John H. Ip

Syndromes of accelerated atherosclerosis: Role of vascular injury and smooth muscle cell proliferation

Vascular injury represents a critical initiating event in the pathogenesis of various vascular diseases, including atherosclerosis. This review discusses 1) the current understanding and a new pathologic classification of vascular injury; 2) the resultant cellular pathophysiologic responses, specifically, lipid accumulation, platelet aggregation, thrombus formation and smooth muscle cell proliferation; 3) the role of vascular injury in the pathogenesis of spontaneous and accelerated atherosclerosis; and 4) emerging therapeutic approaches in preventing these vascular diseases. The process of type I vascular injury (nondenuding functional injury) followed by lipid accumulation, monocyte and platelet adhesion, smooth muscle cell proliferation and resultant plaque formation represents the prevalent view of the early stages of spontaneous atherogenesis. The syndromes of accelerated atherosclerosis (namely, heart transplant atherosclerosis, coronary vein graft disease and restenosis after percutaneous transluminal coronary angioplasty) appear to share etiologic mechanisms with spontaneous atherosclerosis by means of the response to injury hypothesis. However, type II and type III vascular injury (denuding endothelial and intimal injury with or without medial damage) followed by thrombus and its organization by smooth muscle cell proliferation and subsequent fibrosis appear to be responsible for the vascular process. This accelerated and premature occlusive process accounts for significant morbidity and mortality in patients with these conditions. Better understanding of the nature of vascular injury and its pathophysiologic responses in these clinical situations may aid in developing therapeutic strategies for preventing these vascular diseases.

The role of platelets, thrombin and hyperplasia in restenosis after coronary angioplasty

Coronary angioplasty has become a successful and widely used treatment for patients with coronary artery disease since its first clinical application in 1977. The primary success rate has improved despite the increase in procedure and case complexity. However, acute reocclusion and late restenosis, which constitute the most important problems after successful angioplasty, continue to occur in about 5% and 35% of patients within 3 to 6 months, respectively. Angioscopic and pathologic observations have suggested that a multifactorial pathophysiologic process accounts for acute reocclusion, involving marked thrombosis, intimal dissection, medial and subintimal hemorrhage, vascular recoil and vasocontriction. In contrast, chronic restenosis involves the development of fibrocellular intimal hyperplasia within a milieu created by vascular injury, platelet activation, thrombin generation and the release of mitogens. Although current pharmacologic approaches, which involve antithrombotic and anticoagulant therapy, have been largely ineffective in eliminating acute reocclusion and chronic restenosis, recent advances in the research in thrombosis, platelet receptors and smooth muscle growth regulation have allowed new therapeutic options to be tested in the experimental setting, with subsequent potential clinical applications in patients.

The Porcine Model for the Understanding of Thrombogenesis and Atherogenesis

The hypothesis originated by Carl Rokitansky a century ago that thrombosis contributes substantially to atherosclerosis has been rekindled by accumulating experimental and clinical evidence. On the basis of our experience with the experimental porcine model, several important biologic determinants of thrombosis have been identified. The degree of vascular injury seems to be the primary determinant of the thrombotic response. In addition, hemodynamic shear stress and the presence of the von Willebrand factor have important roles in the process of thrombosis. Although there is little evidence that thrombosis is a factor in the initiation of spontaneous, or naturally occurring, atherosclerosis, substantial evidence suggests that thrombosis has an essential role in the progression of spontaneous atherosclerosis and also in the early pathogenic process of the syndromes of accelerated atherosclerosis-namely, heart transplant atherosclerosis, vein graft disease, and coronary restenosis after angioplasty. Advances in the understanding of vascular injury and of the interactions of blood cells with the vascular wall have allowed development of new experimental antithrombotic strategies and subsequent clinical applications in the prevention of these vascular diseases.

Determinants of Pace‐Terminable Ventricular Tachycardia: Implications for Implantable Antitachycardia Devices

The next generation of implantable antitachycardia devices incorporate anti‐tachycardia pacing for the treatment of ventricular tachycardia. To evaluate the potential determinants of pace terminability, we analyzed 62 episodes of induced monomorphic ventricular tachycardia. We found that the tachycardia cycle length and cycle length variability are the major determinants of pace terminability. These findings should be considered in the designing of ventricular tachycardia detection and termination algorithms.

Antithrombotic Therapy in Cardiovascular Diseases

Thrombosis within the circulatory system has been recognized as the principal mechanism responsible for cardiovascular morbidity and mortality. The pathogenic processes leading to thrombosis in various disease states and in various sites, such as the coronary arteries, cardiac chambers, and prosthetic heart valves, appear to be different. Thrombosis in the coronary arteries depends on the activation of both platelets and clotting system. On the other hand, thrombus formation in dilated cardiac chambers depends mainly on the clotting system, and platelets may play a minor role; while prosthetic valve thrombosis appears to depend on the activation primarily of the coagulation system and secondarily of the platelets. Thus, understanding of these pathologic mechanisms are essential in the formulation of therapeutic and preventive strategies in these disease entities. This review will discuss: (1) the pathogenesis of thrombosis and its antithrombotic therapeutic implications in the coronary arteries, the cardiac chambers, and the prosthetic heart valves; and (2) the emerging antithrombotic agents.

Surveillance of AF recurrence post-surgical AF ablation using implantable cardiac monitor

BackgroundAlthough pulmonary vein isolation is an effective treatment for recurrent atrial fibrillation (AF), there is no consensus on the definition of success or follow-up strategies. Existing data are limited to intermittent Holter or transtelephonic monitoring with reliance on patient symptoms.ObjectiveWe sought to determine the outcomes of surgical ablation and post-ablation AF surveillance with a leadless implantable cardiac monitor (ICM).MethodsForty-five patients with drug-refractory paroxysmal or persistent AF underwent video-assisted epicardial ablation using a bipolar radiofrequency clamp. An ICM was implanted subcutaneously post-ablation to assess AF recurrence. AF recurrence was defined as ≥1 AF episode with a duration of ≥30xa0s. The device-stored data was downloaded weekly over the internet, and all transmitted events were reviewed.ResultsA total of 1,220 AF automatic and patient-activated AF episodes were analyzed over a follow-up of 12u2009±u20093xa0months. Of these episodes, 46% were asymptomatic. Furthermore, only 66% of the patient-activated episodes were AF. AF recurrence was highest in first 4xa0weeks and substantially decreased 6xa0months post-ablation. The overall freedom from AF recurrence at the end of follow-up was 60%. When 48-h Holter recordings were compared with the device-stored episodes, the sensitivity of the device to detect AF was 98%, and the specificity was 71%.ConclusionsThe ICM provides an objective measure of AF ablation success and may be useful in making clinical decisions. This device may be used in future ablation studies to develop a more rigorous definition of procedural success.

Exploration of the atherosclerotic plaque

During the past 3 decades we have achieved a better understanding of the atherosclerotic process. It has been described as a series of changes in the intima of arteries consisting of the focal accumulation of lipids, complex carbohydrates, blood and blood products, fibrous tissues, and calcium that are also associated with changes in the media. The process begins with a vascular injury that is complicated by the deposition of cholesterol esters and cholesterol. It is followed by the accumulation of lipid ladened monocytes as well as the initiation of immune mechanisms. The proliferation of smooth muscle cells into the lesion assures its permanence by the synthesis of fibrous tissue. Platelet aggregation, thrombosis and hemorrhage are all key components of plaque progression, that ultimately are associated with vascular occlusion and focal vascular spasm. Calcium plays an important role in the development of hard, ulcerated lesions. Atherosclerotic risk factors are believed to accelerate the progression of atherosclerotic plaques and the control of these risk factors may retard their proliferation and progression.

Risk stratification post myocardial infarction identification of patients at high risk of sudden cardiac death

Sudden cardiac death is a major unresolved problem in the management and prevention of coronary artery disease; it is estimated to account for 350000 cardiac deaths annually in the United States1. This statistic warrants the growing interest in investigating the possible mechanisms of sudden death and to identify the potential high risk patients. Emerging pathological and clinical data has allowed us to formulate an evolving concept regarding sudden death. We have previously proposed a new classification of sudden cardiac death of four types based on the possible underlying pathophysiological process2. Type 1 sudden cardiac death relates to the syndrome of instantaneous sudden death of individuals who did not have previously known coronary artery disease. Type II sudden death relates to sudden death occurring with the acute phase of (< 2 weeks) an acute coronary syndrome. Type III sudden death relates to events occurring within the 3 to 5 year period after myocardial infarction. Type IV relates to sudden death occurring in patients with chronic coronary artery disease and remote myocardial infarction. Based on pathological and clinical data, type I sudden death appears to occur in the setting of acute coronary occlusion, usually throm-botic, leading to electrical instability and depending on the availability of microvascular collateral, subsequent development of fatal arrhythmia can occur.

Thrombosis, antithrombotic therapy and sudden death

Emerging pathological and clinical data has allowed us to formulate an evolving concept regarding thrombosis and sudden death. Several fundamental relevant issues need to be addressed before we go on. First, cardiac death is always sudden since it is generally the result of an abrupt electrical phenomenon. The question is when it occurs in term of timing. Four different stages of sudden death can be identified. Second, emphasis on the pathogenic mechanism of sudden death has always been placed on the primary electrical component of the heart related to ventricular function (substrate), accumulating evidence suggests that acute thrombosis and ischemia (isichemia) may also play an important role in sudden death; depending on the stages of sudden death, one or both of these pathogenic mechanisms predominate. Third, in most antithrombotic trials, sudden cardiac death is not properly defined in terms of timing nor in terms of mechanisms. Nevertheless, there is enough information to provide us with the relevant hypothesis. With this background, we will discuss the four different stages of sudden death, the pathogenic mechanisms, and the role of antithrombotic therapy in each stage of sudden death (Table 1).

The learning curve associated with the implantation of the Nanostim leadless pacemaker

PurposeUse of novel medical technologies, such as leadless pacemaker (LP) therapy, may be subjected to a learning curve effect. The objective of the current study was to assess the impact of operators’ experience on the occurrence of serious adverse device effects (SADE) and procedural efficiency.MethodsPatients implanted with a Nanostim LP (Abbott, USA) within two prospective studies (i.e., LEADLESS ll IDE and Leadless Observational Study) were assessed. Patients were categorized into quartiles based on operator experience. Learning curve analysis included the comparison of SADE rates at 30xa0days post-implant per quartile and between patients in quartile 4 (>u200910 implants) and patients in quartiles 1 through 3 (1–10 implants). Procedural efficiency was assessed based on procedure duration and repositioning attempts.ResultsNanostim LP implant was performed in 1439 patients by 171 implanters at 60 centers in 10 countries. A total of 91 (6.4%) patients experienced a SADE in the first 30xa0days. SADE rates dropped from 7.4 to 4.5% (pxa0=u20090.038) after more than 10 implants per operator. Total procedure duration decreased from 30.9u2009±xa019.1xa0min in quartile 1 to 21.6u2009±xa013.2xa0min (pxa0<u20090.001) in quartile 4. The need for multiple repositionings during the LP procedure reduced in quartile 4 (14.8%), compared to quartiles 1 (26.8%; pxa0<u20090.001), 2 (26.6%; pxa0<u20090.001), and 3 (20.4%; pxa0=u20090.03).ConclusionsLearning curves exist for Nanostim LP implantation. Procedure efficiency improved with increased operator experience, according to a decrease in the incidence of SADE, procedure duration, and repositioning attempts.