Background
Patients with rheumatoid arthritis have an increased risk for cardiovascular disease. Because of accelerated atherosclerosis and changes in left ventricular (LV) geometry, circumferential and longitudinal (C&L) LV systolic dysfunction (LVSD) may be impaired in these patients despite preserved LV ejection fraction. The aim of this study was to determine the prevalence of and factors associated with combined C&L LVSD in patients with rheumatoid arthritis.
Methods
One hundred ninety-eight outpatients with rheumatoid arthritis without overt cardiac disease were prospectively analyzed from January through June 2014 and compared with 198 matched control subjects. C&L systolic function was evaluated by stress-corrected midwall shortening (sc-MS) and tissue Doppler mitral annular peak systolic velocity (S′). Combined C&L LVSD was defined if sc-MS was <86.5% and S′ was <9.0 cm/sec (the 10th percentiles of sc-MS and S′ derived in 132 healthy subjects).
Results
Combined C&L LVSD was detected in 56 patients (28%) and was associated with LV mass (odds ratio, 1.03; 95% CI, 1.01–1.06; P = .04) and concentric LV geometry (odds ratio, 2.76; 95% CI, 1.07–7.15; P = .03). By multiple logistic regression analysis, rheumatoid arthritis emerged as an independent predictor of combined C&L LVSD (odds ratio, 2.57; 95% CI, 1.06–6.25). The relationship between sc-MS and S′ was statistically significant in the subgroup of 142 patients without combined C&L LVSD ( r = 0.40, F < 0.001), having the best fitting by a linear function (sc-MS = 58.1 + 3.34 × peak S′; r 2 = 0.19, P < .0001), absent in patients with combined C&L LVSD.
Conclusions
Combined C&L LVSD is detectable in about one fourth of patients with asymptomatic rheumatoid arthritis and is associated with LV concentric remodeling and hypertrophy. Rheumatoid arthritis predicts this worrisome condition, which may explain the increased risk for cardiovascular events in these patients.
Notice of Clarification
The aim of this “notice of clarification” is to analyze in brief the similarities and to underline the differences between the current article (defined as “paper J”) and a separate article entitled “Prevalence and Factors Associated with Subclinical Left Ventricular Systolic Dysfunction Evaluated by Mid-Wall Mechanics in Rheumatoid Arthritis” (defined as “paper E”), which was written several months before paper J, and recently accepted for publication by the journal “Echocardiography” (Cioffi et al. ). We wish to explain more clearly how the manuscript described in “paper J” relates to the “paper E” and the context in which it ought to be considered.
Data in both papers were derived from the same prospective database, so that it would appear questionable if the number of the enrolled patients and/or their clinical/laboratory/echocardiographic characteristics were different. Accordingly, both papers reported that 198 patients with rheumatoid arthritis (RA) were considered and their characteristics were identical, due to the fact that they were the same subjects (this circumstance is common and mandatory among all studies in which the patients were recruited from the same database). These are the similarities between the papers.
In paper E, which was written several months before paper J, we focused on the prevalence and factors associated with impaired circumferential left ventricular (LV) systolic function measured as mid-wall shortening (corrected for circumferential end-systolic stress). We found that 110 patients (56% of the whole population) demonstrated this feature. Thus, these 110 patients were the object of the study described in paper E, in which we specifically analyzed the factors associated with the impairment of stress-corrected mid-wall shortening (sc-MS). The conclusions of that paper were: (i) subclinical LV systolic dysfunction (LVSD) is detectable in more than half RA population without overt cardiac disease as measured by sc-MS, (ii) RA per se is associated with LVSD, and (iii) in RA patients only LV relative wall thickness was associated with impaired sc-MS based upon multivariate logistic regression analysis.
Differently, in the paper J, we focused on the prevalence and factors associated with combined impairment of circumferential and longitudinal shortening (C&L) in 198 asymptomatic patients with RA. We found that 56 patients (28% of the whole population) presented this feature. Thus, these 56 patients were analyzed in detail in this study, as well as the factors associated with the combined impairment of C&L shortening. In paper J, we evaluated sc-MS as an indicator of circumferential systolic LV shortening, and we also determined the average of tissue Doppler measures of maximal systolic mitral annular velocity at four different sampling sites ( S’) as an indicator of longitudinal LV systolic shortening. This approach clearly demonstrates that in paper J, we analyzed data deriving from the tissue Doppler analysis, which were not taken into any consideration in paper E.
The investigation described in paper J made evident several original and clinically relevant findings. In patients with RA: (i) the condition of combined C&L left ventricular systolic dysfunction (LVSD) is frequent; (ii) these patients have comparable clinical and laboratory characteristics with those without combined C&L LVSD, but exhibit remarkable concentric LV geometry and increased LV mass, a phenotype that can be consider a model of compensated asymptomatic chronic heart failure; (iii) RA is an independent factor associated with combined C&L LVSD; (iv) no relationship between indexes of circumferential and longitudinal function exists in patients with combined C&L LVSD, while it is statistically significant and positive when the subgroup of patients without combined C&L LVSD is considered, having the best fitting by a linear function. All these findings are unique to the paper J and are not presented (they could not have been) in paper E.
It appears clear that, starting from the same 198 patients included in the database, different sub-groups of patients were selected and analyzed in the two papers (they had different echocardiographic characteristics) and, consequently, different factors emerged by the statistical analyses as covariates associated with the different phenotypes of LVSD considered.
Importantly, both papers E and J had a very long gestation because all reviewers for the different journals found several and important issues that merited to be addressed: a lot of changes were proposed and much additional information was required, particularly by the reviewers of paper E. Considering this context, it emerges that although paper E was written well before paper J, the two manuscripts were accepted at the same time (we received the letters of acceptance within a couple of weeks). Thus, the uncertainty about the fate of both manuscripts made it very difficult (if not impossible) to cite either of them in the other one and, afterward, we just did not think about this point anymore. Of note, the idea to combine in the analysis longitudinal function came therefore well after the starting process of revision of the paper E and was, in some way inspired by a reviewer’s comment. That is why we did not put both findings in the same paper.
We think that our explanations provide the broad audience of your journal a perspective of transparency and our respect for the readers’ right to understand how the work described in the paper J relates to other work by our research group.
Giovanni Cioffi
On behalf of all co-authors
Ombretta Viapiana, Federica Ognibeni, Andrea Dalbeni, Davide Gatti, Carmine Mazzone, Giorgio Faganello, Andrea Di Lenarda, Silvano Adami, and Maurizio Rossini
In patients with rheumatoid arthritis, changes in left ventricular (LV) geometry toward a concentric fashion (concentric remodeling or hypertrophy) have been widely found in an early stage of the disease. These typologies of LV geometric patterns are closely and consistently associated with depressed LV midwall mechanics and circumferential LV myocardial systolic dysfunction in several groups of patients, such as those with arterial hypertension, type 2 diabetes mellitus, heart failure (HF) with preserved LV ejection fraction (LVEF), aortic stenosis, chronic kidney disease, and obstructive sleep apnea. Similarly, reduced LV longitudinal function has been detected in patients with rheumatoid arthritis, depending mostly on the level of disease activity. Considered individually, circumferential and longitudinal (C&L) LV systolic dysfunction (LVSD) must be presumed to be reliable indicators of the transitional state between asymptomatic subtle LVSD and clinically manifest congestive HF. Furthermore, these conditions are potent prognosticators of adverse cardiovascular (CV) outcomes, as definitively demonstrated in patients with hypertension, type 2 diabetes mellitus, and aortic stenosis and in the subset of patients with chronic HF in whom LVEF is preserved.
Analogous to patients with HF and preserved LVEF, type 2 diabetes mellitus, or arterial hypertension, C&L LVSD might coexist in some patients with rheumatoid arthritis. The prevalence and predictors of this condition are unknown in patients with rheumatoid arthritis, and its early detection might be important for the clinical management of these subjects, who have a significantly higher mortality rate than the general population (approximately 1.6-fold higher), mainly because of CV disease, and comparable with that found in patients with type 2 diabetes mellitus.
Accordingly, we designed this prospective study to assess (1) the prevalence of combined C&L LVSD in patients with asymptomatic rheumatoid arthritis without histories and clinical signs of cardiac disease, (2) the clinical and echocardiographic variables associated with combined C&L LVSD, (3) whether rheumatoid arthritis per se is a prognosticator of this condition, and (4) how the indexes of C&L function are related to one another in these patients.
Methods
Study Population
The design of the study was prospective. Patients >18 years of age with diagnoses of rheumatoid arthritis ascertained by clinical and laboratory examination underwent echocardiographic, clinical, and laboratory evaluations. All subjects were free of symptoms and clinical signs attributable to some cardiac disease. Exclusion criteria were a history of myocardial infarction, myocarditis, or HF; coronary heart disease diagnosed by clinical or electrocardiographic evaluation at rest and by exercise, scintigraphy, or stress echocardiography; alcoholic cardiomyopathy; primary hypertrophic cardiomyopathy; asymptomatic known LVSD; prior myocardial revascularization; significant valve heart disease; and atrial fibrillation. All patients with rheumatoid arthritis who were evaluated from January 1, 2014, to June 30, 2014, at our Italian referral centers in Verona, Trieste, and Trento and who met the inclusion and exclusion criteria for the study were recruited. During this period, 228 patients were visited and were taken into consideration as participants in the study. Among these patients, 30 were excluded (histories of myocardial infarction in 10, histories of HF in four, moderate or severe aortic stenosis in six, and atrial fibrillation in 10), leaving a final number of 198 subjects who represented the population analyzed in this study.
Participant rheumatologists were provided with a form designed to capture all essential CV risk factor information, laboratory values, data on the clinical expression of rheumatoid arthritis, and current medical therapy (including medications for CV risk factor control), reported at the time of the visit. Rheumatoid arthritis state of activity was classified as high according to the need to administer a disease-modifying antirheumatic drug and in accordance with the measured Clinical Disease Activity Index (CDAI). All information was subsequently input into statistical software for the analyses.
Control Groups
For the purposes of this study, we selected two distinct groups suitable as control subjects. One hundred thirty-two healthy subjects with normal systemic blood pressure, serum glycemic levels, lipid profiles, and echocardiographic findings who were not receiving any medical treatment constituted the first group, defined as “healthy control subjects,” with the sole aim of identifying the range of normal values of stress-corrected midwall shortening (sc-MS) and tissue Doppler mitral annular peak systolic velocity (S′) for defining the condition of combined C&L LVSD (for details, see the “Echocardiography” section). These 132 subjects were statistically comparable with the 198 patients with rheumatoid arthritis enrolled in the study for age, gender, and body mass index according to the following procedure: Gower’s generalized distance from each of the healthy individuals was computed and ranked in ascending order. The distance was calculated using these variables ordered as follows: age, gender, and body mass index. We gave priority of matching to each variable (in this case, age first, then gender, then body mass index), and all variables were considered together in the statistical procedure. When we ran the analysis, we had a new disposition of the patients in the database: the healthy control subjects were merged with the patients with rheumatoid arthritis in ascending order. According to our input, the first healthy control subjects on the list had the highest probability of having similar age (the variable with the highest priority) as the patients with rheumatoid arthritis and some difference in body mass index (the variable with the lowest priority). The 132 healthy control subjects and 198 patients with rheumatoid arthritis were then defined by taking for every three close patients with rheumatoid arthritis the two closest healthy control subjects (selected from a pool of 186 patients). This large number ( n = 186) of accessible patients made negligible the difference in all variables used for the matching between patients with rheumatoid arthritis and healthy control subjects.
Furthermore, a second control group, defined as the “non–rheumatoid arthritis group matched for comorbidities,” was selected and compared with the study group of patients with rheumatoid arthritis; it was composed of 198 patients without rheumatoid arthritis, matched with those with rheumatoid arthritis for age, gender, body mass index, presence of hypertension, and presence of diabetes using the same statistical procedure described above. These 198 non–rheumatoid arthritis “control” patients were selected by taking the closest control subject for every patient with rheumatoid arthritis. These patients, who did not have rheumatoid arthritis, were selected from an original cohort of 437 consecutive patients who underwent clinical and echocardiographic evaluation at Villa Bianca Hospital during a CV assessment at a primary prevention clinic during the same recruitment period as for patients with rheumatoid arthritis. After the first selection, excluding 180 patients <35 or >80 years of age (to correspond to the age range of the study population with rheumatoid arthritis) and those with at least one risk factor for CV events, the 198 non–rheumatoid arthritis patients matched for comorbidities were selected from a final pool of 257 patients. Thus, the groups were matched on exposure (rheumatoid arthritis) and not heart structure and function (the end point of the study), so this cannot be considered a case-control study. Although prospective, it must be considered a study with a matched cross-sectional design.
All patients gave written informed consent, and the study was approved by ethics committees at all participating centers. The study protocol conformed to the ethical guidelines of the Declaration of Helsinki as revised in 2000.
Echocardiography
Transthoracic echocardiography was performed according to a standardized protocol. M-mode, two-dimensional (2D), color Doppler, and spectral Doppler images were acquired and stored on compact discs or magneto-optical disks and forwarded for final interpretation at the Echocardiography Core Laboratory at Villa Bianca Hospital. LV chamber dimensions and wall thickness were measured according to American Society of Echocardiography recommendations, and LV mass was calculated using Devereux’s formula. LV mass was normalized for height 2.7 , and LV hypertrophy was defined as LV mass ≥ 49.2 g/m 2.7 for men and LV mass ≥ 46.7 g/m 2.7 for women. Relative wall thickness was calculated as the ratio of twice the posterior wall thickness to LV diameter, both measured at end-diastole, and was indicative of concentric LV geometry if ≥0.43. LV end-diastolic and end-systolic volumes were measured using the biplane method of disks from 2D apical four-chamber and two-chamber views and used to calculate LVEF. LV stroke volume was measured using the pulsed-wave LV outflow tract Doppler velocity-time integral and LV outflow tract diameter.
Circumferential LV systolic function was assessed at the midwall level by measuring the systolic shortening of the LV minor axis, as previously described. The model was similar to that commonly used to calculate LV mass. A constant ratio of the volume of its inner and outer halves during the cardiac cycle was assumed. Therefore,
( LVIDd + H d ) 3 − LVIDd 3 = ( LVIDn + H n ) 3 − LVIDn 3 ,
( LVIDd + H d / 2 ) 3 − LVIDd 3 = ( LVIDs + H s / 2 ) 3 − LVIDs 3 ,
( LVIDd + PWTd / 2 + IVSTd / 2 ) − ( LVIDs + H s / 2 ) ( LVIDd + PWTd / 2 + IVSTd / 2 ) ,
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