Bayesian principles or Gestalt perception for clinical judgment

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Coronary prevention in two European areas with different risk levels, Stockholm and Sicily : doctors' risk judgments and statin utilization

Introduction International guidelines on the primary prevention of cardiovascular disease recommend that preventive measures should be based on the doctors’ quantitative total risk assessment of the patient. Treatment is recommended when the patient’s risk is above a certain threshold. Risk scoring systems have been developed to assist clinicians with risk estimates. However, in clinical practice this estimation is usually made subjectively. This implies that factors unrelated to the true risk of the patients may influence the doctors’ risk estimates and decisions about treatment. Aim We aimed to study coronary preventive care in two areas with different coronary risk levels, with special reference to doctors’ attitudes in investigating risk factors, and their risk assessments and decisions about treatment. In accordance with the different levels of cardiovascular risk in the areas studied, we also aimed to test the hypothesis that the same set of risk factors may be perceived as indicating higher risk in a high-risk country, than in a low-risk country. Methods The studies were performed in two European areas, one with a high and the other with a low level of population cardiovascular risk, Stockholm county and Sicily, respectively. Questionnaires on doctors’ clinical practice (Study I) and written patient cases (Studies II-IV) were presented to random samples of doctors in Stockholm and in Sicily. The cases were constructed according to the Framingham scoring system, ranging from very high- to very low-risk cases. Differences in the use of statins and coronary mortality in the populations (Study V) were studied by collecting official data from the health care systems in both areas. Results and Discussion There were differences in the management of hyperlipidaemia (Study I). More doctors in Stockholm investigated lipids in patients with other cardiovascular risk factors. The cholesterol level at which doctors started lipid-lowering treatment was higher in Stockholm than in Sicily. In Study II, General Practitioners (GPs) were asked to evaluate nine written patient cases. Their coronary risk estimates showed large variability, especially in high-risk cases, and in general the risk was underestimated compared to the risk calculated according to the Framingham equations. Contrary to the hypothesis, GPs in Stockholm made lower estimates and less often decided to start lipid-lowering treatment than was the case in Sicily. A possible reason for this is that a high background risk level of the population tends to suppress the risk estimate of an individual with a certain set of risk factors, and vice versa if the population risk is low. Support to such line of thinking was found comparing risk estimates and decisions about treatment between doctors who usually deal with coronary preventive care: GPs, cardiologists and internists (Study III). Compared to the other specialists, cardiologists, who usually deal with high-risk patients, showed lower risk estimates when assessing the same set of patient cases. In study IV we found that the task of risk rating and the task of making decisions about treatment did not mutually influence each other. Female GPs and GPs with shorter clinical experience were more likely to make correct decisions. The differences in coronary risk ratings and decisions about treatment observed in the two areas with different population coronary risk levels may be related to the use of statins in the whole population of the respective area. Study V investigated the time trends in the relations between population coronary risk levels, expressed as coronary mortality, and use of statins, in the period 2001-2011. In both areas there was a reduction in coronary mortality and an increase in statin utilization. A larger reduction in coronary mortality was observed in Stockholm compared to Sicily, whereas the statin utilization increased more in Sicily than in Stockholm. Thus, the changes over time in statin utilization seem inversely associated with the changes in coronary mortality. However, the influence of other variables that are independent of the population coronary risk, such as cost containment policies, socioeconomic gradients in the use of statins, and drug discontinuation rate, must be taken into account. Conclusions There are several differences in primary coronary prevention between the two European areas with different population cardiovascular risk profiles. Doctors’ quantitative risk estimates and decisions about treatment are influenced by factors not directly related to the actual risk of the patients, and seem tentatively to be inversely related to the background cardiovascular risk in the population. The differences in primary coronary prevention may contribute to an increase in statin utilization that is not justified by changes in population coronary risk. The results of the thesis may help in the development of decision tools and recommendations for primary coronary prevention

Primary Cardiovascular Disease Prevention: Risk Factors Control vs. Imaging Subclinical Atherosclerosis

The burden of cardiovascular disease in developed countries has shown dramatic improvements over the last 50 years, largely due the identification and control of major risk factors including, smoking hypertension and high cholesterol. However, due to the significant increase in obesity and diabetes CVD incidence rates will not reduce as far over over the next years. Risk prediction in asymptomatic individuals remains a major challenge. Primary preventive treatment is currently based on the assessment of individual's global risk mainly through screening of conventional risk factors and their treatment with lifestyle intervention and pharmacotherapy, often based on multivariate risk equations, and yet a large proportion of CVD still occurs in individuals who are classified as carrying low- or intermediate-risk according to the risk scores. Atherosclerosis is the most common pathophysiologic process underlying CVD, often after a prolonged asymptomatic phase during which it may be possible to modify the course of the disease. Unlike conventional probabilistic risk scores, non-invasive imaging techniques such as carotid intima-media thickness (CIMT) along with plaque assessment (Figure 2), measured by B-mode ultrasound, and coronary calcium scoring (CAC) detected by CT scan have the advantage of direct visualization of the consequences of atherosclerosis on the arterial system. We consider the proposal that imaging of subclinical atherosclerosis is superior to risk equations as it directly identifies the disease and can effectively predict the risk of future CV events in low- and intermediate-risk individuals. In addition, imaging can improve the adherence to guidelines based treatment in patients and their physicians

Coronary Artery Microcalcification: Imaging and Clinical Implications

Strategies to prevent acute coronary and cerebrovascular events are based on accurate identification of patients at increased cardiovascular (CV) risk who may benefit from intensive preventive measures. The majority of acute CV events are precipitated by the rupture of the thin cap overlying the necrotic core of an atherosclerotic plaque. Hence, identification of vulnerable coronary lesions is essential for CV prevention. Atherosclerosis is a highly dynamic process involving cell migration, apoptosis, inflammation, osteogenesis, and intimal calcification, progressing from early lesions to advanced plaques. Coronary artery calcification (CAC) is a marker of coronary atherosclerosis, correlates with clinically significant coronary artery disease (CAD), predicts future CV events and improves the risk prediction of conventional risk factors. The relative importance of coronary calcification, whether it has a protective effect as a stabilizing force of high-risk atherosclerotic plaque has been debated until recently. The extent of calcium in coronary arteries has different clinical implications. Extensive plaque calcification is often a feature of advanced and stable atherosclerosis, which only rarely results in rupture. These macroscopic vascular calcifications can be detected by computed tomography (CT). The resulting CAC scoring, although a good marker of overall coronary plaque burden, is not useful to identify vulnerable lesions prone to rupture. Unlike macrocalcifications, spotty microcalcifications assessed by intravascular ultrasound or optical coherence tomography strongly correlate with plaque instability. However, they are below the resolution of CT due to limited spatial resolution. Microcalcifications develop in the earliest stages of coronary intimal calcification and directly contribute to plaque rupture producing local mechanical stress on the plaque surface. They result from a healing response to intense local macrophage inflammatory activity. Most of them show a progressive calcification transforming the early stage high-risk microcalcification into the stable end-stage macroscopic calcification. In recent years, new developments in noninvasive cardiovascular imaging technology have shifted the study of vulnerable plaques from morphology to the assessment of disease activity of the atherosclerotic lesions. Increased disease activity, detected by positron emission tomography (PET) and magnetic resonance (MR), has been shown to be associated with more microcalcification, larger necrotic core and greater rates of events. In this context, the paradox of increased coronary artery calcification observed in statin trials, despite reduced CV events, can be explained by the reduction of coronary inflammation induced by statin which results in more stable macrocalcification

Carotid arterial stiffness and intima-media thickness : A little impact of uric acid

Accurate assessment of cardiovascular (CV) risk is essential for clinical decision making. Serum uric acid  has been proposed as a novel additional CV risk

Coronary Atherosclerosis Imaging

Identifying patients at increased risk of coronary artery disease, before the atherosclerotic complications become clinically evident, is the aim of cardiovascular prevention. Imaging techniques provide direct assessment of coronary atherosclerotic burden and pathological characteristics of atherosclerotic lesions which may predict the progression of disease. Atherosclerosis imaging has been traditionally based on the evaluation of coronary luminal narrowing and stenosis. However, the degree of arterial obstruction is a poor predictor of subsequent acute events. More recent techniques focus on the high-resolution visualization of the arterial wall and the coronary plaques. Most acute coronary events are triggered by plaque rupture or erosion. Hence, atherosclerotic plaque imaging has generally focused on the detection of vulnerable plaque prone to rupture. However, atherosclerosis is a dynamic process and the plaque morphology and composition may change over time. Most vulnerable plaques undergo progressive transformation from high-risk to more stable and heavily calcified lesions, while others undergo subclinical rupture and healing. Although extensive plaque calcification is often associated with stable atherosclerosis, the extent of coronary artery calcification strongly correlates with the degree of atherosclerosis and with the rate of future cardiac events. Inflammation has a central role in atherogenesis, from plaque formation to rupture, hence in the development of acute coronary events. Morphologic plaque assessment, both invasive and non-invasive, gives limited information as to the current activity of the atherosclerotic disease. The addition of nuclear imaging, based on radioactive tracers targeted to the inflammatory components of the plaques, provides a highly sensitive assessment of coronary disease activity, thus distinguishing those patients who have stable disease from those with active plaque inflammation

The Role of Inflammation in Cardiovascular Disease

Atherosclerosis is a chronic inflammatory disease, in which the immune system has a prominent role in its development and progression. Inflammation-induced endothelial dysfunction results in an increased permeability to lipoproteins and their subendothelial accumulation, leukocyte recruitment, and platelets activation. Recruited monocytes differentiate into macrophages which develop pro- or anti-inflammatory properties according to their microenvironment. Atheroma progression or healing is determined by the balance between these functional phenotypes. Macrophages and smooth muscle cells secrete inflammatory cytokines including interleukins IL-1β, IL-12, and IL-6. Within the arterial wall, low-density lipoprotein cholesterol undergoes an oxidation. Additionally, triglyceride-rich lipoproteins and remnant lipoproteins exert pro-inflammatory effects. Macrophages catabolize the oxidized lipoproteins and coalesce into a lipid-rich necrotic core, encapsulated by a collagen fibrous cap, leading to the formation of fibro-atheroma. In the conditions of chronic inflammation, macrophages exert a catabolic effect on the fibrous cap, resulting in a thin-cap fibro-atheroma which makes the plaque vulnerable. However, their morphology may change over time, shifting from high-risk lesions to more stable calcified plaques. In addition to conventional cardiovascular risk factors, an exposure to acute and chronic psychological stress may increase the risk of cardiovascular disease through inflammation mediated by an increased sympathetic output which results in the release of inflammatory cytokines. Inflammation is also the link between ageing and cardiovascular disease through increased clones of leukocytes in peripheral blood. Anti-inflammatory interventions specifically blocking the cytokine pathways reduce the risk of myocardial infarction and stroke, although they increase the risk of infections

Coronary Microvascular Dysfunction

Many patients with chest pain undergoing coronary angiography do not show significant obstructive coronary lesions. A substantial proportion of these patients have abnormalities in the function and structure of coronary microcirculation due to endothelial and smooth muscle cell dysfunction. The coronary microcirculation has a fundamental role in the regulation of coronary blood flow in response to cardiac oxygen requirements. Impairment of this mechanism, defined as coronary microvascular dysfunction (CMD), carries an increased risk of adverse cardiovascular clinical outcomes. Coronary endothelial dysfunction accounts for approximately two-thirds of clinical conditions presenting with symptoms and signs of myocardial ischemia without obstructive coronary disease, termed "ischemia with non-obstructive coronary artery disease" (INOCA) and for a small proportion of "myocardial infarction with non-obstructive coronary artery disease" (MINOCA). More frequently, the clinical presentation of INOCA is microvascular angina due to CMD, while some patients present vasospastic angina due to epicardial spasm, and mixed epicardial and microvascular forms. CMD may be associated with focal and diffuse epicardial coronary atherosclerosis, which may reinforce each other. Both INOCA and MINOCA are more common in females. Clinical classification of CMD includes the association with conditions in which atherosclerosis has limited relevance, with non-obstructive atherosclerosis, and with obstructive atherosclerosis. Several studies already exist which support the evidence that CMD is part of systemic microvascular disease involving multiple organs, such as brain and kidney. Moreover, CMD is strongly associated with the development of heart failure with preserved ejection fraction (HFpEF), diabetes, hypertensive heart disease, and also chronic inflammatory and autoimmune diseases. Since coronary microcirculation is not visible on invasive angiography or computed tomographic coronary angiography (CTCA), the diagnosis of CMD is usually based on functional assessment of microcirculation, which can be performed by both invasive and non-invasive methods, including the assessment of delayed flow of contrast during angiography, measurement of coronary flow reserve (CFR) and index of microvascular resistance (IMR), evaluation of angina induced by intracoronary acetylcholine infusion, and assessment of myocardial perfusion by positron emission tomography (PET) and magnetic resonance (CMR)

The Impact of Mental Stress on Cardiovascular Health - Part II

Endothelial dysfunction is one of the earliest manifestations of atherosclerosis, contributing to its development and progression. Mental stress induces endothelial dysfunction through increased activity of the sympathetic nervous system, release of corticotropin-releasing hormone from the hypothalamus, inhibition of nitric oxide (NO) synthesis by cortisol, and increased levels of pro-inflammatory cytokines. Mental-stress-induced increased output of the sympathetic nervous system and concomitant withdrawal of the parasympathetic inflammatory reflex results in systemic inflammation and activation of a neural–hematopoietic–arterial axis. This includes the brainstem and subcortical regions network, bone marrow activation, release of leukocytes into the circulation and their migration to the arterial wall and atherosclerotic plaques. Low-grade, sterile inflammation is involved in all steps of atherogenesis, from coronary plaque formation to destabilisation and rupture. Increased sympathetic tone may cause arterial smooth-muscle-cell proliferation, resulting in vascular hypertrophy, thus contributing to the development of hypertension. Emotional events also cause instability of cardiac repolarisation due to brain lateralised imbalance of cardiac autonomic nervous stimulation, which may lead to asymmetric repolarisation and arrhythmia. Acute emotional stress can also provoke severe catecholamine release, leading to direct myocyte injury due to calcium overload, known as myocytolysis, coronary microvascular vasoconstriction, and an increase in left ventricular afterload. These changes can trigger a heart failure syndrome mimicking acute myocardial infarction, characterised by transient left ventricular dysfunction and apical ballooning, known as stress (Takotsubo) cardiomyopathy. Women are more prone than men to develop mental-stress-induced myocardial ischemia (MSIMI), probably reflecting gender differences in brain activation patterns during mental stress. Although guidelines on CV prevention recognise psychosocial factors as risk modifiers to improve risk prediction and decision making, the evidence that their assessment and treatment will prevent CAD needs further evaluation