Early statin therapy in acute coronary syndromes.

Patients who survive an acute coronary syndrome are at much higher risk of a recurrent event within the following year than patients with stable coronary syndromes. Risk factor modification, including statin therapy, lowers the risk of recurrent events over many years, but also to reduces the high risk of an another event within the weeks to months following the initial acute coronary syndrome. The mechanisms that contribute to this benefit are likely related to improvements in endothelial function, a decrease in vascular inflammation, and reduced prothrombotic factors. The effects of statins may be mediated by cholesterol reduction, cholesterol-independent effects (particularly by decreasing isoprenoids), and mechanisms that are independent of inhibiting HMG CoA reductase. Observational studies show an early reduction in mortality with statin therapy started before discharge from hospital after an acute coronary syndrome. Several randomized controlled trials also support a rapid reduction in the risk of recurrent events after starting statins during the hospital admission for an acute coronary syndrome. Early statin therapy is also related to improved compliance and use of statins several years after a coronary event. Thus early statin therapy may improve both early and long-term secondary prevention efforts.

Endothelium-derived nitric oxide regulates arterial elasticity in human arteries in vivo.

Arterial elasticity is determined by structural characteristics of the artery wall and by vascular smooth muscle tone. The identity of endogenous vasoactive substances that regulate elasticity has not been defined in humans. We hypothesized that NO, a vasodilator released constitutively by the endothelium, augments arterial elasticity. Seven healthy young men were studied. A 20-MHz intravascular ultrasound catheter was introduced through an arterial sheath to measure brachial artery cross-sectional area, wall thickness, and intra-arterial pressure. After control was established, indices of elasticity (pressure-area relationship, instantaneous compliance, and stress-strain, pressure-incremental elastic modulus (E(inc)), and pressure-pulse wave velocity relationships) were examined over 0 to 100 mm Hg transmural pressure obtained by inflation of an external cuff. Thereafter, the basal production of endothelium-derived NO was inhibited by N(G)-monomethyl-L-arginine (L-NMMA) (4 and 8 mg/min). Finally, nitroglycerin (2.5 and 12.5 microgram/min), an exogenous donor of NO, was given to relax the vascular smooth muscle. Elasticity was measured under all of these conditions. L-NMMA (8 mg/min) decreased brachial artery area (P=0.016) and compliance (P<0.0001) and increased E(inc) (P<0.01) and pulse wave velocity (P<0.0001). Nitroglycerin (12.5 microgram/min) increased brachial artery area (P<0.001) and compliance (P<0.001) and decreased pulse wave velocity (P=0.02). NO, an endothelium-derived vasodilator, augments arterial elasticity in the human brachial artery. Loss of constitutively released NO associated with cardiovascular risk factors may adversely affect arterial elasticity in humans.

Relationship of clinical presentation and calcification of culprit coronary artery stenoses.

Coronary artery calcification is increased in the presence of atherosclerosis. However, there is great variability in the calcification of individual coronary stenoses, and the clinical significance of this finding remains unknown. We tested the hypothesis that culprit lesions associated with myocardial infarction or unstable angina are less calcified than are stenoses associated with stable angina. The study consisted of 78 patients who underwent intravascular ultrasound imaging of culprit stenoses after the placement of a stent. Seventeen patients presented with stable angina; 43, with unstable angina; and 18, with myocardial infarction. The extent of coronary calcification was measured by the angle of its arc and was quantified with a computer-based protractor. The arc of calcium was measured in the stented area at the point of maximal calcification and also as an average of the calcification found at proximal, middle, and distal stent segments. The maximal arc of calcium decreased progressively from patients with stable angina (91+/-10 degrees ) to those with unstable angina (59+/-8 degrees ) and to those with myocardial infarction (49+/-11 degrees, P=0.014). Similarly, the average arc of calcium was greatest (32+/-7 degrees ) in patients with stable angina, less (15+/-4 degrees ) in patients with unstable angina, and least (10+/-5 degrees ) in patients with acute myocardial infarction (P=0.014). These associations remained significant after adjustment for other factors that potentially affect arterial calcification. Acute coronary syndromes are associated with a relative lack of calcium in the culprit stenoses compared with stenoses of patients with stable angina. These findings have implications for the understanding of the biology of acute coronary syndromes as well as for the identification of coronary stenoses by methods that rely solely on the presence of calcium.

Role of endothelin-1 in the active constriction of human atherosclerotic coronary arteries.

BACKGROUND: Atherosclerotic coronary arteries are prone to constriction but the underlying causes are incompletely understood. We tested the hypothesis that endothelin-1 (ET-1), a potent vasoconstrictor, contributes to the heightened tone of atherosclerotic human coronary arteries. METHODS AND RESULTS: In 8 patients with coronary artery disease (CAD) and 8 patients with angiographically smooth coronary arteries (normal), we infused BQ-123, an antagonist of the ET(A) receptor, into a major coronary artery (infused artery) at 40 nmol/min for 60 minutes. The infused artery in the CAD patients contained a >50% stenosis. Using quantitative angiography, we compared the dilation of the infused artery with another, noninfused coronary artery. To estimate the magnitude of the contribution of ET-1 to coronary tone, we compared the dilation to BQ-123 with that elicited by intracoronary nitroglycerin (200 microgram). BQ-123 induced significant dilation in the normal arteries (7.3% at 60 minutes, P<0.001 versus noninfused arteries) and a greater dilation in the CAD arteries (16.3% at 60 minutes, P<0.001 versus infused normal arteries). The dilation at stenoses was particularly pronounced (21.6% at 60 minutes, P<0.001 versus infused CAD arteries). Compared with the dilation from nitroglycerin, ET-1 contributed to 39% of the coronary tone in normal arteries, 74% of tone in CAD arteries, and 106% of tone at stenoses (P<0.01). CONCLUSIONS: ET-1 accounts for nearly all the resting tone in atherosclerotic coronary arteries, especially at stenoses. Inhibitors of ET-1, by relieving constriction, may significantly lessen the hemodynamic significance of coronary stenoses and thereby reduce myocardial ischemia.

Endothelial function and coronary artery disease.

The endothelium produces a number of vasodilator and vasoconstrictor substances that not only regulate vasomotor tone, but also the recruitment and activity of inflammatory cells and the propensity towards thrombosis. Endothelial vasomotor function is a convenient way to assess these other functions, and is related to the long-term risk of cardiovascular disease. Lipids (particularly low density lipoprotein cholesterol) and oxidant stress play a major role in impairing these functions, by reducing the bioavailability of nitric oxide and activating pro-inflammatory signalling pathways such as nuclear factor kappa B. Biomechanical forces on the endothelium, including low shear stress from disturbed blood flow, also activate the endothelium increasing vasomotor dysfunction and promoting inflammation by upregulating pro-atherogenic genes. In contrast, normal laminar shear stress promotes the expression of genes that may protect against atherosclerosis. The sub-cellular structure of endothelial cells includes caveolae that play an integral part in regulating the activity of endothelial nitric oxide synthase. Low density lipoprotein cholesterol and oxidant stress impair caveolae structure and function and adversely affect endothelial function. Lipid-independent pathways of endothelial cell activation are increasingly recognized, and may provide new therapeutic targets. Endothelial vasoconstrictors, such as endothelin, antagonize endothelium-derived vasodilators and contribute to endothelial dysfunction. Some but not all studies have linked certain genetic polymorphisms of the nitric oxide synthase enzyme to vascular disease and impaired endothelial function. Such genetic heterogeneity may nonetheless offer new insights into the variability of endothelial function.

Percutaneous coronary intervention and subsequent endovascular beta-radiation brachytherapy in a 14-year-old with repaired anomalous left coronary artery from pulmonary artery.

Anomalous origin of the left coronary artery from pulmonary artery (ALCAPA) is a rare congenital anomaly. Re-establishment of the dual coronary system is the standard treatment, although the long-term outcome after surgical repair is not well defined. We report a case in which coronary stenting was performed to treat left anterior descending artery lesions eight months after surgical repair of ALCAPA. The patient then developed rapid in-stent restenosis within three months, which was successfully treated by rotational atherectomy, balloon angioplasty, and catheter-based beta-radiation brachytherapy. Follow-up angiograms after three and six months showed no recurrent in-stent restenosis. This represents the first report of coronary stenting in the setting of ALCAPA, and the first report of catheter-based intracoronary radiation therapy in a pediatric patient.

Risk factors for mastitis in breastfeeding women: results of a prospective cohort study.

OBJECTIVES: To identify potential risk factors for the development of mastitis in breastfeeding women. METHODS: A prospective cohort study with questionnaire and telephone follow-up was conducted. Women were recruited after delivery at either the teaching hospital or the only private hospital with an obstetric service during May to December 1994 in Newcastle, New South Wales and were followed up at home for six months. 1,075 breastfeeding women were recruited and were sent follow-up questionnaires at three, eight and 26 weeks post-delivery. RESULTS: Mastitis occurred in 20% (95% CI 18-22%) of women during the first six months. Factors that were statistically significantly and independently related to mastitis were: past history of mastitis (adjusted Hazard Ratio=1.74, 1.07-2.81), university or college education (HR=1.93, 1.18-3.16), blocked duct (HR=2.43, 1.68-3.49), cracked nipples (HR=1.44, 1.00-2.07), use of creams on nipples (HR=1.83, 1.22-2.73), particularly papaya cream (Relative Risk = 1.83, 1.36-2.47), and always starting with the alternate breast on consecutive feeds (HR=2.28, 1.50-3.44). CONCLUSIONS: Women with a past history of mastitis had an increased risk of developing mastitis. Blocked ducts and cracked nipples serve as warning signs for mastitis. Use of some creams may increase the risk of mastitis and their value should be tested in clinical trials. IMPLICATIONS: We have identified several pre-natal and post-natal markers for increased risk of mastitis that may assist in its early identification and treatment. The use of creams on nipples may introduce pathogens that cause mastitis and should be avoided.

Usefulness of intravascular ultrasound in preventing stenting of hazy areas adjacent to coronary stents and its support of support spot-stenting.

The uncertain significance of hazy areas at the margins of coronary stents may lead to further, at times unnecessary, stenting. However, the risk of restenosis increases substantially when additional stents are deployed. We used intravascular ultrasound (IVUS) to identify the causes of hazy segments adjacent to stents. We identified 13 cases with hazy regions adjacent to coronary stents and 20 controls without hazy regions matched by age, gender, and vessel stented. Hazy regions were defined from the angiogram as reduced contrast density without a clearly defined intimal tear, dissection, thrombus, or stenosis (> 50%). IVUS images were obtained from the reference, stent, and hazy and control regions adjacent to the stent. Computerized planimetery was used to measure the vessel, lumen, and plaque cross-sectional areas (CSAs), the maximum arc of calcium, and the eccentricity ratio (minimum:maximum lumen diameter). There were no significant differences between hazy and control segments in the vessel, lumen, and plaque CSAs. All lumen CSAs were >4.0 mm2. Compared with control regions, the hazy regions had calcified plaque more often (69% vs 25%; odds ratio [OR] 6.75, 95% confidence intervals [CI] 1.82 to 25.0]) and more frequent intimal tears (23% vs 0%, OR 6.67, 95% CI 1.98 to 35.0). Haziness was particularly associated with calcified plaque and eccentric lumen (p = 0.037). Thus, haziness at the margins of coronary stents is often caused by calcified plaque. IVUS can differentiate calcified plaques from intimal tears and thereby obviate unnecessary stenting.

What has intravascular ultrasound taught us about plaque biology?

Intravascular ultrasound (IVUS) has a defined role in the cardiac catheterization laboratory to assess lesion severity and the procedural success of vascular interventions. However, IVUS has also contributed to our understanding of the biology of atherosclerosis and restenosis. In acute coronary syndromes, IVUS has revealed varying degrees of stenosis, thrombosis, and plaque derangement typical of the plaque disruption seen in many pathologic studies of patients who have died of this condition. IVUS has demonstrated that the culprit lesions of patients surviving acute coronary syndromes also tend to be softer, with less calcium, and tend to have more plaque with positive arterial remodeling (compensatory enlargement) than lesions causing stable coronary syndromes. Arterial remodeling is also an important component of restenosis after coronary interventions. IVUS has suggested that interventions that reduce restenosis tend to have a greater impact on preventing negative remodeling (constriction) rather than reducing neointimal proliferation. Oxidant stress may be an important contributor to negative remodeling, as IVUS has demonstrated this anatomy at sites of coronary artery spasm. Positive remodeling seen by IVUS is also associated with impaired endothelial vasomotor dysfunction, and IVUS studies have demonstrated the contribution of vasomotor tone to arterial elasticity. Future directions include integrating IVUS with other imaging modalities, such as angiography, to study the interaction of anatomic and physiologic factors in atherosclerosis progression, and using the raw ultrasound signal to distinguish plaque components and differences in wall strain that may identify vulnerable plaques.

Rheolytic thrombectomy for in-stent thrombosis: creating a diagnostic window.

Acute-stent thrombosis is a relatively uncommon complication of coronary artery stenting, however, it is a potentially catastrophic event. In this case report of stent thrombosis, rheolytic thrombectomy is used to reestablished flow within the artery and, thereby, facilitate intravascular ultrasound. This documented that inadequate stent expansion, residual disease, and tissue prolapse through the stent at an angulated segment of the artery are factors that may underlie thrombosis. This case illustrates that rheolytic thrombectomy is feasible in subacute thrombosis, and that this approach facilitates diagnostic evaluation and treatment of underlying factors involved in stent thrombosis.

Pathophysiology of atherosclerosis: development, regression, restenosis.

There is now a very large number of patients with coronary artery disease who have also undergone percutaneous interventions such as coronary angioplasty. Atherosclerosis and restenosis are two distinct pathologic processes with different underlying pathophysiologic mechanisms, different natural histories, different clinical presentations, and treatment strategies. Management strategies to target both processes are currently poorly applied in clinical practice. The development of integrated management strategies to target atherosclerosis, as well as restenosis in the postprocedural period remains a priority.

Treating ambulatory ischemia in coronary disease by manipulating the cell biology of atherosclerosis.

Obstructive coronary artery disease is the most common cause of morbidity and mortality in the developed world. Our understanding of the pathobiology of coronary atherosclerosis provides us with new opportunities to reduce myocardial ischemia by interventions that address these mechanisms directly. These interventions include lipid-lowering therapies that improve local coronary vasomotion, inflammation, and the procoagulant state. These interventions have also been shown to result in important reductions in clinical events, including angina pectoris, myocardial ischemia and infarction, and death. Ambulatory electrocardiography provides a versatile and quantifiable measure of regional myocardial ischemia. Reductions in ischemia, as quantified by this diagnostic modality, are associated with improved clinical outcomes that may reflect improvements in the cellular pathophysiology of coronary atherosclerosis. This review discusses new information regarding the interactions between low-density lipoprotein cholesterol, the cell biology of atherosclerosis, and the activity of ischemia in patients with coronary artery disease.

Lack of compensatory enlargement at sites of coronary vasospasm: identification by ultrasound and successful treatment with stenting.

The case of a young man with spontaneous vasospasm at two sites in his left anterior descending coronary artery is described. Intravascular ultrasound demonstrated mild eccentric atherosclerosis with smaller total artery cross-sectional area (defined as the external elastic membrane) compared with reference segments. Impaired compensatory enlargement (remodeling) in response to mild atherosclerosis may derive from one or more biologic mechanisms that are also responsible for vasospasm. This characteristic is easily identified by intravascular ultrasound. In this case, coronary stenting of the vasospastic sites led to excellent long-term control of symptoms more than 1 year after intervention.

Relation between endothelial dysfunction and the acute coronary syndrome: implications for therapy.

Endothelial dysfunction is present in patients with atherosclerosis, even in the early stages of disease, before plaque formation. Thus, it is a useful marker for early cardiovascular disease. In recent studies, statin therapy has been shown to improve endothelial function by increasing production of nitric oxide, a key vasodilator, from the endothelium. The improvement in endothelial function occurs by lipid lowering as well as by nonlipid mechanisms. These effects begin early in treatment, supporting prompt initiation of statin therapy. The functional benefits that result from an improvement in endothelial dysfunction include enhanced myocardial perfusion, reduced duration and burden of transient myocardial ischemia, and reduced angina pectoris. As dysfunctional endothelium encourages the recruitment of leukocytes into the arterial wall and thereby predisposes to inflammation and plaque disruption, improvement in endothelial function leads to plaque stabilization.

Lipid-lowering therapy after coronary revascularization.

Atherosclerosis is often asymptomatic, unrecognized, and undertreated. Lumen irregularities are important angiographic findings that should be addressed aggressively through risk factor modification, medical therapy, and coronary revascularization. Both angiographic and clinical benefits have been demonstrated with lipid reduction therapy in randomized clinical trials. Coronary revascularization is indicated for symptom relief and improvement in quality of life in patients with acute coronary syndromes at "intermediate" and "high" risk of subsequent death or myocardial infarction. In patients following percutaneous coronary intervention (PCI), future cardiac events may be related to lumen renarrowing or to progression of atherosclerotic disease at sites remote from the site of coronary revascularization. The time course of restenosis is relatively self-limiting, generally occurring within 6-12 months after the procedure. Clinical events occurring > 1 year after PCI generally relate to new lesions or progression of existing atherosclerotic disease. Patients with diabetes mellitus may be at higher risk for late coronary events than nondiabetic patients. In post-coronary artery bypass surgery (CABG) patients, the majority of late events relate to degeneration of saphenous vein grafts. Lipid lowering therapy after coronary revascularization has been shown to prevent clinical events related to plaque instability and inhibit progression of saphenous vein graft disease. Thus, there are 2 goals in management of patients with symptomatic coronary artery disease: (1) to relieve the flow-limiting stenosis, and (2) to prevent future clinical events with aggressive lipid lowering and modification of other risk factors. Patients, specialists, and primary care physicians each need to take accountability for this risk-factor modification.

Where do developing World clinicians obtain evidence for practice: a case study on pneumonia.

There are few data on the practice of evidence based medicine in the developing world, nor on the actual sources of evidence that clinicians use in practice. To test the hypothesis that there was variation between and within developing countries in the proposed management of a patient with hospital acquired pneumonia, and that part of the variation can be explained by the sources of evidence used. Questionnaire responses to hypothetical case history. Investigators from 6 centres within the International Clinical Epidemiology Network (INCLEN) in China, Thailand, India, Egypt, and Kenya. Doctors chosen to represent primary and secondary hospital practice in the regions of the study centres. Investigations and initial treatments which would be ordered for a hypothetical 60-year-old woman who develops pneumonia 5 days after hospital admission, whether local data on antibiotic sensitivities are available and where information would be obtained to guide management. Chest x-ray and sputum gram stain/culture were consistently the most commonly ordered investigations, there being much greater variation in the initial treatment choices with either penicillin, a third-generation cephalosporin or aminoglycoside being the most popular choice. Textbooks were the commonest form of information source, and access to a library, textbooks and journals were statistically significantly associated with appropriate choice of investigations, but not treatment. Access to local antibiotic sensitivities was associated with appropriate initial treatment choice. Improving access to information in the literature and to local data may increase the practice of evidence-based medicine in the developing world.