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The optimal antithrombotic regimen for patients with atrial fibrillation (AF) who had an acute coronary syndrome (ACS) or have undergone percutaneous coronary intervention (PCI) is not known. The authors sought to determine which antithrombotic regimen best balances safety and efficacy. AUGUSTUS, a multicenter 2 × 2 factorial design randomized trial compared apixaban with vitamin K antagonist (VKA) and aspirin with placebo in patients with AF with recent ACS and/or PCI treated with a P2Y 12 inhibitor. We conducted a 4-way analysis comparing safety and efficacy outcomes in the 4 randomized groups. The primary outcome was a composite of all-cause death, major or clinically relevant nonmajor bleeding, or hospitalization for cardiovascular causes over 6-month follow-up. Secondary outcomes included individual components of the primary endpoint. A total of 4,614 patients were enrolled. All patients were treated with a P2Y 12 inhibitor. The primary endpoint occurred in 21.9% of patients randomized to apixaban plus placebo, 27.3% randomized to apixaban plus aspirin, 28.0% randomized to VKA plus placebo, and 33.3% randomized to VKA plus aspirin. Rates of major or clinically relevant nonmajor bleeding and hospitalization for cardiovascular causes were lower with apixaban and placebo compared with the other 3 antithrombotic strategies. There was no difference between the 4 randomized groups with respect to all-cause death. In patients with AF and a recent ACS and/or PCI, an antithrombotic regimen that included a P2Y 12 inhibitor and apixaban without aspirin resulted in a lower incidence of the composite of death, bleeding, or cardiovascular hospitalization than regimens including VKA, aspirin, or both. (An Open-label, 2 x 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Aspirin Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention; NCT02415400) [ABSTRACT FROM AUTHOR]

Introduction: Early afterdepolarizations (EADs) can give rise to triggered activity and thereby produce cardiac arrhythmias. We used the whole-cell patch clamp technique to examine the relationship between L-type Ca2+ channel window current and the generation of EAOs in single ventricular myocytes isolated from guinea pig hearts. Methods and Results: With a high concentration of EGTA in the internal solution and Na+-containing physiologic external solution, EADs were induced in undamped cells by injecting intracellular depolarizing current pulses. During voltage clamp protocols designed to simulate action potentials interrupted by EADs, we recorded an inward shift in total current up to 0.7 pA/pF over 400 msec at test steps in the range of the take-off potential for EADs. Cd2+ (0.2 mM) blocked most of the inward shift of current during the test steps and abolished EADs. When the same voltage clamp protocol was used following perfusion with an Na+-free, K+-free external solution, the Cd2+-sensitive inward currents recorded during the test steps were similar to those obtained in physiologic external solution. The overlapping range of potentials for partial activation of the d and f variables of L-type Ca-2+ current ("window" region) measured in Na+-free, K+-free external solution was virtually the same as the voltage range of the Cd2+-sensitive inward currents. Conclusion: Our experiments suggest that: (1) EADs can arise under conditions of high EGTA buffering of intracellular [Ca=2+]; and (2) under these conditions, L-type Ca2+ channel window current plays a major role in the initiation of EADs. [ABSTRACT FROM AUTHOR]

The early afterdepolarization, which is an interruption of repolarization, can evoke a second upstroke or a salvo of action potentials. It is suggested that the electrophysiological characteristics of the early afterdepolarization can produce a lengthening of the QT interval and that the second upstroke and salvo of activity that may .follow, it can explain many features of torsade de pointes and of certain other ventricular tachycardias. The early afterdepolorization, torsade de pointes, and repetitive monomorphic idiopathic ventricular tachycardia are all induced by bradycardia or by o preceding long RR interal. The R-on-T phenomenon is also discussed. [ABSTRACT FROM AUTHOR]

Objective: The aim was to study changes in contractile proteins which accompany marked hypertrophy and heart failure in mammalian hearts initially containing predominantly V3 isomyosin. Methods: Left ventricular myosin and myofibrillar ATPase activity and right ventricular actomyosin ATPase activity were measured in normal guinea pig hearts, in hearts which were hypertrophied as a result of progressive left ventricular systolic overload following ascending aortic banding, and in hypertrophied hearts from animals which showed signs of overt congestive heart failure. Male guinea pigs weighing 225-275 g at the time of aortic banding were used for the studies. Results: Left ventricular myosin and myofibrillar ATPase activity and right ventricular actomyosin ATPase activity were correlated with body weight, left and right ventricular weight, and left ventricular peak systolic pressure during aortic occlusion. Left ventricular myosin ATPase activity and right ventricular actomyosin ATPase activity were markedly depressed in hypertrophied ventricles compared to control ventricles. Cardiac myofibrillar ATPase activity was lower in hypertrophied failing hearts than in control hearts over a wide range of calcium concentrations. In control animals and in those without heart failure, there was a nearly identical inverse relationship between left ventricular mass up to 1600 mg and myosin ATPase activity. Hypertrophied failing hearts were larger but showed little further reduction in cardiac myosin ATPase activity. Representative gel scans of non-dissociating pyrophosphate gels of left ventricular myosin from an 8 d postoperative aortic constricted animal and from its age and weight matched control showed predominantly Vi isomyosin with small amounts of Vi isoenzyme. However, preparations taken from guinea pigs 16 d after aortic constriction showed only the Vi isoform, whereas the Vi isoform was still apparent in control. Hypertrophied failing left ventricles developed less pressure per unit mass during brief aortic occlusion than non-failing left ventricles with comparable myosin ATPase activities. Conclusions: These observations raise important questions as to the distribution of myosin isoforms in the normal adult guinea pig, and the possibility that myosin ATPase activity might be altered by post-translational modification. Although cardiac myosin ATPase activity correlates with left ventricular performance, it cannot fully explain the depressed performance of failing hearts in this model. Additional immunological studies of cardiac contractile proteins are required as well as studies designed to explore the implications of altered myosin ATPase activity for both contractile function and overall cellular homeostasis. [ABSTRACT FROM PUBLISHER]

Chronic hypophosphataemia is associated with reversible depression in myocardial performance of the intact heart. To define the basis for this, we studied the mechanical and electrical properties of isolated left ventricular papillary muscles from rats with 6 weeks of phosphorus depletion (P6), 6 weeks of phosphorus repletion and age-matched controls (C). Muscles were perfused with Tyrode's solution (Ca2+ = 2.4 mmol·litre−1, K+ = 4.0 mmol·litre−1, dextrose = 5.5 mmol·litre−1) and driven at 0.1 Hz. P6 muscles had slowed isometric relaxation (T1/2R), depressed velocity of shortening and relaxation and prolongation of the transmembrane action potential to 75% of complete repolarisation. These results suggest that the slow relaxation phase may be the result of the prolonged APD75 and that the depressed myocardial performance in the intact heart may be based on impaired relaxation and reduced the velocity of shortening associated with hypophosphataemia. This view is supported by our finding that these alterations are reversible with phosphate repletion. [ABSTRACT FROM PUBLISHER]

The results of previous studies of the relation between the surface electrocardiogram and cellular transmembrane potentials have suggested that the T wave configuration of the ECG is the result of a difference in the duration of endocardial and epicardial action potentials. Ventricular hypertrophy induced by renal hypertension in rats is associated with lengthening of action potential duration and a reproducible decrease in T wave magnitude. Therefore, this model was used to study the relation between the surface T wave configuration and regional differences in action potential duration. ECGs were recorded from hypertensive (HBP) and sham-operated (SHAM) rats. The hearts from these animals were removed and transmembrane action potentials were recorded by standard microelectrode techniques from endocardial and epicardial preparations. We found that the normally peaked T waves seen in the ECG of SHAM rats was reduced by 35% in the ECG of HBP rats. This reduction of T wave magnitude was associated with similar duration of epicardial and endocardial action potentials in HBP rats. However, peaked T wave in SHAM ECG was not accompanied by a significant disparity in the duration of the epicardial and endocardial action potentials. Thus, there is no simple, consistent correlation between surface T wave configuration and regional differences in intracellular action potential duration in rats. [ABSTRACT FROM PUBLISHER]

The effect of membrane potential on the manifestations of ouabain-induced alterations in the electrical activity of shortened sheep cardiac Purkinje fibres was studied by a microelectrode technique. The level of membrane potential was modulated by passing intracellular polarizing current. It was found that the toxic electrical effects induced by exposure to ouabain vary according to the level of membrane potential. [ABSTRACT FROM PUBLISHER]

An essay is presented on the vicissitudes of dialectic in conflict based on the second volume of Jean-Paul Sartre's "Critique de la raison dialectique" and the "Les Aventures de la dialectique," by Maurice Merleau-Ponty. It states that Sartre's book supported Marxism as a philosophy and tool of knowledge. It mentions that a new liberalism was introduced by Merleau-Ponty's work which rejected the principles of Marxism, Communism, and Sartre.

Teaching working-class adults is becoming increasingly important to the future of the urban university. For many educators this raises an imposing new problem: how to teach students who are academically ill-prepared for college. Far from being a special academic "problem," we have found working-class adults capable of as serious searching for truth and profound insight as any group we have encountered, either as students ourselves or as teachers. By teaching to their strengths, and not struggling against their weaknesses, we have met with impressively high levels of preparation, attendance, and participation. Their performance has been all the more remarkable given that they are adults with family, job, and often union responsibilities. Some see the very existence of "higher education" threatened by the influx of adults to whom college level education has previously been inaccessible. Such educators are even more disturbed by the universities' need for these new students in a time of financial difficulty. As the postwar baby boom wanes and traditional students no longer regard college as an automatic step, these educators view the university's dilemma as: either suffer severe cutbacks or broaden the student base, severely watering down the level of education. We, on the contrary, believe that these new students, going to college for understanding — not job skills — can have a healthy influence on college education. In this paper we intend to report on one such class of students with whom we worked during the academic year 1975-76. We will first describe our experience with the class, then analyze the elements which we believe explain the exciting process which went on there. We will then explore the basic pedagogical issues at stake in teaching this kind of student. [ABSTRACT FROM AUTHOR]

The effects of amrinone on conduction in the intact canine heart were studied. Intracardiac His-electrode catheter recordings were used to measure the functional refractory period (FRP) of the AV node and conduction time through the AV node (A2H2 interval) and in the His-Purkinje system (H2V2 interval). Amrinone (2.5 to 10 mg/kg) shortened the FRP and A2H2 in a dose-dependent manner but had no significant effect on H2V2. In hearts where AV conduction was depressed by treatment with verapamil, propranolol, or ouabain, amrinone partially reversed this depression. Amrinone also shortened the recovery time of spontaneous sinoatrial (SA) node activity following a train of rapid atrial stimulation. This effect was also observed after depression of SA nodal recovery with verapamil, propranolol, or ouabain. These results indicate that amrinone enhances AV conduction and SA nodal activity in the normal heart and may favorably influence depressed AV conduction and SA nodal activity induced by a variety of cardioactive agents. [ABSTRACT FROM AUTHOR]

Milvexian, an oral activated Factor XI (FXIa) inhibitor, is in clinical studies where it may be combined with antiplatelet agents, including aspirin and/or clopidogrel, to prevent thromboembolic diseases. This phase I trial assessed safety, pharmacokinetics, and pharmacodynamics of milvexian coadministration with aspirin and/or clopidogrel in healthy participants through 3 drug-drug interaction studies using a 3-period, 3-treatment, crossover design. A total of 113 participants were randomized to receive milvexian (200 mg; twice daily for 5 days) or matched placebo coadministered with once-daily aspirin (325 mg for 5 days) and/or clopidogrel (Day 1: 300 mg; Days 2–5: 75 mg). Milvexian was safe and well tolerated, with and without aspirin and/or clopidogrel. Eight mild bleeding adverse events (AEs) were reported in 5 of 113 participants across various treatment arms. Peak and total exposures of milvexian were similar with or without clopidogrel and/or aspirin. Exposure-dependent prolongation of activated partial thromboplastin time and reduction of FXI clotting activity by milvexian were similar with coadministration of aspirin and/or clopidogrel. Milvexian, with or without coadministration of aspirin and/or clopidogrel, did not affect bleeding time or platelet aggregation. Administration of milvexian alone or with aspirin and/or clopidogrel was safe and well tolerated without increased incidence of AEs, including bleeding. Pharmacokinetic and pharmacodynamic effects of milvexian, including bleeding time, were similar with or without aspirin and/or clopidogrel. ClinicalTrials.gov Identifier: NCT03698513. [ABSTRACT FROM AUTHOR]