician to his patient. In consideration for prescribing DAPT (drug, dosage and duration) the clinician will have to weigh the potential benefits (reduction in death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke) and risks (severe or life-threatening bleeding) for each and every patient.

Fractional flow reserve (FFR): changing the practice of interventional cardiology.

Fractional flow reserve (FFR) has become an extremely valuable tool for assessing the hemodynamic significance of intermediate coronary lesions. This manuscript delineates the current guidelines regarding the use of FFR and discusses emerging indications for the use of this diagnostic tool and how they compare with and complement non-invasive or other invasive diagnostic modalities. The manuscript addresses some of the key unanswered questions related to FFR, the potential pitfalls of this tool and discusses future directions of use and research.

Emerging oral anticoagulants for stroke prevention in patients with non-valvular atrial fibrillation.

In patients with atrial fibrillation (AF) warfarin has been the mainstay therapy for stroke prevention. In recent randomized clinical trials (RCTs) oral direct thrombin inhibitor (Dabigatran) and factor Xa inhibitors (Rivaroxaban and Apixaban) challenged the efficacy and safety benchmarks set by warfarin. These drugs boast a rapid onset of action, shorter half-life and fewer drug and dietary interactions. Moreover, these new anticoagulants do not require monitoring, titration or dose adjustments. These agents have already been approved for prevention of stroke or systemic embolism in patients with AF. Uncertainty regarding suitability, efficacy and safety in certain patient subsets and issues related to the ability effectively monitor the pharmacodynamic effects and reverse the therapeutic effects of these drugs should be addressed as we engage in a widespread use of these agents in various patient subsets.

Routine stress testing after percutaneous coronary interventions.

Percutaneous coronary intervention (PCI) is the most frequently performed cardiovascular procedure. Many physicians caring for post-PCI patients have routinely subjected patients to periodic stress testing. In the recent years, due to widespread use of drug eluting stents the combined rates of major adverse cardiac events (MACE) and in-stent restenosis (ISR) dropped <10% in the initial 12 months post-PCI, with only half of these patients bearing symptoms. This has translated into reduced pre-test probability of post-PCI ischemia. Consequently, the beneficial effect of this practice came into question. Moreover, in addition to its financial implications, routine post-PCI stress testing may carry potential harm: medication or exercise induced arrhythmia, infarction and/or death, patient irradiation exposure, false-positive tests resulting in excessive invasive testing or interventions, and the illusion of "wellness" in the face of a somewhat unpredictable disease. This review addresses the role stress testing post-PCI: it is concluded that routine stress testing in clinically stable asymptomatic post-PCI patients should be discouraged. Selective utilization of stress testing in patients with exceptionally high risk of ISR or MACE can be utilized to answer important clinical questions or guide and refine clinical care.

Ablation of ventricular tachycardia.

Ablation is an important management tool for the treatment of ventricular arrhythmias. Even at experienced centers ventricular tachycardia ablation carries a minor but significant risk for potential complications, including vascular and thromboembolic complications, air embolism, volume overload and the precipitation of congestive heart failure, cardiac tamponade from catheter perforation or from steam pop with RF energy delivery, valve or subvalvular support structure disruption, conduction system disruption with development of heart block, coronary artery injury when ablating in the coronary cusps region or trying to gain access to the LV chamber, precipitation of cardiogenic shock from ablation of viable myocardium in patients with marginal reserve and failure to resuscitate or precipitation of cardiogenic shock from repeated VT induction, and with epicardial ablation the potential complications of epicardial access, coronary arteries and phrenic nerve damage. Recognition of these risks is paramount for their avoidance with careful pre-procedure planning and intraprocedural technique being essential to minimize the potential for complications.

Complications associated with catheter ablation of atrial fibrillation.

Atrial fibrillation is the most common clinical arrhythmia, affecting millions of people worldwide and utilizing billions of dollars annually in heath care costs associated with the disease. Catheter based ablation, centering around the electrical isolation of the pulmonary veins, has emerged as a viable treatment option for patients with symptomatic paroxysmal or persistent atrial fibrillation. Because of the complex nature of the procedure, there are a number of potential complications which can occur which are related to problems with vascular access, mechanical complications resulting from catheter manipulation within the heart, cardioembolic complications, and complications arising from the effects of radiofrequency ablations in the left atrium. The most frequent complications arise from pseudoaneurysms, arterio-venous fistulas, hematomas, neurologic events (stroke and transient ischemic attacks), and pericardial effusion/tamponade. An evolving understanding of the risks of the procedure have helped to minimize complications by changing ablation strategies to avoid lesion delivery within the veins, emphasizing careful attention during the procedure to anticoagulation, utilizing intracardiac ultrasound and electroanatomic mapping systems for better visualization of intracardiac structures, and recognizing complications promptly during and after the procedure. Hopefully, improved techniques in the future will help to further improve the safety of catheter ablation of atrial fibrillation to allow for continued growth of this procedure.

Active site mutants in the six regulatory particle ATPases reveal multiple roles for ATP in the proteasome.

A family of ATPases resides within the regulatory particle of the proteasome. These proteins (Rpt1-Rpt6) have been proposed to mediate substrate unfolding, which may be required for translocation of substrates through the channel that leads from the regulatory particle into the proteolytic core particle. To analyze the role of ATP hydrolysis in protein breakdown at the level of the individual ATPase, we have introduced equivalent site-directed mutations into the ATPbinding motif of each RPT gene. Non-conservative substitutions of the active-site lysine were lethal in four of six cases, and conferred a strong growth defect in two cases. Thus, the ATPases are not functionally redundant, despite their multiplicity and sequence similarity. Degradation of a specific substrate can be inhibited by ATP-binding-site substitutions in many of the Rpt proteins, indicating that they co-operate in the degradation of individual substrates. The phenotypic defects of the different rpt mutants were strikingly varied. The most divergent phenotype was that of the rpt1 mutant, which was strongly growth defective despite showing no general defect in protein turnover. In addition, rpt1 was unique among the rpt mutants in displaying a G1 cell-cycle defect. Proteasomes purified from an rpt2 mutant showed a dramatic inhibition of peptidase activity, suggesting a defect in gating of the proteasome channel. In summary, ATP promotes protein breakdown by the proteasome through multiple mechanisms, as reflected by the diverse phenotypes of the rpt mutants.

Two syntaxin homologues in the TGN/endosomal system of yeast.

Intracellular membrane traffic is thought to be regulated in part by SNAREs, integral membrane proteins on transport vesicles (v-SNAREs) and target organelles (t-SNAREs) that bind to each other and mediate bilayer fusion. All known SNARE-mediated fusion events involve a member of the syntaxin family of t-SNAREs. Sequence comparisons identify eight such proteins encoded in the yeast genome, of which six have been characterized. We describe here the remaining two, Tlg1p and Tlg2p. These have the expected biochemical properties of t-SNAREs, and are located in separable compartments which correspond to a putative early endosome and the yeast equivalent of the TGN, respectively. They co-precipitate with the v-SNARE Vti1p, which is implicated in Golgi-endosome traffic and, remarkably, binds to five different syntaxins. Tlg1p also binds the plasma membrane v-SNARE Snc1p. Both Tlg1p and Tlg2p are required for efficient endocytosis and to maintain normal levels of TGN proteins. However, neither is required for intra-Golgi traffic. Since no further syntaxins have been identified in yeast, this implies that the Golgi apparatus can function with a single syntaxin, Sed5p.