Original Article Herz DOI 10.1007/s00059-015-4320-5 Received: 16 December 2014 Revised: 21 February 2015 Accepted: 3 April 2015 © Urban & Vogel 2015
Giovanni Cioffi1 · Ombretta Viapiana2 · Federica Ognibeni2 · Andrea Dalbeni2 · Davide Gatti2 · Silvano Adami2 · Carmine Mazzone3 · Giorgio Faganello3 · Andrea Di Lenarda3 · Maurizio Rossini2 1 Department of Cardiology, Villa Bianca Hospital, Trento, Italy 2 Division of Rheumatology, Department of Medicine, University and Azienda Ospedaliera Universitaria
Integrata of Verona, Verona, Italy 3 Cardiovascular Center, Health Authority n° 1 and University of Trieste, Trieste, Italy
Prevalence and factors related to left ventricular systolic dysfunction in asymptomatic patients with rheumatoid arthritis A prospective tissue Doppler echocardiography study The higher mortality rate of patients with rheumatoid arthritis (RA) has been linked tocardiovascular (CV) disease [1–3]. Patients with RA have a chronic inflammatory state of the vascular system, accelerated atherosclerotic processes, increased arterial stiffness, and changes in left ventricular (LV) geometry. All these conditions, which have been detected and described by several authors in patients with RA without overt cardiac disease and analyzed in primary prevention [4–10], may predispose these patients to LV systolic dysfunction (LVSD). While it has been well established that vascular involvement and changes in LV geometry arise at the onset of the disease, there are conflicting data on the existence of an asymptomatic phase of cardiac disease in these patients, in which subclinical LVSD develops and heralds adverse CV events [10– 17]. Furthermore, no information is available on the potential role of RA per se as a clinical condition promoting LVSD in addition to the traditional CV risk factors. LVSD can be reliably detected by assessing mitral annular peak systolic velocity (S’) withtissue Doppler pulsed-wave spectral imaging, which estimates the systolic
function of longitudinal LV myocardial fibers and has emerged as one of the most powerful prognosticators for CV disease in the realm of noninvasive cardiac imaging [18–24]. Using this echocardiographic technique, we prospectively studied a large cohort of patients with RA without presence or history of symptoms of cardiac disease with the aim of testing the hypotheses (1) that the condition of “subclinical LVSD” is widely present in these subjects and (2) that RA per se is an independent prognosticator of LVSD. We also assessed the clinical and echocardiographic factors related to LVSD in patients with RA.
Methods Study population Study participants were 198 adults with RA diagnosed after clinical and laboratory examination. They were recruited from 1 January 2014 to 31 June 2014 in three Italian referral centers (Verona, Trieste, Trento) where they underwent echocardiographic, clinical, and laboratory evaluations. All subjects were free of symptoms
and clinical signs of cardiac disease. Exclusion criteria were: a history of myocardial infarction, myocarditis, or heart failure; coronary heart disease diagnosed by clinical and electrocardiographic evaluation at rest and by the results of exercise/scintigraphy/echo-stress testing; alcoholic cardiomyopathy; primary hypertrophic cardiomyopathy; asymptomatic known LVSD; prior myocardial revascularization; significant valvular heart disease; atrial fibrillation.
Control groups The first control group, comprising 132 healthy subjects, who had normal blood pressure, serum glycemic levels, lipid profile, normal echocardiographic findings (including LV mass, geometry, wall motion, and ejection fraction) and who did not receive any medical treatment, was identified with the sole reason of assessing the range of normal values of S’ to define LVSD (for details, see “Echocardiography” section). These 132 subjects were statistically comparable with those enrolled in the study for age, sex, and body mass index according to the following Herz
1
Original Article Table 1 Main clinical characteristics of the 198 study patients with rheumatoid arthritis Variables Clinical Age (years) Female gender (%) Body mass index (kg/m2) Hypertension (%) Dyslipidemia (%) Diabetes (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (bpm) Laboratory Glycemia (mg/dl) Hemoglobin (gr/dl) GFR (ml/min/1.73m2) GFR 300 mg/g) (%) C-reactive protein (mg/l) Rheumatoid factor positive (%) Cyclic citrullinated peptide positive (%) Pharmacological treatment Beta-blockers (%) ACEi/ARB (%) Diuretics (%) Calcium antagonists (%) Anti-platelet agents (%) Statins (%) NSAIDs (%) Methotrexate (%) Hydroxychloroquine (%) Immunomodulatory and anticytotoxic agents (%) Corticosteroids (%)
Rheumatoid arthritis patients (n = 198)
Healthy controls (n = 132)
61 ± 12 71 25.8 ± 4.7 53 46 11 134 ± 17 82 ± 9 70 ± 10
61 ± 16 63 25.2 ± 4.2 0 0 0 130 ± 13 81 ± 6 68 ± 9
99 ± 36 13.7 ± 1.4 92 ± 25 8 209 [179–238] 116 [95–138] 104 [76–164] 6 6.0 [1.5–7.3] 53 44
85 ± 4 14.6 ± 1.7 81 ± 15 0 232 [177–295] 164 [133–196] 103 [51–225] 0 2.9 [0.9–6.7] -
19 36 20 13 22 28 32 50 12 60
-
47
-
ACEi angiotensin-converting enzyme inhibitors, ARB angiotensin T1 receptor blockers, GFR glomerular filtration rate, LDL low-density lipoprotein, NSAIDs nonsteroidal anti-inflammatory drugs.
procedure: a Gower’s generalized distance from each healthy individual and each RA patient was computed and all patients were ranked in ascending order in the database. The distance was calculated using these variables ordered as follows: age, gender, body mass index. The 132 healthy controls and 198 RA patients were then demarcated and coupled by taking for every three close patients with RA the two closest controls (selected by a pool of 186 patients). Subsequently, the 198 patients with RA were compared with a second control
2
Herz
group, composed of 198 patients without RA, matched for age, sex, body mass index, and prevalence of hypertension and diabetes by the same statistical procedure described above. The 198 controls were designated by taking for every one close patient with RA the one closest control. These subjects were selected from a pool of 257 patients at Villa Bianca Hospital who consecutively underwent clinical and echocardiographic evaluations for CV risk assessment in primary prevention during the same period of enrollment as the patients with RA.
All patients gave written informed consent and the study was approved by the ethicscommittees in all participating centers. The study protocol conforms to the ethical guidelines of the Declaration of Helsinki as revised in 2000.
Echocardiography All Doppler echocardiographic studies were performed using an Alpha Esaote unit (Florence, Italy) equipped with a 2.5– 3.5-MHz annular-array transducer by experienced cardiologists who followed a standardized protocol. Images were stored on CD or MO disks and forwarded to the Echocardiography Core Laboratory at Villa Bianca Hospital of Trento, Italy, for final interpretation. Sonographers (GC, FO) were blinded to the clinical data. LV chamber dimensions and wall thicknesses were measured using the American Society of Echocardiography guidelines and LV mass was calculated using a validated formula [25]. LV mass was normalized for height to the 2.7 power and LV hypertrophy was defined as LV mass ≥ 49.2 g/m2.7 for men and ≥ 46.7 for women [26]. Relative wall thickness was calculated as the ratio of the 2* end-diastolic posterior wall thickness to LV diameter and indicated concentric LV geometry if ≥ 0.43 (the 97.5th percentile in a normal population) [27]. LV end-diastolic and end-systolic volumes and stroke volume were measured by the biplane method of disks from two-dimensional apical fourchamber and two-chamber views and was used to calculate the LV ejection fraction (LVEF; defined as reduced if
Giovanni Cioffi1 · Ombretta Viapiana2 · Federica Ognibeni2 · Andrea Dalbeni2 · Davide Gatti2 · Silvano Adami2 · Carmine Mazzone3 · Giorgio Faganello3 · Andrea Di Lenarda3 · Maurizio Rossini2 1 Department of Cardiology, Villa Bianca Hospital, Trento, Italy 2 Division of Rheumatology, Department of Medicine, University and Azienda Ospedaliera Universitaria
Integrata of Verona, Verona, Italy 3 Cardiovascular Center, Health Authority n° 1 and University of Trieste, Trieste, Italy
Prevalence and factors related to left ventricular systolic dysfunction in asymptomatic patients with rheumatoid arthritis A prospective tissue Doppler echocardiography study The higher mortality rate of patients with rheumatoid arthritis (RA) has been linked tocardiovascular (CV) disease [1–3]. Patients with RA have a chronic inflammatory state of the vascular system, accelerated atherosclerotic processes, increased arterial stiffness, and changes in left ventricular (LV) geometry. All these conditions, which have been detected and described by several authors in patients with RA without overt cardiac disease and analyzed in primary prevention [4–10], may predispose these patients to LV systolic dysfunction (LVSD). While it has been well established that vascular involvement and changes in LV geometry arise at the onset of the disease, there are conflicting data on the existence of an asymptomatic phase of cardiac disease in these patients, in which subclinical LVSD develops and heralds adverse CV events [10– 17]. Furthermore, no information is available on the potential role of RA per se as a clinical condition promoting LVSD in addition to the traditional CV risk factors. LVSD can be reliably detected by assessing mitral annular peak systolic velocity (S’) withtissue Doppler pulsed-wave spectral imaging, which estimates the systolic
function of longitudinal LV myocardial fibers and has emerged as one of the most powerful prognosticators for CV disease in the realm of noninvasive cardiac imaging [18–24]. Using this echocardiographic technique, we prospectively studied a large cohort of patients with RA without presence or history of symptoms of cardiac disease with the aim of testing the hypotheses (1) that the condition of “subclinical LVSD” is widely present in these subjects and (2) that RA per se is an independent prognosticator of LVSD. We also assessed the clinical and echocardiographic factors related to LVSD in patients with RA.
Methods Study population Study participants were 198 adults with RA diagnosed after clinical and laboratory examination. They were recruited from 1 January 2014 to 31 June 2014 in three Italian referral centers (Verona, Trieste, Trento) where they underwent echocardiographic, clinical, and laboratory evaluations. All subjects were free of symptoms
and clinical signs of cardiac disease. Exclusion criteria were: a history of myocardial infarction, myocarditis, or heart failure; coronary heart disease diagnosed by clinical and electrocardiographic evaluation at rest and by the results of exercise/scintigraphy/echo-stress testing; alcoholic cardiomyopathy; primary hypertrophic cardiomyopathy; asymptomatic known LVSD; prior myocardial revascularization; significant valvular heart disease; atrial fibrillation.
Control groups The first control group, comprising 132 healthy subjects, who had normal blood pressure, serum glycemic levels, lipid profile, normal echocardiographic findings (including LV mass, geometry, wall motion, and ejection fraction) and who did not receive any medical treatment, was identified with the sole reason of assessing the range of normal values of S’ to define LVSD (for details, see “Echocardiography” section). These 132 subjects were statistically comparable with those enrolled in the study for age, sex, and body mass index according to the following Herz
1
Original Article Table 1 Main clinical characteristics of the 198 study patients with rheumatoid arthritis Variables Clinical Age (years) Female gender (%) Body mass index (kg/m2) Hypertension (%) Dyslipidemia (%) Diabetes (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (bpm) Laboratory Glycemia (mg/dl) Hemoglobin (gr/dl) GFR (ml/min/1.73m2) GFR 300 mg/g) (%) C-reactive protein (mg/l) Rheumatoid factor positive (%) Cyclic citrullinated peptide positive (%) Pharmacological treatment Beta-blockers (%) ACEi/ARB (%) Diuretics (%) Calcium antagonists (%) Anti-platelet agents (%) Statins (%) NSAIDs (%) Methotrexate (%) Hydroxychloroquine (%) Immunomodulatory and anticytotoxic agents (%) Corticosteroids (%)
Rheumatoid arthritis patients (n = 198)
Healthy controls (n = 132)
61 ± 12 71 25.8 ± 4.7 53 46 11 134 ± 17 82 ± 9 70 ± 10
61 ± 16 63 25.2 ± 4.2 0 0 0 130 ± 13 81 ± 6 68 ± 9
99 ± 36 13.7 ± 1.4 92 ± 25 8 209 [179–238] 116 [95–138] 104 [76–164] 6 6.0 [1.5–7.3] 53 44
85 ± 4 14.6 ± 1.7 81 ± 15 0 232 [177–295] 164 [133–196] 103 [51–225] 0 2.9 [0.9–6.7] -
19 36 20 13 22 28 32 50 12 60
-
47
-
ACEi angiotensin-converting enzyme inhibitors, ARB angiotensin T1 receptor blockers, GFR glomerular filtration rate, LDL low-density lipoprotein, NSAIDs nonsteroidal anti-inflammatory drugs.
procedure: a Gower’s generalized distance from each healthy individual and each RA patient was computed and all patients were ranked in ascending order in the database. The distance was calculated using these variables ordered as follows: age, gender, body mass index. The 132 healthy controls and 198 RA patients were then demarcated and coupled by taking for every three close patients with RA the two closest controls (selected by a pool of 186 patients). Subsequently, the 198 patients with RA were compared with a second control
2
Herz
group, composed of 198 patients without RA, matched for age, sex, body mass index, and prevalence of hypertension and diabetes by the same statistical procedure described above. The 198 controls were designated by taking for every one close patient with RA the one closest control. These subjects were selected from a pool of 257 patients at Villa Bianca Hospital who consecutively underwent clinical and echocardiographic evaluations for CV risk assessment in primary prevention during the same period of enrollment as the patients with RA.
All patients gave written informed consent and the study was approved by the ethicscommittees in all participating centers. The study protocol conforms to the ethical guidelines of the Declaration of Helsinki as revised in 2000.
Echocardiography All Doppler echocardiographic studies were performed using an Alpha Esaote unit (Florence, Italy) equipped with a 2.5– 3.5-MHz annular-array transducer by experienced cardiologists who followed a standardized protocol. Images were stored on CD or MO disks and forwarded to the Echocardiography Core Laboratory at Villa Bianca Hospital of Trento, Italy, for final interpretation. Sonographers (GC, FO) were blinded to the clinical data. LV chamber dimensions and wall thicknesses were measured using the American Society of Echocardiography guidelines and LV mass was calculated using a validated formula [25]. LV mass was normalized for height to the 2.7 power and LV hypertrophy was defined as LV mass ≥ 49.2 g/m2.7 for men and ≥ 46.7 for women [26]. Relative wall thickness was calculated as the ratio of the 2* end-diastolic posterior wall thickness to LV diameter and indicated concentric LV geometry if ≥ 0.43 (the 97.5th percentile in a normal population) [27]. LV end-diastolic and end-systolic volumes and stroke volume were measured by the biplane method of disks from two-dimensional apical fourchamber and two-chamber views and was used to calculate the LV ejection fraction (LVEF; defined as reduced if
