Echocardiography in clinical practice: the burden of arterial hypertension. A multicenter Italian survey

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1 (1) 24, & 1 Macmillan Publishers Limited All rights reserved /1 $32. ORIGINAL ARTICLE Echocardiography in clinical practice: the burden of arterial hypertension. A multicenter Italian survey C Cuspidi 1,2, F Negri 1,2, V Giudici 2, A Capra 1, ML Muiesan 3, E Agabiti-Rosei 3, G de Simone 4, N De Luca 5, G Tocci 6 and A Morganti 7, on behalf of the Working Group on Heart and Hypertension of the Italian Society of Hypertension 1 Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Milano, Italy; 2 Istituto Auxologico Italiano, Milano, Italy; 3 Department of Medical and Surgical Sciences, University of Brescia, Brescia, Italy; 4 Department of Clinical and Experimental Medicine, Naples, Italy; 5 Dipartimento di Medicina Clinica e Scienze Cardiovascolari ed Immunologiche, Università Federico II, Napoli, Italy; 6 Division of Cardiology, II Faculty of Medicine, University of Rome La Sapienza, Sant Andrea Hospital, Rome, Italy and 7 Chair of Internal Medicine and Hypertension Center, Ospedale S. Giuseppe, Milano, Italy Little information is available about the burden of hypertension on echo-lab activity in current practice. The aim of the present nation-wide survey in outpatient echo-labs was to investigate the prevalence rates of (1) echo examinations performed for the evaluation of hypertensive cardiac damage; (2) reports providing quantitative data on left ventricular (LV) structure and geometry; (3) LV hypertrophy (LVH) in hypertensives referred to echo labs. The study was carried out in 14 outpatient echo-labs across Italy. Prescriptions written by general practitioners were used to identify the indications for the examinations. Estimates of LVH were derived from original echo reports or were calculated from LV primary measures, when available, with Devereux s formula in a post-analysis. Echo examination was performed in 2449 subjects (1245 men and 14 women); hypertension was the indication for echo in 745 (3.4) cases. In this subgroup, LV mass (LVM), LVM indexed to body surface area, LVM indexed to height 2.7 and relative wall thickness ratio were reported in 58, 59, 54 and 52, respectively. LVH was present in 53 of untreated hypertensives and, among treated patients, in 45 and 65 of those with and without blood pressure control, respectively. Our findings show that (1) hypertension accounts for approximately one-third of echo examinations performed in clinical practice; (2) a large fraction of echo reports do not provide quantitative data on LVM and LV geometry, (3) LVH is highly prevalent in hypertensives referred to echo labs for assessment of cardiac damage. (1) 24, ; doi:1.138/jhh.9.78; published online 12 November 9 Keywords: hypertension; echocardiography; left ventricular hypertrophy Introduction Left ventricular hypertrophy (LVH) is a cardinal feature of hypertensive heart disease, reflecting the effects on the heart of chronic exposure to blood pressure (BP) overload as well as the influence of growth substances operating in individuals with a BP elevation. 1,2 A large body of evidence indicates that echocardiographic (echo) LVH is an independent predictor of cardiovascular (CV) mortality and morbidity in both normotensive and hypertensive subjects of different ethnicities. 3 5 Furthermore, Correspondence: Professor C Cuspidi, Clinical Research Unit, Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Istituto Auxologico Italiano, Viale della Resistenza 23, Meda, Milano 36, Italy. cesare.cuspidi@unmib.it Received 2 May 9; revised 4 August 9; accepted 13 September 9; published online 12 November 9 reduction of left ventricular mass (LVM) by antihypertensive treatment has been shown to determine a significant decrease in CV risk, independently of accompanying risk factors and BP-lowering effects. 6 9 Finally, echo provides data on other morphological and functional characteristics (LV concentric or eccentric geometry, global LV systolic and diastolic function, regional wall mechanics, left atrial size and so on) that also correlate with incident CV events Despite the importance of the information provided by echo, current guidelines do not include this examination among those routinely recommended for hypertensive patients, largely because of concern about the burden for any health-care system of its systematic implementation. Recently, however, a step forward has been made by the 7 European Society of Hypertension/European Society of Cardiology guidelines, 13 which have

2 396 included echo among the recommended examinations to be performed before initiation of and during treatment, particularly in elderly subjects in whom LVH is common, 14 although not specifically indicated in the primary work-up. Several studies have been devoted to the role played by echo in the CV risk stratification of hypertensive patients managed in the clinical practice as well as the cost-effectiveness of this procedure in detecting LVH and guiding proper antihypertensive treatment. 18,19 Although there is an increasing pressure to include echo among the routine examinations of hypertensive patients, at this time the indication is left to the doctors clinical judgment. Thus, limited information is available on how often general practitioners request echo for hypertension compared with other indications and what is the burden of echo-lab for this specific indication. Furthermore, it is not well known which type of specific information echo labs provide to referred hypertensive patients. We have addressed these issues in a nation-wide survey involving a large number of patients sent from general practitioners to several echo labs. The primary aim of the survey was to determine the percentage of echo requested by practitioners for hypertension. The secondary aim was to see what type of information echo centres provide under these circumstances. Methods Thirteen hospital or echo-labs located over the entire Italian territory were asked to participate in the project. To be eligible for the study they had to fulfill the following three inclusion criteria: (1) diagnostic activity performed in the adult outpatient setting only; (2) no exclusive commitment in particular groups of patients (that is, heart failure, renal insufficiency/transplantation, hypertension); (3) a minimum number of 1 echo examinations per year. Twenty centres fulfilled all these criteria; 15 of them who adhered to the study were requested to consecutively enroll outpatients of either sex, provided their age was X18 years. More precisely, each centre was requested to include a minimum number of patients, consecutively referred to by general practitioners, whose written prescriptions were used to identify the indications for echo as well as to define hypertension, corresponding at least to 5 of the examinations performed during the last year (that is, 5 patients for centres performing 1 examinations per year, 1 for those performing examinations). No specific exclusion criteria were recommended for patients enrolment. No instructions were given to the centres about the echo measures to be included in the diagnostic report to collect unbiased data on the extent of the information provided. Information about patients demographic data, medical history and medications were collected at the echo-labs by a questionnaire administered by the attending physicians. Clinic BP was recommended to be measured by using a mercury sphygmomanometer; measurements were performed after the subjects had rested for 3 5 min in the sitting position. Three measurements were taken from the non-dominant arm, at 1-min intervals and the average was used to define patient s representative values. BP control by treatment was defined as a value o14/9 mm Hg. Two files per patient were ed to the Department of Clinical Medicine and Prevention, University of Milano-Bicocca, acting as the coordinating centre for the final analysis: (1) the questionnaire containing demographic and clinical data and (2) the echo diagnostic report. As mentioned in the introduction, the primary aim of the study was to assess the frequency of echo exams requested in current practice for detection of hypertensive early cardiac damage and related problems. The secondary aim was to quantify the percentage of exams resulting in reporting echo quantitative data such as LVM (calculated according to standard formulae), LV geometrical patterns and indices of diastolic function. The tertiary aim was the assessment of the prevalence of LVH in relation to BP values and the presence or absence of antihypertensive treatment. The protocol of the study was approved by the Ethics Committee of the coordinating centres (Istituto Auxologico Italiano and University of Milano-Bicocca). Statistical analysis Statistical analysis, performed by the SAS System (version 6.12; SAS Institute Inc., Cary, NC, USA), was mainly descriptive and consisted of calculations of means±s.d. for continuous variables as well as numbers and percentages for discrete variables. When necessary, mean values were compared by Student s t-test for independent samples. Categorical data were analysed by the w 2 -test or Fischer s exact test when appropriate. A Po.5 was considered statistically significant. Results Of the 15 units that had adhered to the study, 14 effectively enrolled patients (see Appendix). Briefly, the basic characteristics of participating centres were the following: six served as outpatients echolabs within university departments (four of internal medicine and two of clinical cardiology) and the remaining eight within hospital cardiology units. Overall, the echo-labs examined approximately patients yearly. Recruitment of patients began in February 8 and ended in June of the same year. A total of 2647 patients were involved; of these, 198 were excluded

3 because the echo reports were not available. Thus, 2449 subjects, who represented approximately 12 of the total patients population examined over a period of 1 year, were eligible for the data analysis. Their main characteristics are reported in Table 1. Briefly, 1245 were men and 14 women, 15.7 current smokers and 5.9 had type 2 diabetes mellitus. Demographic characteristics of excluded participants were similar to the included ones. As shown in Figure 1, 745 subjects (3.4) underwent an echo examination because of hypertension-related problems (that is, search LVH before treatment, follow-up of a previously detected LVH or resistant hypertension) with, however, a large variation between centres (8 68) (Figure 2). In 1 out of 14 centres, encompassing the large majority of the patients (n ¼ 197), however, the range was consistently narrower (from to 4). In the remaining 174 patients, ischaemic heart disease, valvular heart disease, heart failure or arrhythmias accounted for 45 of the indications (Figure 1). In both groups, a previous echo examination had been carried out in more than 5 of the cases. Compared with the group referred to echolabs for hypertension, those referred for other medical problems were younger, had a lower systolic BP/diastolic BP, a lower prevalence obesity and a lower use of antihypertensive drugs. Heart rate, prevalence of current smoking and diabetes and LVM index (LVMI) were similar in the two groups (Table 2). The information included by the echo-labs in the diagnostic report is shown in Figure 3. Primary measures of LV structure such as LV internal diameter, interventricular septum and posterior wall thickness at end-diastole were included in almost all reports, both when patients were referred for hypertension and when they were referred to for other indications. This was also the case for LV ejection fraction. In contrast, calculated measures such as LVM, LVM indexed to body surface area, LVM indexed to height, 2.7 relative wall thickness and early-to-late diastolic mitral flow (E/A) ratio were included in a lower percentage of reports, and similarly in patients referred to for hypertension or for other indications. In patients referred to for hypertension, LVM indexed to height 2.7 was not provided at all by 8 centres and that indexed to body surface area by 6 centres. Eighty two percent of patients referred to echolabs for hypertension were on antihypertensive treatment (38.3 on monotherapy, 35.6 on two drugs and 25.1 on more than two drugs). Blockers of the renin angiotensin system (angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers) were the most frequently prescribed drugs (66) followed by diuretics (38), calcium antagonists (29) and b-blockers (22). BP was controlled (o14/9 mm Hg) in 35 of the treated patients. Data on LVH prevalence (defined as LVMI 451 g/ m 2.7 in men and 447 g/m 2.7 in women) were derived Table 1 Demographic and clinical characteristics of the study population (n ¼ 2449) Variable Value Data missing (n) Age (years) 58.5± Age o4 years, () 13.9 Age 4 64 years () 43.4 Age 464 years () 42.7 Male prevalence () 5.8 Weight (kg) 72.9± Height (m) 1.81± Body surface area (m 2 ) 1.66± Body mass index (kg m 2 ) 26.1± Systolic blood pressure (mm Hg) 135.3±17.5 Diastolic blood pressure (mm Hg) 81.3±9.9 Heart rate (beats min 1 ) 71.8± Current smokers () Former smokers () 18.1 Diabetes () 5.9 Overweight (body mass index kg m -2 )() Obesity (body mass index kg m 2 )() First echo examination () Antihypertensive drugs () 59.7 Cardiac murmur () Recent electrocardiogram available () HYPERTENSION Ischemic Heart Disease Valve Disease Arrhytmia Heart Failure Miscellanea CV Risk Factors Syncope Figure 1 Indications for an echo examination in the whole population study (n ¼ 2449 patients). from original echo reports (n ¼ 439) or calculated by Devereux s formula from the provided primary measures (n ¼ 36). LVH was present in 57 of the hypertensive patients, the value was 53 in untreated hypertensives, 45 in treated hypertensives with BP control and 65 in the 35 treated hypertensives without BP control. Finally, prevalence rates of LV systolic dysfunction, defined as a LV ejection fraction o45, and LV diastolic dysfunction, defined as an E/A ratio o.7, were 4.1 and 18.3, respectively

4 Total Population Center 1 Center 2 Center 3 Center 4 Center 5 Center 6 Center 7 Center 8 Center 9 Center 1 Center 11 7 Men Center 1 Center 2 Center 3 Center 4 Center 5 Center 6 Center 7 Center 8 Center 9 Center 1 Center 11 Center 12 Center 13 Center 14 Center 1 Center 2 Center 12 Center 13 Center 14 Women Center 3 Center 4 Center 5 Center 6 Center 7 Center 8 Center 9 Center 1 Center 11 Center 12 Center 13 Center 14 Figure 2 Prevalence rates of echo examinations performed for hypertension-related problems among the 14 participant centres. Data are reported for the whole study population, and, separately for men and women. Table 2 Demographic, clinical and echo characteristics of subjects referred for hypertension (group I) and for other reasons (group II) to an echo-lab Variable Patients referred for hypertension (n ¼ 745) Patients referred for other reasons (n ¼ 174) P-value Value Data missing (n) Value Data missing (n) Age (years) 6.2± ± Male prevalence () NS Body mass index (kg m 2 ) 27.± ± o.1 Systolic blood pressure (mm Hg) 141.3± ±17.4 o.1 Diastolic blood pressure (mm Hg) 85.5± ±9.6 o.1 Clinic heart rate (beats min 1 ) 71.2± ± NS Current smokers () NS Diabetes () NS Obesity () o.1 First echo examination () NS Antihypertensive drugs () o.1 Cardiac murmur () NS Recent electrocardiogram available () NS LVM (g) 182.1± ± LVM/BSA (g m 2 ) 112.4± ± NS LVM/height (g/m 2.7 ) 47.1± ± NS Ejection fraction () 66.5± ± o.1 Peak E velocity (cm) 69.8± ± Peak A velocity (cm) 75.1± ± NS E/A ratio.99± ± Abbreviations: BSA, body surface area; LVM, left ventricle mass; E/A, early-to-late mitral peak flow velocity ratio; NS, not significant. Discussion The present nation-wide survey show that (1) hypertension accounts for approximately 3 of echo examinations currently performed in outpatient hospital or academic echo labs; (2) a quite large fraction of echo reports do not provide quantitative data on LVM and LV geometry, although this is the

5 399 LVM LVMI (BSA) and LVMI (h2,7) LVMI (BSA or h 2,7 ) EF RWT E/A Figure 3 Prevalence rates of assessment of left ventricular mass (LVM), LVM indexed to body surface area and height 2.7, LV relative wall thickness (RTW) and early-to-late mitral peak flow velocity ratio (E/A,) ejection fraction (EF), calculated from the original echo reports in group I (patients referred for hypertension). main indication for arterial hypertension; (3) LVH is a highly prevalent phenotype in the setting of both untreated and treated hypertensive patients referred to echo-labs for the assessment of preclinical cardiac damage. The prevalence of hypertension as the main indication for echo consistently varied among the centres (8 68); it should be remarked, however, that most of the centres, encompassing up to 78 of the study population, showed a narrower range (from to 4). More than three quarters of patients undergoing an echo for hypertension-related problems were on antihypertensive treatment, mostly based on two or more drugs in combination. This finding suggests that echo is mostly requested for treatment-induced protection monitoring (that is, evaluation of progression or regression of LVH), rather than for quantifying total CV risk in untreated subjects and for initial therapeutic decision making. This is also supported by the observation that at least one echo examination had been previously performed in more than 5 of hypertensives. Indisputable evidence indicates that echo data may improve CV risk stratification, independently of BP levels and concomitant risk factors. The utility of echocardiography in the management of a chronic condition such as hypertension, however, is strongly dependent on the accurate detection of clinically relevant abnormalities (for example, LVH, LV systolic and diastolic dysfunction) and the measurement of serial changes in quantitative parameters. Several National and International guidelines state that cardiac hypertensive involvement should be properly estimated by LVM and geometry according to the validated formulae 13,22,23 at least in a number of patients. In spite of these recommendations, our data clearly indicate that LVH in clinical practice was assessed only in half of the cases simply by the measurement of wall thickness and not by calculating LVM with validated formulae. This finding confirms and expand previous information from a pilot regional survey analysing 211 echo reports by 1 physicians operating in 73 non-academic hospital and out-of hospital echo labs of Lombardia. 24 Although LVH might be also identified by an increased LV posterior and septal thickness, the accuracy and predictive value of LV wall thickness measurements in detecting LVH is lower than calculated LVM. 25 A study in 92 hypertensives comparing LVH prevalence, as measured by wall thickness dimensions versus LVMI calculation according to gender-specific criteria, showed that the former approach tended to over- and underestimate LVH in males and females, respectively, and its accuracy was 7 compared with LVMI calculation. 26 The assessment of echo LVH has the additional advantage of providing an accurate evaluation of LV geometry and function. Classification of left ventricular geometry, evaluation of ejection fraction, midwall fractional shortening and diastolic indices have been shown to provide a prognostic information additional to and sometimes independent of

6 4 LVM. 8,1,27 In our series, ejection fraction was calculated in almost all patients (92); this was not the case for other reliable indexes of LV geometry and filling such as relative wall thickness (65), early (E) and late (A) mitral peak flow velocity and their E/A ratio (6). Omission of these parameters reduces the impact of echo exam in stratifying CV risk related to LV geometric patterns, in detecting and grading LV diastolic dysfunction, with potential consequences on decision making affecting therapy choice and prevention of heart failure. Left ventricle hypertrophy was found in more than 5 of the hypertensive patients; the prevalence of this adverse cardiac phenotype was highest in treated individuals with unsatisfactory clinic BP control (65), intermediate in untreated individuals (53) and lowest in those with controlled BP (45). Again, large differences in LVH prevalence occurred among the 14 centres (from 25 to 9); it should be noted, however, that a narrower range (from 45 to 73) was found in 11 out of 14 centres, which enrolled more than 85 of the study population. The prevalence of hypertensive LVH, as assessed by echo, has been shown to be related to demographic and clinical factors, such as ethnicity, age, race, gender, severity and time of exposure to BP overload, coexistent diseases and risk factors as well as to the cut-offs and indexation methods used for LVH definition. 28 In particular, LVH rates vary with the severity of BP, ranging from less than in mild hypertension to more than 8 in severe, refractory hypertension. In our series, LVH prevalence was consistently higher than that found in studies conducted in population-based samples and in untreated hypertensives attending at specialist centres. 29,3 Our values, however, are in line with that reported (7) in a large Spanish survey of 946 essential hypertensives from primary care centres. 31 Several factors may explain the high prevalence of LVH in our survey: (1) old age (less than 7 of our patients were o4 years); (2) duration of hypertension (less than were untreated, that is, in the initial phase); moreover, up to 5 of patients had a previous echo examination and was reassessed for LVH regression; (3) non-standardized identification of LV interfaces due to the lack of a reading centre. This latter methodological aspect could be in part responsible for large differences in LVH prevalence seen among the centres. Both centres with the highest LVH prevalence, for example, measured LV primary parameters only. As we calculated LVMI in a post hoc analysis according to Devereux s formula, ignoring, however, the fact that the reading method was used to measure LV thickness and diameter (that is, Penn Convention or ASE Method), this would have markedly overestimated the prevalence of LVH. Some additional aspects, including study limitations, need to be commented. The number needed to detect LVH (that is, number of patients examined/number of LVH cases diagnosed) was 1.75, reflecting a favourable cost-effect ratio as a consequence of an appropriate referral for echo by general practitioners. It should be pointed out, however, that this ratio was obtained by identifying LVH as LVMI 451 g/m 2.7 in men and 47 g/m 2.7 in woman in a post hoc analysis, a method that has been shown to maximize the population risk attributable to LVH; 32 LVH data provided by the original echo report may have yielded a higher ratio, thus reducing the practical impact of echo on CV risk stratification. The generalizability of our findings may be limited by the fact that these data pertain to a relatively small number of echo-labs involved in the present survey. Finally, clinic BP control was determined by a single visit rather than repeated measurements. Our results showing that hypertension is the first cause for echo referral to an ultrasound lab have been obtained in a country where the costs of the procedure in the hypertensive setting are entirely or partly supported by the Italian National Health Service; thus, they should not be generalized to different National medical systems. In conclusion, data provided by this multicenter nation-wide survey supports the growing role of echo in the management of hypertension, by showing that search for cardiac organ damage in the whole population represents the main indication for current practice of outpatient eco-labs. It also shows that LVH is still a highly frequent phenotype in hypertension, despite therapeutic interventions. Finally, our observations indicate that the accuracy of ultrasonographic procedures for LVH detection needs to be improved. What is known about the topic K Left ventricular hypertrophy (LVH) is an independent predictor of cardiovascular mortality and morbidity in both normotensive and hypertensive subjects of different ethnicities. K Several studies have been devoted to the role played by echo in the cardiovascular risk stratification of hypertensive patients managed in the clinical practice as well as the cost-effectiveness of this procedure in detecting LVH and guiding proper antihypertensive treatment. What this study adds K Hypertension accounts for approximately 3 of echo examinations currently performed in Italy. K A quite large fraction of echo-reports do not provide quantitative data on left ventricular mass and geometry, although this is the main indication for arterial hypertension. K LVH is a highly prevalent phenotype in the setting of both untreated and treated hypertensive patients referred to echo-labs for the assessment of preclinical cardiac damage. Conflict of interest The authors declare no conflict of interest.

7 Acknowledgements The work was supported by a grant from the Italian Society of Hypertension. References 1 Ruilope LM, Schmieder RE. Left ventricular hypertrophy and clinical outcomes in hypertensive patients. Am J Hypertens 8; 21: Schmieder RE. The role of non-haemodynamic factors in the genesis of LVH. Nephron Dial Transplant 5; : Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991; 114: Vakili BA, Okin PM, Devereux RB. Prognostic implications of left ventricular hypertrophy. Am Heart J 1; 141: Taylor HA, Penman AD, Han H, Dale-Michael A, Sketon TN, Fox ER et al. Left ventricular architecture and survival in African-Americans free of coronary heart disease (from the Atherosclerosis Risk in Communities [ARIC] study). Am J Cardiol 7; 99: Koren MJ, Ulin RJ, Laragh JH, Devereux RB. 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8 42 subjects and in patients with systemic hypertension, mitral regurgitation and dilated cardiomyopathy. Am J Cardiol 1986; 57: Leibowitz D, Planer D, Ben-Ibgi F, Rott D, Weiss AT, Bursztyn M. Measurement of wall thickness alone does not accurately assess the presence of left ventricular hypertrophy. Clin Exp Hypertens 7; 29: Aurigemma GP, Gottdiener JS, Shemanski L, Gardin J, Kizman D. Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly. The Cardiovascular Health Study. J Am Coll Cardiol 1; 37: Alfakih K, Reid S, Hall A, Sivananthan MU. The assessment of left ventricular hypertrophy in hypertension. J Hypertens 6; 24: Mancia G, Carugo S, Grassi G, Lanzarotti A, Schiavina S, Cesana G et al. Prevalence of left ventricular hypertrophy in hypertensive patients without and with blood pressure control. Data from the PAMELA population. Hypertension 2; 39: Cuspidi C, Meani S, Valerio C, Sala C, Fusi V, Zanchetti A et al. Age and target organ damage in essential hypertension: role of the metabolic syndrome. Am J Hypertens 7; : Coca A, Gabriel R, de la Figuera M, Lopez-Sendon JL, Fernandez R, Sagastagoitia JD et al. on behalf of the VITAE Investigators. The impact of different echocardiographic diagnostic criteria on the prevalence of left ventricular hypertrophy in essential hypertension: the VITAE study. J Hypertens 1999; 17: de Simone G, Kizer JR, Chinali M, Roman MJ, Best LG, Lee ET et al. Normalization for body size and population-attributable risk of left ventricular hypertrophy. The Strong Heart Study. Am J Hypertens 5; 18: Appendix List of investigators Bonanomi C, Settimi E, Danzi GB. Divisione di Cardiologia; IRCCS, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano; Branzi G, Lonati L, Parati G. Divisione di Cardiologia Ospedale San Luca, Istituto Auxologico Italiano, Milano; Capra A, Giannattasio C, Trocino G, Casati A. Dipartimento di Medicina Clinica e Prevenzione e Clinica Medica Generale, Divisione di Cardiologia, Ospedale San Gerardo, Monza; Chiappa L, Paggi A, Morganti A. UO Medicina Generale e Servizio di Cardiologia Ospedale S Giuseppe e Università degli Studi di Milano; Longo M, Valerio C, Marconi M. Centro Trasfusionale e di Immunoematologia Fondazione Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, Milano; Macca G. UO Cardiologia Clinica San Carlo, Paderno Dugnano; Milan A. Dipartimento di Medicina ed Oncologia Sperimentale, Divisione di Medicina Interna, Universita di Torino; Negri F, Giudici V, Re A, Cuspidi C. Istituto Auxologico Italiano, Meda; Pellizzoli S, Robustelli F. Divisione di Cardiologia, Ospedale di Morbegno; Rao MAE, Iovino GL, Arcucci O, N De Luca Dipartimento di Medicina Clinica e Scienze Cardiovascolari, Università degli Studi Federico II, Napoli; Salvetti M, Paini A, Galbassini G. Dipartimento di Scienze Mediche e Chirurgiche, Universita di Brescia; Tocci G, Ciavarella M, Volpe M. Unita Operativa Complessa di Cardiologia, II Facolta di Medicina e Chirurgia, Universita La Sapienza, Roma; Vaccarella A. Servizio di Cardiologia- Presidio Operativo e di Ricerca di Casatenovo I.N.R.C.A-IRCCS; Veglia MG. UO Cardiologia Ospedale Madonna delle Grazie, Matera.