Disease trends over time and CD4+CCR5+ T-cells expansion predict carotid atherosclerosis development in patients with systemic lupus erythematosus.

BACKGROUND AND AIM: Patients with Systemic Lupus Erythematosus (SLE) present increased cardiovascular mortality compared to the general population. Few studies have assessed the long-term development and progression of carotid atherosclerotic plaque in SLE patients. Our aim was to investigate the association of clinical and laboratory markers of disease activity and classical cardiovascular risk factors (CVRF) with carotid atherosclerosis development in SLE patients in a prospective 5-year study. METHODS AND RESULTS: Clinical history and information on principal CVRFs were collected at baseline and after 5 years in 40 SLE patients (36 women, mean age 42 ± 9 years; 14.4 ± 7 years of mean disease duration) and 50 age-matched controls. Carotid Doppler ultrasonography was employed to quantify the atherosclerotic burden at baseline and at follow up. Clinimetrics were applied to assess SLE activity over time (SLEDAI). The association between basal circulating T cell subsets (including CD4+CCR5+; CD4+CXCR3+; CD4+HLADR+; CD4+CD45RA+RO-, CD4+CD45RO+RA- and their subsets) and atherosclerosis development was evaluated. During the 5-year follow up, 32% of SLE patients, developed carotid atherosclerosis compared to 4% of controls. Furthermore, considering SLEDAI changes over time, patients within the highest tertile were those with increased incidence of carotid atherosclerosis independently of CVRF. In addition, increased levels of CD4+CCR5+ T cells were independently associated with the development of carotid atherosclerosis in SLE patients. CONCLUSION: Serial clinical evaluations over time, rather than a single point estimation of disease activity or CVRF burden, are required to define the risk of carotid atherosclerosis development in SLE patients. Specific T cell subsets are associated with long-term atherosclerotic progression and may further be of help in predicting vascular disease progression.

The role of T and B cells in human atherosclerosis and atherothrombosis.

Far from being merely a passive cholesterol accumulation within the arterial wall, the development of atherosclerosis is currently known to imply both inflammation and immune effector mechanisms. Adaptive immunity has been implicated in the process of disease initiation and progression interwined with traditional cardiovascular risk factors. Although the body of knowledge regarding the correlation between atherosclerosis and immunity in humans is growing rapidly, a relevant proportion of it derives from studies carried out in animal models of cardiovascular disease (CVD). However, while the mouse is a well-suited model, the results obtained therein are not fully transferrable to the human setting due to intrinsic genomic and environmental differences. In the present review, we will discuss mainly human findings, obtained either by examination of post-mortem and surgical atherosclerotic material or through the analysis of the immunological profile of peripheral blood cells. In particular, we will discuss the findings supporting a pro-atherogenic role of T cell subsets, such as effector memory T cells or the potential protective function of regulatory T cells. Recent studies suggest that traditional T cell-driven B2 cell responses appear to be atherogenic, while innate B1 cells appear to exert a protective action through the secretion of naturally occurring antibodies. The insights into the immune pathogenesis of atherosclerosis can provide new targets in the quest for novel therapeutic targets to abate CVD morbidity and mortality.

From endothelial dysfunction to atherosclerosis.

It has recently emerged that endothelial dysfunction is an early step in the development of atherosclerosis and is mainly characterised by a reduction in the bioavailability of nitric oxide. All of the traditional cardiovascular (CV) risk factors (dyslipidemia, arterial hypertension, hyperglycemia and diabetes) are associated with endothelial dysfunction, and oxidised low-density lipoproteins, the renin-angiotensin axis and insulin resistance play important roles in the pathogenesis of impaired endothelial function. The increased expression of adhesion molecules and pro-inflammatory cytokines leads to abnormal endothelium-dependent vasodilation which could be investigated using vasoreactivity tests such as flow-mediated dilation in the brachial artery. Recently, new evidences showed that the immune system plays an important role in the pathogenesis of endothelial dysfunction and atherosclerosis with a particular regard towards autoimmunity. The high prevalence of the atherosclerotic process in systemic autoimmune diseases supports the hypothesis of the immune pathogenesis. Evaluating coronary microvascular dysfunction by means of transthoracic echocardiography with non-invasive coronary flow reserve assessment is particularly interesting as it could detect preclinical impairment of coronary microvascular function. The discovery that the mechanisms responsible for endothelial damage have a genetic basis could improve the approach to CV diseases. This review summarises the most important aspects of the pathogenesis and development of endothelial dysfunction, with particular attention to the role of traditional CV risk factors, the usefulness of vasoreactivity tests, and the future perspectives opened by genetic studies.

Role of quantitative myocardial perfusion PET as a clinical translation research tool.

In biology and medicine, "translational research" indicates the "translation" from the language of molecular biology in animal experiments to human physiology in order to improve our insight into the molecular mechanisms underlying the progression of cardiac diseases and to verify the mechanism of action or the potential of newly developed drugs. Positron emission tomography (PET) plays a major role in this setting due to four major characteristics: 1) extremely high sensitivity; 2) excellent temporal resolution; 3) the possibility to label molecules without altering their chemical properties and 4) the short half live of isotopes. These features make PET as an unique method able to display in the same image format different variables related to the physiology of the myocardium under different pathophysiological states, thus allowing a more precise geographical correlation of the different processes underlying disease or drug effect. This paper will review the literature available about the utilization of PET in the setting of cardiovascular pathophysiology and drug development. This task will be accomplished by describing the theory and practice of methods available to measure myocardial blood flow and to characterize myocardial metabolism in order to obtain a more precise clarification of disease phenotype. Similarly the potential of this method in defining drug effectiveness in clinical trial will be discussed, in order to offer an overview of the potential for the noninvasive measurement of physiological variables in the modern medicine.

Radionuclide PET and PET/CT in coronary artery disease.

In the present review, the basis of non invasive assessment of CAD, the most recent technical developments and results obtained by PET in cardiovascular research and clinical cardiology are described. PET has provided a wealth of new information in the field of cardiac pathophysiology and remains the gold standard for non-invasive measurements of MBF and CFR against which new techniques should be tested. The possibility to combine this relevant functional information with the anatomic details on luminal and arterial wall abnormalities, provided by multislice CT with or without the use of "hybrid" scanners, offers new opportunities for comprehensive non-invasive assessment of CAD and efficacy of new treatments.

Diagnostic and clinical perspectives of fusion imaging in cardiology: is the total greater than the sum of its parts?

Positron emission tomography, cardiovascular magnetic resonance and multislice computed tomography have contributed to changing our pathophysiological understanding of many conditions. Clinically, they have provided new tools for the identification of preclinical disease and a better understanding of how disease progresses. The application of these imaging modalities to preclinical disease and the use of these techniques in patients with overt cardiovascular disease are reviewed.

Dobutamine-induced hyperaemia inversely correlates with coronary artery stenosis severity and highlights dissociation between myocardial blood flow and oxygen consumption.

OBJECTIVES: To compare the relationship between dobutamine myocardial blood flow (MBF), rate-pressure product (RPP) and stenosis severity in patients with coronary artery disease (CAD). METHODS: 27 patients with single-vessel CAD were allocated to three groups based on stenosis severity: group 1, 50-69% (n = 9); group 2, 70-89% (n = 9); and group 3, >or= 90% (n = 9). Nine normal volunteers served as controls. Resting and dobutamine MBF were measured by positron emission tomography in the territory subtended by the stenosis (Isc) and remote myocardium (Rem). Mean left ventricular MBF was used for controls. RESULTS: In group 1, mean dobutamine MBF-Isc (2.48 (SD 0.48 ml/min/g)) and dobutamine MBF-Rem (2.70 (0.50) ml/min/g, NS) were comparable. In groups 2 and 3, dobutamine MBF-Isc (1.91 (0.44) and 1.22 (0.21) ml/min/g) was significantly lower than dobutamine MBF-Rem (2.27 (0.28) and 1.98 (0.25) ml/min/g, p < 0.02 and p < 0.005, respectively). An inverse relation between dobutamine MBF and stenosis severity existed both in Isc (r = 0.79, p < 0.001) and in Rem territories (r = 0.71, p < 0.001). For any given RPP, dobutamine MBF was greater in controls than in Rem (p < 0.05), which in turn was greater than in Isc (p < 0.05). CONCLUSION: Dobutamine MBF inversely correlated with stenosis severity and achieved significant flow heterogeneity for coronary stenoses > 70%. Dobutamine MBF and RPP were dissociated in both Isc and Rem segments in patients compared with controls.

Coronary microvascular dysfunction in male patients with Anderson-Fabry disease and the effect of treatment with alpha galactosidase A.

OBJECTIVE: To measure coronary flow reserve (CFR), an index of microvascular function, in Anderson-Fabry disease (AFD) at baseline and after enzyme replacement therapy (ERT). METHODS AND RESULTS: Mean (SD) myocardial blood flow (MBF) at rest and during hyperaemia (adenosine 140 microg/kg/min) was measured in 10 male, non-smoking patients (53.8 (10.9) years, cholesterol 5.5 (1.3) mmol/l) and in 24 age matched male, non-smoking controls (52.0 (7.6) years, cholesterol 4.5 (0.6) mmol/l) by positron emission tomography (PET). Resting and hyperaemic MBF and CFR (hyperaemic/resting MBF) were reduced in patients compared with controls (0.99 (0.17) v 1.17 (0.25) ml/g/min, p < 0.05; 1.37 (0.32) v 3.44 (0.78) ml/g/min, p < 0.0001; and 1.41 (0.39) v 3.03 (0.85), p < 0.0001, respectively). This coronary microvascular dysfunction was independent of cholesterol concentrations. PET was repeated in five patients after 10.1 (2.3) months of ERT; resting and hyperaemic MBF and CFR were unchanged after ERT (0.99 (0.16) v 0.99 (0.16) ml/g/min; 1.56 (0.29) v 1.71 (0.3) ml/g/min; and 1.6 (0.37) v 1.74 (0.28), respectively; all not significant). CONCLUSIONS: The results of the present study show that patients with AFD have very abnormal coronary microvascular function. These preliminary data suggest that ERT has no effect on coronary microvascular dysfunction. Further work is necessary to determine whether treatment at an earlier stage in the course of the disease may improve coronary microvascular function in patients with AFD.

Rigid-body transformation of list-mode projection data for respiratory motion correction in cardiac PET.

High-resolution cardiac PET imaging with emphasis on quantification would benefit from eliminating the problem of respiratory movement during data acquisition. Respiratory gating on the basis of list-mode data has been employed previously as one approach to reduce motion effects. However, it results in poor count statistics with degradation of image quality. This work reports on the implementation of a technique to correct for respiratory motion in the area of the heart at no extra cost for count statistics and with the potential to maintain ECG gating, based on rigid-body transformations on list-mode data event-by-event. A motion-corrected data set is obtained by assigning, after pre-correction for detector efficiency and photon attenuation, individual lines-of-response to new detector pairs with consideration of respiratory motion. Parameters of respiratory motion are obtained from a series of gated image sets by means of image registration. Respiration is recorded simultaneously with the list-mode data using an inductive respiration monitor with an elasticized belt at chest level. The accuracy of the technique was assessed with point-source data showing a good correlation between measured and true transformations. The technique was applied on phantom data with simulated respiratory motion, showing successful recovery of tracer distribution and contrast on the motion-corrected images, and on patient data with C15O and 18FDG. Quantitative assessment of preliminary C15O patient data showed improvement in the recovery coefficient at the centre of the left ventricle.

Coronary recanalisation, myocardial viability, and ventricular remodelling after infarction.

It is important to identify the mechanisms that determine the progression to left ventricular remodelling after an acute myocardial infarction, in order that patients can be treated before the development of overt heart failure.

The heart failure revascularisation trial (HEART): rationale, design and methodology.

BACKGROUND: Most patients with heart failure due to left ventricular systolic dysfunction (LVSD) secondary to coronary artery disease (CAD) have evidence of myocardium in jeopardy (reversible ischaemia and/or stunning hibernation). It is not known whether revascularisation in such cases is safe or beneficial. AIMS: To determine whether revascularisation will improve the survival of patients with LVSD and heart failure secondary to CAD and myocardium in jeopardy. METHODS: This is a randomised controlled trial comparing revascularisation or not, in addition to optimal medical therapy with ACE inhibitors, beta-blockers, aldosterone antagonists and an anti-thrombotic agent. Patients must have heart failure requiring treatment with diuretics, a left ventricular ejection fraction <35% and evidence of coronary disease. Myocardial viability and ischaemia are assessed by a broad range of techniques including stress echocardiography and nuclear imaging. All imaging tests are reviewed in core laboratories to ensure uniform reporting. Any conventional revascularisation technique is permitted. The primary outcome measure is all cause mortality. Symptoms, quality of life and health economic issues will also be explored. Assuming an annual mortality of 10% in the control group and allowing for substantial cross-over rates, a study of 800 patients followed for 5 years has 80% power with an alpha of 0.05 (two-sided) to show a 25% reduction in mortality with revascularisation. RESULTS: At the time of writing 180 patients have been screened for inclusion, 111 have consented to participate and 70 have been randomised. The results of viability testing are awaited in 22 patients. Twenty-six patients had been investigated for myocardial viability and/or by angiography prior to consent, as part of the routine practice in that cardiology department. Of 68 patients who have completed assessment only after consent, 47 (69%) were included. The principal reason for drop-out between consent and randomisation was lack of evidence of myocardial ischaemia or hibernation. CONCLUSION: The HEART trial will help to determine whether investigation of myocardial ischaemia and/or viability with a view to revascularisation should become part of the routine care of patients with heart failure due to LVSD and CAD.

Mismatch between insulin-mediated glucose uptake and blood flow in the heart of patients with Type II diabetes.

AIMS/HYPOTHESIS: We investigated the effect of physiological hyperinsulinaemia on global and regional myocardial blood flow and glucose uptake in five patients with Type II (non-insulin-dependent) diabetes mellitus and seven healthy control subjects. METHODS: Myocardial blood flow was assessed by positron emission tomography with oxygen-15 labelled water (H(2)(15)O) either before or after 1 h of euglycaemic hyperinsulinaemia. Myocardial glucose uptake was assessed by positron emission tomography and fluorine-18 labelled fluorodeoxyglucose ((18)FDG). RESULTS: During hyperinsulinaemia, myocardial blood flow increased from 0.91+/-0.03 to 1.00+/-0.03 ml(.)min(-1.)g(-1) in control subjects ( p<0.005) and from 0.81+/-0.02 to 0.95+/-0.04 ml(.)min(-1.)g(-1) in diabetic patients ( p<0.0005). Corresponding glucose uptakes were 0.56+/-0.01 and 0.36+/-0.02 micro mol(.)min(-1.)g(-1) ( p<0.0001), respectively. During hyperinsulinaemia, the regional distribution of myocardial blood flow and glucose uptake showed higher values in the septum and anterolateral wall (short axis) and in the mid-ventricle (long axis) in control subjects, and insulin action was circumscribed to these regions. In diabetic patients, the regional distribution of glucose uptake was similar; however, insulin-induced increase of myocardial blood flow was mainly directed to the postero-inferior areas (short axis) and to the base (long axis) of the heart, thus cancelling the predominance of the anterior wall observed before insulin administration. CONCLUSION/INTERPRETATION: These results provide evidence that insulin-mediated regulation of global myocardial blood flow is preserved in Type II diabetic patients. In contrast, the regional re-distribution of myocardial blood flow induced by insulin is directed to different target areas when compared with healthy subjects, thereby resulting in a mismatch between blood flow and glucose metabolism.