We appreciate the work of Rudominer et al, who
recently published a report describing the association of rheumatoid
arthritis (RA) with increased left ventricular mass

Arslan

Birdane

Corrao

Gonzalez-Juanatey

Hedges

Rudominer

Crossref

A meta-analysis of the effect size of rheumatoid arthritis on left ventricular mass: Comment on the article by Rudominer et al

CORRAO, Salvatore

SCAGLIONE, Rosario

CALVO, Luigi

LICATA, Giuseppe

Archivio istituzionale della ricerca - Università di Palermo

CD25() regulatory T cells in antitumor therapy reveals alterna-tive pathways for suppression of autoreactive cytotoxic T lympho-cyte responses. J Exp Med 2001;194:823–32.3. Wood KJ, Sakaguchi S. Regulatory T cells in transplantationtolerance. Nat Rev Immunol 2003;3:199–210.4. Bayry J, Triebel F, Kaveri SV, Tough DF. Human dendritic cellsacquire a semimature phenotype and lymph node homing poten-tial through interaction with CD4CD25 regulatory T cells.J Immunol 2007;178:4184–93.5. Houot R, Perrot I, Garcia E, Durand I, Lebecque S. HumanCD4CD25high regulatory T cells modulate myeloid but notplasmacytoid dendritic cells activation. J Immunol 2006;176:5293–8.6. Onishi Y, Fehervari Z, Yamaguchi T, Sakaguchi S. Foxp3natural regulatory T cells preferentially form aggregates on den-dritic cells in vitro and actively inhibit their maturation. Proc NatlAcad Sci U S A 2008;105:10113–8.7. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M,Fehervari Z, et al. CTLA-4 control over Foxp3 regulatory T cellfunction. Science 2008;322:271–5.8. Tang Q, Boden EK, Henriksen KJ, Bour-Jordan H, Bi M, Blue-stone JA. Distinct roles of CTLA-4 and TGF- in CD4CD25regulatory T cell function. Eur J Immunol 2004;34:2996–3005.9. Brunner-Weinzierl MC, Hoff H, Burmester GR. Multiple func-tions for CD28 and cytotoxic T lymphocyte antigen-4 duringdifferent phases of T cell responses: implications for arthritis andautoimmune diseases. Arthritis Res Ther 2004;6:45–54.10. Friedline RH, Brown DS, Nguyen H, Kornfeld H, Lee J, Zhang Y,et al. CD4 regulatory T cells require CTLA-4 for the mainte-nance of systemic tolerance. J Exp Med 2009;206:421–34.11. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA,Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferationand fatal multiorgan tissue destruction, revealing a critical nega-tive regulatory role of CTLA-4. Immunity 1995;3:541–7.12. Waterhouse P, Penninger JM, Timms E, Wakeham A, ShahinianA, Lee KP, et al. Lymphoproliferative disorders with early lethalityin mice deficient in Ctla-4. Science 1995;270:985–8.13. Verhagen J, Gabrysova L, Minaee S, Sabatos CA, Anderson G,Sharpe AH, et al. Enhanced selection of FoxP3 T-regulatorycells protects CTLA-4-deficient mice from CNS autoimmunedisease. Proc Natl Acad Sci U S A 2009;106:3306–11.DOI 10.1002/art.24795A meta-analysis of the effect size of rheumatoidarthritis on left ventricular mass: comment on thearticle by Rudominer et alTo the Editor:We appreciate the work of Rudominer et al, whorecently published a report describing the association of rheu-matoid arthritis (RA) with increased left ventricular mass (1).The findings of Rudominer and colleagues are consistent withthe findings of our own previous study of RA patients, which iscited by the authors (2). Patients with RA have both structuraland functional left ventricular involvement. In these patients,we have previously demonstrated that diastolic dysfunction(detected as impaired relaxation abnormalities during leftventricular filling) is directly correlated with structural changesin the left ventricle, specifically, changes involving left ventric-ular mass, interventricular septal thickness, and left ventricularposterior wall thickness (2). In RA patients, these all seem tobe features of the systemic disease process, and diastolicdysfunction seems to be a consequence of left ventricularstructural changes. However, it is probable that these findingsonly partially explain the cardiovascular morbidity in RA.Indeed, in a study of RA patients (with no exclusioncriteria), we observed a peculiar cardiac picture among pa-tients who had no symptoms of cardiac disease (3). Thepopulation of RA patients in that study seemed to share 3characteristics: minimal posterior pericardial effusion, alter-ation of the aortic root (detected as an increased prevalence ofValsalva sinus aneurysms), and both valvular and valvular cordthickening. However, even though left ventricular mass wasgreater overall in the RA group, the difference was notstatistically significant in patients versus controls. We believethat heart involvement in RA results from the disease’ssystemic inflammatory process, which explains the high rates ofcardiac mortality in RA patients. Thus, we completely agreewith the conclusions discussed by Rudominer et al and thinkthat the collective scientific community has achieved an im-portant goal in demonstrating that different populations withRA (both Mediterranean [2,3] and North American [1]) havethe same clinical cardiac features (i.e., a higher left ventricularmass index and abnormalities consistent with impaired leftventricle relaxation).We undertook a meta-analysis of previously publishedreports (1–4) to summarize the effect size of RA on leftventricular mass index in patients compared with healthycontrols. We searched for data pertaining to left ventricularmass index, which had been determined using echocardiogra-phy. Unfortunately, in the studies by Arslan et al (5) andGonzalez-Juanatey et al (6), left ventricular mass index was notcalculated; therefore, we excluded these studies from ouranalysis. We computed the modified Glass statistic usingpooled sample standard deviation and Cochran’s Q statistic.The pooled mean effect size estimate was calculated accordingto methods described by Hedges and Olkin (7). Figure 1 showsthe pooled estimation of effect size using a fixed-effects modelFigure 1. Forest plot of the effect size in the meta-analysis, using afixed-effects model. Squares represent the effect sizes in the previousstudies. The diamond and dotted line represent the pooled effect sizein the meta-analysis. Horizontal lines represent the 95% confidenceinterval (95% CI). The Glass statistic (mean difference standardizedby pooled standard deviation) and 95% CI are shown as the pooledmean effect size estimate. For the overall fixed-effects model, P 0.0001.LETTERS 2851(7). This model was used since there was low interstudy vari-ation. The data from our meta-analysis support the findings ofRudominer et al, and help to describe the effect of RA on theheart. In conclusion, we believe that left ventricular structuraland functional changes are one of the established clinicalfeatures of RA, and the challenge will now be to find ways toutilize this information both to optimize clinical monitoringand to reduce cardiovascular mortality in RA patients.Salvatore Corrao, MDRosario Scaglione, MDLuigi Calvo, MDGiuseppe Licata, MDUniversity of PalermoPalermo, Italy1. Rudominer RL, Roman MJ, Devereux RB, Paget SA, Schwartz JE,Lockshin MD, et al. Independent association of rheumatoid arthri-tis with increased left ventricular mass but not with reduced ejectionfraction. Arthritis Rheum 2009;60:22–9.2. Corrao S, Salli L, Arnone S, Scaglione R, Pinto A, Licata G.Echo-Doppler left ventricular filling abnormalities in patients withrheumatoid arthritis without clinically evident cardiovascular dis-ease. Eur J Clin Invest 1996;26:293–7.3. Corrao S, Salli L, Arnone S, Scaglione R, Amato V, Cecala M, et al.Cardiac involvement in rheumatoid arthritis: evidence of silentheart disease. Eur Heart J 1995;16:253–6.4. Birdane A, Korkmaz C, Ata N, Cavusoglu Y, Kasifoglu T, DoganSM, et al. Tissue Doppler imaging in the evaluation of the left andright ventricular diastolic functions in rheumatoid arthritis. Echo-cardiography 2007;24:485–93.5. Arslan S, Bozkurt E, Sari RA, Erol MK. Diastolic function abnor-malities in active rheumatoid arthritis evaluation by conventional-Doppler and tissue Doppler: relation with duration of disease. ClinRheumatol 2006;25:294–9.6. Gonzalez-Juanatey C, Testa A, Garcia-Castelo A, Garcia-Porrua C,Llorca J, Ollier WE, et al. Echocardiographic and Doppler findings inlong-term treated rheumatoid arthritis patients without clinically evi-dent cardiovascular disease. Semin Arthritis Rheum 2004;33:231–8.7. Hedges LV, Olkin I. Statistical methods for meta-analysis. 1st ed.London: Academic Press; 1985.DOI 10.1002/art.24813Aortic stiffness and left ventricular hypertrophy inrheumatoid arthritis: comment on the article byRudominer et alTo the Editor:In the recent article by Rudominer et al (1), theauthors reported an association of rheumatoid arthritis (RA)with increased left ventricular (LV) mass but not with reducedejection fraction. Rudominer and colleagues also suggestedthat a pathophysiologic link might exist between chronicinflammation and LV hypertrophy, even though LV systolicfunction was preserved in their study population.LV hypertrophy might be useful in predicting cardio-vascular events independent of traditional risk factors. Inaddition, arterial stiffness has been described as an indepen-dent predictor of cardiovascular mortality both in patients withcardiovascular disease and in the general population (2–4).In a population of patients with RA, we investigatedboth ventricular mass and aortic elasticity, which is consideredan important determinant of LV function and coronary bloodflow. Aortic elasticity was assessed using a 2-dimensionalguided M-mode evaluation of the systolic aortic diameter (Ds)and the diastolic aortic diameter (Dd) at a location 3 cm abovethe aortic valve; using simultaneous electrocardiography, Ddwas measured at the peak of the R wave, and Ds was measuredat the point of maximal anterior motion of the aortic wall. Forboth diameters, 5 measurements were taken and then aver-aged. Indices of aortic elasticity were calculated as follows:aortic strain  100(Ds  Dd)/Dd; aortic distensibility (2[Ds  Dd]/Dd[PP]) (given as cm2/dyn 106) where PP ispulse pressure (calculated as Ps  Pd); and aortic stiffness ln(Ps/Pd)/([Ds  Dd]/Dd) where Ps and Pd are systolic anddiastolic blood pressures, respectively, measured in mm Hg,and where ln(Ps/Pd) refers to the natural logarithm of therelative pressure.In a population of 93 randomly enrolled RA patients,we observed increased mean SD LVmass (101 29 gm/m2),decreased aortic strain and distensibility indices (8  5% and3.2  2.5 cm2/dyn 106, respectively), and an increasedstiffness index (10.5  9.7). From this cohort, we then selected35 patients who had no hypertension, valve disease, or historyof cardiovascular disease (mean  SD age 57.8  7.7 years,mean  SD RA disease duration 10  8 years). In thesepatients, we observed increased mean  SD LV mass (92 53.1 gm/m2), decreased aortic strain and distensibility indices(9 3.8% and 3.6 0.8 cm2/dyn 106, respectively), and anincreased stiffness index (7.6  2.6).Patients were then divided into 2 subgroups based ontheir C-reactive protein levels (0.5 mg/dl versus 0.5 mg/dl);LV mass was not significantly different between the 2 groups.LV mass and other morphologic and functional cardiac para-meters were compared. In a univariate analysis, indexed LVmass tended to correlate with aortic distensibility, but this wasnot significant (P  0.069). In a multivariate analysis, LV masssignificantly correlated with aortic distensibility (P  0.04) butonly tended to correlate with aortic strain (P  0.06).The stiffening of the aorta and other central arteriesrepresents a potential risk factor for increased cardiovascularmorbidity and mortality (2–4). Furthermore, an associationbetween impaired aortic elasticity and LV hypertrophy hasbeen demonstrated in previous studies (5,6). Our findingsconfirm those of Rudominer and colleagues (1) and demon-strate an association between some aspects of impaired aorticelasticity and increased LV mass in RA patients. Thesefindings suggest that patients with RA could have preclinicalatherosclerosis, even without having hypertension or othercardiovascular risk factors. A decrease in aortic elasticity couldinfluence the natural history of RA and contribute to thedevelopment of cardiovascular disease and left ventriculardysfunction.E. Vizzardi, MDI. Cavazzana, MDA. Ceribelli, MDA. Tincani, MDL. Dei Cas, MDF. Franceschini, MDSpedali CiviliBrescia, Italy2852 LETTERS

A meta-analysis of the effect size of rheumatoid arthritis on left
   ventricular mass: comment on the article by Rudominer et al

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A meta-analysis of the effect size of rheumatoid arthritis on left ventricular mass: comment on the article by Rudominer et al

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