Advances in Cardiology最新文献

Because platelet activation plays an important pathophysiological role in acute coronary syndromes, antiplatelet agents are a mainstay of cardiovascular therapy, both in high-risk primary prevention and in secondary prevention. This is usually done with aspirin in all such cases, and adding a P2Y(12) inhibitor in secondary prevention usually for 1 year after an acute coronary syndrome, especially after stent implantation. P2Y(12) inhibitors include ticlopidine (now rarely used), clopidogrel, prasugrel, and ticagrelor. In the setting of high-risk acute coronary syndromes treated with percutaneous coronary interventions, the addition of a glycoprotein IIb/IIIa antagonist, especially abciximab, is contemplated. Conversely, the role of antiplatelet therapy in preventing stroke after atrial fibrillation has been recently downgraded in most risk classes, in favor of anticoagulants. This chapter provides a general overview of the use of antiplatelet agents in heart disease.

Ticagrelor is a direct-acting, oral, reversibly binding P2Y(12) receptor antagonist. As a cyclopentyltriazolopyrimidine, ticagrelor represents a new chemical class of agents that do not require metabolic activation and have consistent ability to inhibit platelet aggregation. The phase III PLATO study evaluated ticagrelor compared with clopidogrel in 18,624 patients with acute coronary syndromes, and demonstrated a significant reduction in the risk of death from vascular causes/myocardial infarction (MI)/stroke with ticagrelor (9.8 vs. 11.7% with clopidogrel; HR: 0.84; 95% CI: 0.77-0.92; p < 0.001) without a significant increase in PLATO-defined major bleeding (11.6 vs. 11.2%, respectively; p = 0.43). MI and death from vascular causes were separately significantly reduced, and death from any cause and stent thrombosis reductions achieved nominal statistical significance. Ticagrelor showed benefit over clopidogrel in almost all patient subgroups, including patients who had received clopidogrel at randomization, patients with both planned invasive or noninvasive treatment; patients with ST elevation myocardial infarction (STEMI) referred for primary percutaneous coronary intervention, patients with non-STEMI, and patients who underwent bypass surgery. Hence, the PLATO population reflected specifically those patients who would ordinarily receive thienopyridine-based antiplatelet therapy in a clinical setting.

Coronary stents are used during the majority of percutaneous coronary interventions. When compared to medical therapy, they have been shown to decrease mortality for patients with acute coronary syndromes, and to improve symptom control in patients with stable angina. Their use, however, may be complicated by stent thrombosis (ST), a potentially fatal event. Early ST, which occurs during the first month following device implantation, is usually linked to procedural factors, with similar frequencies for bare metal stents and drug-eluting stents (DES). Late and very late (between 1 month and 1 year, respectively, and >1 year after the procedure) ST, which appear to be more frequent with DES, are due to factors such as incomplete stent apposition, delayed or dysfunctional endothelialization, and chronic inflammation. Furthermore, discontinuation of antiplatelet therapy (which includes the association of aspirin and thienopyridines) or resistance to these molecules may also lead to ST. New stent designs as well as the use of more potent antiplatelet therapies should contribute to reducing the incidence of ST in the future.

Vascular endothelial dysfunction refers to a loss of normal homeostatic functions in the blood vessels. It is characterized by reduced vasodilation and enhanced vasoconstriction functions and chronic prothrombotic and inflammatory activity. There is convincing evidence for endothelial dysfunction in obstructive sleep apnea (OSA): OSA is associated with alterations in vascular structures and their elastic properties, increased circulating cell-derived microparticles, reduced endothelial repair capacity, and vascular reactivity. These alterations may be related to the reduced availability of nitric oxide, which has major vasoprotective effects including vasodilation, inhibition of platelet adhesion and aggregation, inhibition of leukocyte-endothelial adhesion and inhibition of smooth muscle cell proliferation. It is unknown whether endothelial dysfunction in OSA is due to alterations in vasoconstriction mechanisms related to angiotensin II or endothelin 1. In OSA, endothelial dysfunction may be related to chronic intermittent hypoxia and to sleep loss and fragmentation. These conditions may increase the levels of various markers of inflammation and oxidative stress, as well as those of increased procoagulant and thrombotic activity. In addition, they may produce an imbalance of vasomotor function. Endothelial dysfunction contributes to the development of atherosclerosis and cardiovascular disorders associated with OSA. However, other diseases that are also associated with endothelial dysfunction are OSA comorbidities, e.g. obesity, insulin resistance, smoking habits and cardiovascular diseases such as hypertension and coronary artery disease. This makes it difficult to demonstrate a causal link between OSA and endothelial dysfunction; nevertheless, evidence for such a link has been produced by therapeutic studies. The administration of continuous positive airway pressure may reverse changes associated with endothelial dysfunction and, therefore, may decrease the risk of cardiovascular disease in OSA patients.

Obstructive sleep apnea (OSA) is characterized by repetitive episodes of complete and partial obstructions of the upper airway during sleep. The diagnosis of OSA requires the objective demonstration of abnormal breathing during sleep by measuring the respiratory disturbance index (RDI, events per hour of sleep), i.e. the frequency of apnea (complete upper airway obstruction), hypopnea (partial upper airway obstruction) and arousals from sleep related to respiratory efforts. OSA is defined by combining symptoms and an RDI ≥5 or by an RDI ≥15 without symptoms. The apnea-hypopnea index (AHI), the frequency of apnea and hypopnea events per hour of sleep, is widely used to define OSA (many clinical and epidemiological studies use this metric). In the general adult population, the prevalence of OSA defined by ≥5 apnea and hypopnea events per hour of sleep associated with excessive sleepiness is approximately 3-7% in men and 2-5% in women. The prevalence of OSA is much higher, e.g. ≥50%, in patients with cardiac or metabolic disorders than in the general population. Risk factors for OSA include obesity (the strongest risk factor), upper airway abnormalities, male gender, menopause and age (the prevalence of OSA associated with a higher risk of morbidity and mortality increases with age and peaks at approximately 55 years of age). OSA is associated with symptoms during sleep (snoring, choking and nocturia) and wakefulness (excessive sleepiness, fatigue and lack of energy) and with sequelae such as psychological changes, alterations in the quality of life, and social, familial and professional performance including vehicle and industrial accidents. The identification of OSA may be a difficult task for the clinician, even in populations in which OSA is highly prevalent such as patients with cardiovascular disorders because they may not present the cardinal signs of the disease, e.g. excessive sleepiness and obesity. Guidelines have been developed to tailor OSA therapy to patients according to the results of their disease evaluation and their preferences.

Obstructive sleep apnea (OSA) is currently considered to be an inflammatory disorder. Evidence suggests that the chronic intermittent hypoxia and, possibly, sleep loss and fragmentation associated with OSA increase the levels of various markers of inflammation, oxidative stress, and procoagulant and thrombotic activity. These alterations may contribute to the development of endothelial and metabolic dysfunction, atherosclerosis and cardiovascular disorders associated with OSA. However, these alterations are also associated with OSA comorbidities, making it difficult to discern which effects are attributable to OSA and/or these other conditions. Well-designed longitudinal and interventional studies that take confounding variables into account are needed to demonstrate a causal link between OSA and inflammation, to assess specific mechanisms that could explain these alterations and to address whether they may be improved by continuous positive airway pressure therapy.

Obstructive sleep apnea (OSA) is characterized by repetitive episodes of complete or partial obstruction of the upper airway during sleep that lead to an increase in airway resistance and respiratory effort. This may produce oxygen desaturation, hypercapnia and central nervous system arousal that restore airflow. OSA is associated with hemodynamic changes that are related to alterations in the activity of the autonomic nervous system. During the course of an apnea, the heart rate may slow down, increase or remain stable. The blood pressure decreases at the start of the apnea and increases at its terminal portion. When ventilation resumes, heart rate, blood pressure and ventilation reach a peak accompanied by an abrupt reduction in left ventricular stroke volume. During the early phase of apnea, sympathetic nerve activity (SNA) is suppressed; it then increases constantly and reaches a peak at the end of apnea and on arousal. As soon as ventilation resumes, there is an abrupt inhibition of SNA in the peripheral blood vessels. The resumption of ventilation occurs in the context of peripheral vasoconstriction and increased peripheral resistance. This situation persists for several seconds after the SNA has ceased, due to the kinetics of norepinephrine uptake, release and washout at the neurovascular junction. Hypoxemia, hypercapnia, lung inflation and blood pressure are important factors that may modulate these autonomic changes. The alterations in the autonomic nervous system are carried over into wakefulness and may contribute to the development of the cardiovascular disorders associated with OSA, including sympathovagal imbalance accompanied with changes in the baroreflex and chemoreflex. The hemodynamic and autonomic dysfunction associated with OSA is improved following treatment with continuous positive airway pressure.

Epidemiological, longitudinal and therapeutic studies have produced convincing evidence that obstructive sleep apnea (OSA) is associated with an increased risk of cardiovascular morbidity and mortality. The strongest evidence supports an independent causal link between OSA and arterial hypertension. OSA may be independently associated with an increased risk for ischemic heart disease, stroke, arrhythmias and mortality. It remains to be determined whether OSA is an independent cause of congestive heart failure and pulmonary hypertension. Confounders and methodological biases are the main reasons for the lack of definitive conclusions in causality studies. Longitudinal studies, adequately powered randomized controlled studies and therapeutic studies involving well-defined participants are all needed to definitively answer the questions surrounding the relationship between OSA and clinical cardiovascular outcomes, comorbidities and intermediate pathogenic mechanisms. OSA is a modifiable risk factor: continuous positive airway pressure administration, the gold standard treatment of OSA, may reduce the early signs of endothelial dysfunction and atherosclerosis, and improve cardiovascular outcomes, such as the mortality related to cardiovascular events, blood pressure, nonfatal coronary events and cardiac function in heart failure patients. However, cardiac patients may not display the typical signs and symptoms of OSA, such as an excessive body mass index and sleepiness. This fact, and the cardiovascular risk associated with OSA, underlines the need for collaborative guidelines to define a diagnostic strategy specifically oriented toward the evaluation of OSA in cardiovascular patients.