Subclinical systolic and diastolic myocardial dysfunction in polyphasic polymyositis/dermatomyositis: a 2-year longitudinal study

Thrity hospitalized PM/DM patients (23/7) were consecutively enrolled with mean age of 42.3±1.6 years (27/3 female/male) without cardiovascular symptoms. Traditional echocardiography and TDI were performed to measure systolic and diastolic echocardiographic variables at the time of diagnosis, 3 months and 2 years later. All patients met the Bohan and Peter [17] and/or 2017 EULAR/ACR classification criteria for definitive PM or DM [1]. Patients presented with malignancy, overlap syndromes, previously diagnosed congenital heart disease, rheumatic fever, hypertension, coronary artery disease, atrial fibrillation, mitral regurgitation exceeding moderate severity, diabetes mellitus, cardiomyopathy, severe renal disease (serum creatinine level≥130 μmol/l) or anaemia (hemoglobine≤13.5 g/dl in male, ≤12.0 g/dl in female) were excluded. Characteristics of the first 3 months of treatment were published earlier [13]. During the follow-up period, 2 female patients were excluded from the study, one had new ECG abnormalities (RV strain signs) with PM/SSc overlap syndrome and pulmonary hypertension; moreover, breast cancer occurred in the other patient baseline results represent the 3 months data of the 28 remaining patients. On the basis of the disease progress, the patients were classified into two groups: monophasic (n=16) and polyphasic (n=12) groups. Patients with monophasic disease course did not experience disease flare and could adhere to steroid tapering, whereas patients with polyphasic disease course experienced disease relapse during the follow-up period. Echocardiographic findings were compared in the different groups and to an age- and sex-matched healthy control group (n=26).

High-resolution computed tomography of the lungs was performed to investigate radiographic abnormalities [pulmonary infections, fibrosis, tuberculosis, and interstitial lung disease (ILD)]. Autoimmune panel (anti-dsDNA, anti-SRP, anti-Scl-70, and myositis profile 3 Blot Strip: Ro52, OJ, EJ, Pl-12, Pl-7, SRP, anti-Jo1, PM-Scl75, PM-Scl100, Ku, and Mi-2B) was performed at the diagnosis and was re-evaluated during the follow-up by membrane-fixed line blots (Euroline Myositis Antigen Profile4, EuroImmun, Lübeck, Germany) according to manufacturer’s instructions.

Traditional echocardiographic measurements and TDI were performed at the time of the diagnosis and at the end of the follow-up period. Transthoracic echocardiography was performed using an ultrasound equipment (Accuson Sequoia) with a 1–5-MHz transducer. All measurements were performed in adherence with the guidelines and standards of the European Society of Echocardiography [18] by a single observer blinded to patient/control status. All measurements were taken on 3 consecutive beats, and the mean values were used. The study protocol was approved by the Ethics Committee of the University of Debrecen (28192/2011-EKU) and written informed consent was obtained from each participant. The study was conducted according to the Declaration of Helsinki (2000).

Left atrial (LA) diameter, left ventricular (LV) end-diastolic (LVEDD) and LV end-systolic diameters (LVESD), thickness of the interventricular septum (IVS), and right atrial (RA) and right ventricular (RV) diameters were measured using 2D and M-mode echocardiography based on the criteria of the European Society of Echocardiography [18].

LV systolic function was characterized both by conventional echocardiographic and TDI parameters. Left ventricular ejection fraction (EF) was assessed according to the biplane Simpson’s method [18]. This method calculates LV volumes by tracing the endocardial borders in apical 4- and 2-chamber views in end-diastole and end-systole. Mitral annular plane systolic excursion (MAPSE) measured in M-mode characterizes the longitudinal function of the left ventricle, and it is an accurate predictor of EF. MAPSE was calculated by placing M-mode cursor through the mitral annulus in a standard apical 4-chamber window and measuring the difference between end-diastolic and end-systolic amount of longitudinal motion of the annulus. The peak myocardial systolic velocity (s) of the lateral site of the mitral annulus (lateral s′) obtained by the TDI method was also used for the evaluation of the LV systolic function.

Mitral inflow velocities were evaluated by pulsed wave Doppler imaging with the sample volume placed at the tip of the mitral leaflets that can be seen on the apical 4-chamber view. Deceleration time of the E wave (DT), peak early (E) and peak late diastolic transmitral flow velocities (A) were measured to calculate the ratio of peak E to peak A velocities (E/A) for the characterization of the diastolic function. The early myocardial diastolic velocity (e′) and the late myocardial diastolic velocity (a′) measured at the lateral site of the mitral annulus by the TDI method are also indices of left ventricular diastolic function, and E/e′ ratio can be applied for the estimation of left ventricular filling pressure.

RV function was calculated according to the fractional area change (FAC: end-diastolic RV area – end-systolic RV area/end-systolic RV area). Tricuspid annular plane systolic excursion (TAPSE) was measured by M-mode to calculate the longitudinal function of the right ventricle. TAPSE was calculated by placing M-mode cursor through the tricuspid annulus in a standard apical 4-chamber window and measuring the difference between the end-diastolic and end-systolic amount of longitudinal motion of the annulus. TDI data were obtained from the tricuspid annulus measuring peak myocardial systolic velocity (tricuspid s′), early myocardial diastolic velocity (tricuspid e′) and late myocardial diastolic velocity (tricuspid a′). Systolic pulmonary artery pressure (sPAP) was calculated from the maximal tricuspid regurgitation velocity and the estimated RA pressure [18].

Data of 28 IIM patients were evaluated, who completed the study. Table 1 shows the demographic, clinical, and serological characteristics of the patients. The mean age at diagnosis was 41.9 ± 1.6 years, the female/male ratio was 25/3. Autoimmune profile confirmed at the time of the diagnosis with myositis profile 3 Blot Strip (anti-Jo 1: 6/28, anti-PM/Scl-100: 1/28, anti-PM-scl-75: 3/28) was re-evaluated with line blot assay (Euroline Myositis Antigen Profile4) and we could detect 4 new autoantibody positivity (1 anti-Mi2, 1 anti-TIF1γ, 2 anti-NXP2). New therapy was released during the 24 months as follows: methotrexate in 5 cases, cyclophosphamide in 2 cases and rituximab in 2 cases; however, steroid was administered in 100% of the cases. The mean blood pressure (130/78 mmHg) was slightly higher at the end of the follow-up period, compared to baseline and control; hence, 7/28 patients had mild hypertension at the end of the study. New-onset diabetes could not be detected during the follow-up period.

The results of the echocardiographic parameters during the follow-up are presented in Table 2. The right atrial (RA: 29.9±0.5 mm, 30.5±0.7 mm, 31.9±1.1 mm, 29.9±0.8 mm) and right ventricular dimensions (RV1: 25.6±0.3 mm, 26.7±0.8 mm, 26.8±1.3 mm, 27.8±1.4 mm; RV2: 26.0±0.7 mm, 25.2±0.7 mm, 28.1±2.4 mm, 27.2±1.1 mm; RV3: 55.6±1.1 mm, 57.3±1.8 mm, 56.5±2.4 mm, 50.3±2.8 mm; RVSA: 9.4±0.3 cm², 11.0±0.8 cm², 9.3±0.4 cm², 9.3±0.5 cm²; RVDA: 17.1±1.1 cm², 16.5±0.6 cm², 16.6±0.7 cm², 17.3±0.9 cm²; control, baseline, monophasic, polyphasic, respectively) were in the normal range and did not change compared either to the controls or to the baseline during the follow-up. LV diameters were also in the normal range. We could not detect any significant changes in LVESD (30.0±0.9 mm, 28.2±0.8 mm, 34.6±2.4 mm, 30.3±1.4 mm; control, baseline, monophasic, polyphasic, respectively), or in the LVEDD (49.3±1.0 mm, 47.1±1.1 mm 44.0±1.8 mm, 50.3±1.4 mm; control, baseline, monophasic, polyphasic, respectively).

Global systolic function of the LV was characterized by the traditionally used parameter, the EF measured by the Simpson’s method. We detected a significantly impaired LVEF in both subgroups at the end of the follow-up compared to the controls (Table 2; Fig. 1); however, it was more pronounced in the polyphasic group where it was significantly lower than the baseline or the monophasic group (62.6±0.6%, 60.9±0.9%, 58.1±0.6%, 51.7±0.7%; control, baseline, monophasic, polyphasic, respectively). The longitudinal left ventricular systolic motion (MAPSE) assessed by M-mode decreased significantly during the 2 years in patients with polyphasic disease patterns compared to the baseline and the control group (18.5±0.6 mm, 18.0±0.7 mm, 17.7±1.0 mm, 14.5±0.6 mm; control, baseline, monophasic, polyphasic, respectively). LV systolic function measured by the TDI method showed major changes: the mitral lateral systolic velocity (lateral s′) was significantly lower in both subgroups at 2 years than at the time of the diagnosis; moreover, the polyphasic group was found to have a remarkable decreased s′ velocity (10.4±0.3 cm/s, 8.6±0.4 cm/s, 8.6±0.4 cm/s, 6.4±0.4 cm/s; control, baseline, monophasic, polyphasic, respectively). The above findings confirm a subclinical left ventricular dysfunction in both subgroups at the end of our study, which could also be detected by the TDI method at the beginning of the disease progress (Fig. 1).

LV diastolic function was evaluated by the characterization of the transmitral inflow Doppler pattern (E/A, DT) and the TDI measurement of the lateral segment of the LV myocardium (lateral e′ and lateral a′ velocities) (Table 2, Fig. 2). Any diastolic abnormalities could not be detected at baseline; however, a grade I diastolic dysfunction appeared both in the monophasic and polyphasic group: significantly lower E/A ratio, a longer DT were measured in the polyphasic and the monophasic group compared to the controls and the baseline timepoint (E/A ratio: 1.33±0.02, 1.32±0.1, 0.84±0.06, 0.68±0.04; DT: 144.7±3.2 msec, 158.3±5.7 msec, 182.8±15.4 msec, 190.8±7.6 msec; control, baseline, monophasic, polyphasic, respectively). Accordingly, the early diastolic lateral myocardial velocity (lateral e′) decreased (12.9±0.2 cm/s, 12.3±0.6 cm/s, 8.7±0.9 cm/s, 7.4±0.3 cm/s; control, baseline, monophasic, polyphasic, respectively) and the late diastolic myocardial velocity (lateral a′) increased significantly in the two disease groups at the end of the follow-up period (10.7±0.3 cm/sec, 11.1±0.8 cm/s, 15.4±1.2 cm/s, 17.3±0.8 cm/s; control, baseline, monophasic, polyphasic, respectively). E/e′ ratio - calculated from the mitral inflow E velocity and the TDI lateral e′ velocity is commonly used to estimate the LV filling pressure. The E/e′ ratio was significantly higher in both groups compared to the controls and the baseline (5.8±0.2, 5.0±0.2, 8.7±0.6, 9.0±0.4; control, baseline, monophasic, polyphasic, respectively). These results show that diastolic dysfunction (grade I – impaired relaxion) appears both in the monophasic and polyphasic groups (Fig. 2). Larger LA diameter supports a further impairment of the diastolic function in the polyphasic group (32.1±0.6 mm, 32.2±0.7 mm, 33.3±0.8 mm, 37.8±0.6 mm; control, baseline, monophasic, polyphasic, respectively).

FAC, TAPSE and the tricuspid systolic velocity (tricuspid s′) were used to characterize RV function. At baseline attenuated FAC and tricuspid s′ velocities could be measured showing a depressed global RV systolic function (FAC: 45.6±1.8%, 37.0±1.5%, 41.0±1.6%, 32.7±1.4%; tricuspid s′: 13.1±0.3 cm/s, 9.6±0.4 cm/s, 9.3±0.5 cm/s, 7.8±0.2 cm/s; control, baseline, monophasic, polyphasic, respectively); however, the longitudinal RV systolic function was similar to the control group (TAPSE: 22.7±0.5 mm, 22.3±0.7 mm, 21.3±0.7 mm, 18.1±0.3 mm; control, baseline, monophasic, polyphasic, respectively). RV systolic function did not decline further in the monophasic group at the end of the follow-up period; however, an additional deterioration was detected in the polyphasic group as demonstrated by the further decline in each systolic RV parameters. Additionally, an RV diastolic dysfunction was also found in the three disease groups which was the most pronounced in the polyphasic subgroup, characterized by the decrease in the tricuspid early diastolic velocity (tricuspid e′: 13.3±0.5 cm/s, 10.7±0.6 cm/s, 9.4±0.7 cm/s, 7.2±0.3 cm/s; control, baseline, monophasic, polyphasic, respectively) and the increase in the tricuspid late diastolic velocity (tricuspid a': 11.5±0.4 cm/s, 14.6±0.9 cm/s, 14.3±0.9 cm/s, 15.1±0.7 cm/s; control, baseline, monophasic, polyphasic, respectively), similarly as observed in the left heart. These findings present a subclinical RV systolic dysfunction (FAC, TAPSE, tricuspid s′) and a RV diastolic dysfunction (tricuspid e′, a′) which was the most severe in the polyphasic group at the end of the study (Fig. 3). We could not detect any direct, or indirect echocardiographic signs of pulmonary hypertension, in either group (data not shown).