The Effect of Hematopoietic Stem Cell Transplantation on Cardiac Mechanics in Systemic Sclerosis

doi:10.21203/rs.3.rs-3959904/v1

Purpose

Systemic sclerosis (SSc) is an autoimmune disease that causes inflammation and fibrosis. Cardiac involvement in SSc is often subclinical and portends a worse prognosis. Autologous hematopoietic stem cell transplant (HSCT) improves survival in SSc but its effect on cardiac function is unknown. This study aimed to assess HSCT’s effect on cardiac mechanics in SSc.

Methods

Participants with SSc were identified from a prospective registry, and grouped according to the receipt of HSCT between 2009 and 2018. The HSCT cohort underwent comprehensive conventional and speckle-tracking echocardiography (STE) pre- and post-HSCT. The non-HSCT cohort received echocardiograms within a similar time frame. Baseline and follow-up clinical and echocardiographic variables were compared within and between groups.

Results

The HSCT cohort (n = 88) was older (59±6 versus 51±11 years, p = 0.002) and more female-predominant (95% vs 75%, p = 0.049) compared to the non-HSCT cohort (n = 20). HSCT recipients showed improved right ventricular (RV) strain globally (18.1±3.9% versus 20.0±4.5%, p < 0.001) and within the RV free wall (20.7±5.3% versus 23.2±5.6%, p < 0.001). While left ventricular (LV) strain did not change, left atrial (LA) reservoir strain improved (35.9±8.7% versus 47.8±11.4%, p < 0.001) and LA stiffness index (0.24±0.12 versus 0.18±0.08, p < 0.001) decreased post-HSCT. No longitudinal changes in STE measures were observed among the non-HSCT cohort. Between-group analysis demonstrated a significant association between HSCT and change in LA reservoir strain (p = 0.002) at follow-up.

Conclusions

RV and LA mechanics significantly improve after HSCT among patients with SSc. This suggests a favorable effect of HSCT on the underlying myocardial pathology caused by SSc.

speckle-tracking strain echocardiography

systemic sclerosis

right ventricle

left atrium

Systemic sclerosis (SSc) is a multisystem autoimmune disorder characterized by vascular dysfunction and progressive fibrosis of the skin and internal organs that causes significant morbidity and mortality in affected individuals. SSc can cause a spectrum of cardiac abnormalities starting early in the disease course, including right ventricular (RV) and left ventricular (LV) systolic and diastolic dysfunction, microvascular coronary disease, arrythmias, and pericardial disease [1]. The prevalence of cardiac involvement in SSc is reported to be 20–25% [2], but is challenging to estimate due to myriad possible manifestations and the variability in the modalities used to diagnose them. Autopsy studies in SSc, however, show much greater prevalence of myocardial fibrosis or pericardial disease implying that the majority of cardiac involvement in SSc is subclinical [3]. Since clinically evident cardiac disease in SSc has a poor prognosis [4], the early identification of cardiac disease and its response to therapy is of paramount importance.

Novel imaging methods such as strain-based imaging, which measures myocardial deformation, have enhanced our ability to identify subclinical cardiac dysfunction. Speckle-tracking echocardiography (STE) is the most widely used technique for assessing strain by quantitatively analyzing the displacement of speckles that track with myocardial motion during the cardiac cycle [5]. LV strain is more sensitive than conventional 2D echocardiography (2DE) in measuring abnormal LV mechanics [6, 7]. Left atrial (LA) strain is a more sensitive marker for identifying LV diastolic function [8] and, notably, LA strain parameters are impaired in patients with SSc despite normal diastolic function by 2DE metrics [9, 10]. Similarly, numerous studies show that RV strain is important in detecting subclinical RV abnormalities in SSc patients not detected by conventional measures of RV function [11].

Autologous hematopoietic stem cell transplant (HSCT) significantly improves event-free survival and quality of life in SSc compared to traditional immunosuppressant therapy [12–14], however, the effects of this treatment on cardiac function have not been studied. This study thus investigated the effect of HSCT on cardiac mechanics in SSc patients using comprehensive echocardiography with 2DE and STE. We hypothesize that HSCT will significantly improve cardiac mechanics in this patient population.

Study Design and Patient Population

All participants with SSc who presented to a single academic institution from 2009–2018 and enrolled in a prospective registry were considered for this study. Detailed inclusion and exclusion criteria for participants undergoing HSCT and the HSCT protocol have previously been described [15, 16]. Specifically, participants were ineligible for HSCT if they had SSc-associated pulmonary arterial hypertension (PAH), LV ejection fraction < 45%, severe unrevascularized coronary artery disease, untreated severe arrhythmia, constrictive pericarditis or hemodynamically significant pericardial effusion [17]. The participants were included in this study if they were eligible for HSCT and received comprehensive 2DE evaluation at both baseline and follow up timepoints. The non-HSCT cohort was comprised of eligible SSc participants from the above-mentioned registry who did not undergo HSCT and had echocardiograms within a similar time frame. This study was approved by the institutional review board of Northwestern University (Chicago, IL, USA). All study participants provided informed consent prior to enrollment.

Clinical Characteristics

Clinical characteristics of each participant in this study were collected from review of medical records. All participants met either 1980 or 2013 American College of Rheumatology classification criteria for SSc [18, 19]. Duration of disease was defined as the time from establishment of SSc diagnosis to initiation of HSCT therapy. Right heart catheterization was performed for each participant prior to HSCT as part of the cardiac evaluation protocol. The modified Rodnan skin score (mRSS) was used to monitor the severity of skin involvement and served as a general marker of disease severity [20]. The mRSS was obtained in the outpatient visit closest to the time of HSCT and at the first outpatient visit following HSCT, within one month when echocardiograms were obtained.

Transthoracic Echocardiography

Two echocardiograms were selected for analysis for each participant. For the HSCT group, baseline was defined as the most recent echocardiogram prior to HSCT and follow-up as the first echocardiogram after the hospitalization encounter for HSCT. For the non-HSCT group, baseline was defined as the first echocardiogram following SSc diagnosis and follow-up as the echocardiogram nearest to one-year post-baseline. Transthoracic echocardiography was performed with a standardized protocol using commercially available ultrasound systems (GE Medical Systems, Milwaukee, Wisconsin and IE33 Phillips Medical Systems, Andover, Massachusetts). All echocardiographic parameters and myocardial strain analysis were performed following the recommendations of the American Society of Echocardiography and European Association of Cardiovascular Imaging [21, 22]. Speckle tracking software was utilized to measure LV, RV and LA myocardial strain (TomTec, Unterschleissheim, Germany).

LV, RV and LA myocardial strain were pre-specified primary measure of interest in our study. LV global longitudinal strain (LVGLS) was obtained using a semi-automated algorithm. LV global circumferential strain (LVGCS), RV global (RVGLS), free-wall (RVFWS) longitudinal strain, and LA reservoir strain were measured manually (Fig. 1). The accuracy of endocardial border tracking was optimized manually, and segments were excluded if unable to be satisfactorily tracked. Participants were excluded if there was a foreshortened chamber, suboptimal visualization, and/or inadequate tracking of two or more segments.

For ease of interpretation, all strain values were reported as absolute values (higher absolute strain values indicate better cardiac mechanics). The ratio of E/e’ to LA reservoir strain was used to non-invasively estimate LA stiffness [23]. Abnormal cutoffs for LV and RV strain parameters were based on American Society of Echocardiography guidelines [21]. Abnormal cutoff for LA reservoir strain was defined as < 39% and LV GCS as < 22.3% based on recent studies [24, 25].

Statistical Analysis

Continuous variables were expressed as mean±standard deviation (SD) if normally distributed, or median (interquartile range [IQR]) if not, and categorical variables were expressed as counts and percentages. Between group comparisons at baseline were tested with two-sample t-test, Wilcoxon rank-sum test, or chi-squared test as appropriate. Longitudinal changes were similarly compared using paired Student’s t test, Wilcoxon signed-rank test, or McNemar’s test. Normality was assessed through a combination of visual inspection, skewness and kurtosis assessment, and the Shapiro-Wilk test.

ANCOVA models were used to evaluate the association of HSCT treatment with differences in changes in strain and clinical measures adjusted for baseline values. Models were additionally adjusted for age, gender, race, and comorbidities. Intra- and inter-observer variability for all strain measures were assessed in 15 randomly selected participants (Supplemental Table 1). Interobserver analysis was performed by having the same observer repeat the analysis 8 months apart. Reproducibility was reported using intraclass correlation coefficient. Statistical analysis was performed using Stata version 12 (StataCorp, College Station, TX) and GraphPad Prism 8 (GraphPad Software, CA). Two-sided p values of < 0.05 were considered significant.

Baseline clinical characteristics

One hundred and fourteen participants from the registry were included in the study. Two participants who underwent HSCT and four participants who did not undergo HSCT were excluded from the final analysis due to poor image quality for STE analysis. A majority (90%) of participants had diffuse SSc and nearly all (99%) were on immunosuppressant therapy prior to HSCT (Table 1). The median (IQR) time between diagnosis of SSc and HSCT was 2.7 (1.5-6.4) years. Compared to HSCT recipients, participants in the non-HSCT cohort were older (59±6 versus 51±11 years, p<0.01), had higher systolic blood pressure, and lower frequency of seropositivity to antinuclear antibody and anti-topoisomerase. Patients in the non-HSCT group were more likely to have a history of coronary artery disease, diabetes mellitus, hyperlipidemia, and were taking concurrent cardiovascular medications, including ACEi/ARB, diuretics, beta-blockers and phosphodiesterase inhibitors.

Among patients who received HSCT, the mean pulmonary artery pressure (mPAP) measured prior to HSCT was 18.4±4.4 mmHg, and 27 (31%) participants had a mPAP greater than 20 mmHg (Supplemental Table 2). Four patients had a mPAP greater than 25 mmHg but were deemed to have post-capillary pulmonary hypertension with elevated left-sided filling pressures and normal pulmonary vascular resistance, and thus were considered appropriate for HSCT.

Table 1. Baseline clinical characteristics of 108 study participants by HSCT status.

Clinical characteristics, No. (%)	HSCT (N=88)	Non-HSCT (N=20)	P-value¹
Age, years, mean±SD	51±11	59±6	<0.01
Female gender	66 (75)	19 (95)	0.05
Race			0.89
Caucasian	67 (76)	14 (70)
African American	10 (11)	3 (15)
Other	11 (13)	3 (15)
Body mass index, kg/m², mean±SD	24±5	25±5	0.41
Heart rate, beats/min, mean±SD	84±14	86±15	0.56
Systolic blood pressure, mmHg, mean±SD	110±15	118±14	0.03
Diastolic blood pressure, mmHg, mean±SD	69±10	70±11	0.64
Hemoglobin, g/dL, mean±SD	12.0±1.7	12.5±1.5	0.20
BNP, pg/mL, median (IQR)	35 (20-70)	42 (22-97)	0.27
mRSS, median (IQR)	21 (13-34)	14 (10-25)	0.05
SSc characteristics and Seropositivity
Diffuse cutaneous SSc	79 (90)	17 (85)	0.54
Antinuclear antibody	86 (98)	16 (80)	<0.01
Anti-RNA polymerase III	30 (34)	9 (45)	0.36
Anti-topoisomerase I	32 (36)	2 (10)	0.02
Anti-centromere	5 (6)	0 (0)	0.27
Comorbidities/Cardiovascular risk factors
Coronary artery disease	2 (2)	3 (15)	0.02
Systemic arterial hypertension	9 (10)	5 (25)	0.08
Diabetes mellitus	1 (1)	2 (10)	0.03
Hyperlipidemia	7 (8)	8 (40)	<0.01
Smoking history	18 (20)	6 (30)	0.35
Medications
Calcium channel blockers	26 (30)	10 (50)	0.08
ACEi/ARB	18 (20)	19 (95)	<0.01
Diuretics	11 (13)	8 (40)	<0.01
Beta-blockers	3 (3)	5 (25)	<0.01
Phosphodiesterase inhibitors	13 (15)	8 (40)	0.01
Prostacyclin receptor agonists	1 (1)	0 (0)	0.63
Endothelin receptor antagonists	2 (2)	2 (10)	0.10
Mycophenolate mofetil	70 (80)	17 (85)	0.58
Prednisone	59 (67)	9 (45)	0.07
Methotrexate	47 (53)	3 (15)	<0.01
Cyclophosphamide	25 (28)	2 (10)	0.09
Hydroxychloroquine	16 (18)	3 (15)	0.74
Biologics or other	16 (18)	1 (5)	0.14
Intravenous Immunoglobulin	11 (13)	2 (10)	0.76
Azathioprine	11 (13)	2 (10)	0.76
Rituximab	14 (16)	1 (5)	0.20
D-penicillamine	1 (1)	0 (0)	0.63

Abbreviations: ACEi: angiotensin-converting enzyme inhibitors; ARB: aldosterone receptor antagonists; BNP: brain natriuretic peptide; HSCT: hematopoietic stem cell transplant; mRSS: modified Rodnan skin score; RNA: ribonucleic acid; SSc: systemic sclerosis.

¹Two-sample t-test, Wilcoxon sum rank test, or chi-squared test as appropriate.

Baseline echocardiographic characteristics

The pre-HSCT echocardiogram was performed a median (IQR) of 2 (1-4) months before HSCT. The median (IQR) time between diagnosis of SSc and baseline echocardiogram was 2.4 (1.3-6) years for the HSCT group, and 0.9 (0.2-1.6) years for the non-HSCT group. At baseline, all mean values of conventional echocardiography measures were within the normal range for both the HSCT and non-HSCT groups, and there were no significant differences in these measures between the groups (Table 2). In the HSCT group, 56% of these patients had abnormal LV GLS, 22% had abnormal LV GCS, 48% had abnormal RV FWS, and 70% had abnormal LA reservoir strain. In the non-HSCT group, 55% had abnormal LV GLS, 30% had abnormal LV GCS, 30% had abnormal RV FWS, and 35% had abnormal LA reservoir strain.

Follow-up echocardiographic findings

The follow-up echocardiographic evaluation was performed a median of 12 (6-14) months after HSCT. Among those patients who did not receive HSCT, the follow-up echocardiographic evaluation was performed a median of 12 (10-13) months after baseline. At follow-up, significant differences were noted in several conventional echocardiographic measures in both groups (Table 2). However, the absolute difference was small, and all follow-up measures remained in the normal range.

Among strain parameters, both RVGLS and RVFWS significantly improved post-HSCT. Regionally, the improvement was observed in the mid (20.4±9.5% vs 23.7±8.0%, p=0.04) and apical segments (15.3±8.6% vs 20.9±9.0%, p<0.01) of the RV free wall, but not in the basal segment. LA reservoir strain also improved (35.9±8.7% vs 47.8±11.4%, p<0.01) and LA stiffness index decreased from 0.24 to 0.18 (p<0.01). No significant changes were observed in LVGLS or LVGCS after HSCT. In the patients who did not receive HSCT, no significant changes in strain parameters were observed.

Table 2. Echocardiographic and clinical measures of 108 study participants by HSCT status.

Echocardiography variables, mean±SD	HSCT (N=88)			Non-HSCT (N=20)
Echocardiography variables, mean±SD	Baseline	Follow-Up	P-value¹	Baseline	Follow-Up	P-value²	P-value³
Left Ventricle
End-diastolic diameter index, cm/m²	2.51±0.30	2.47±0.32	0.14	2.46±0.25	2.54±0.32	0.28	0.52
IVS thickness, cm	0.89±0.18	0.90±0.18	0.68	0.96±0.25	0.93±0.19	0.62	0.18
Posterior wall thickness, cm	0.92±0.16	0.93±0.17	0.51	0.92±0.22	0.93±0.18	0.87	0.97
Mass index, g/m²	74.7±22.0	74.1±21.7	0.82	75.5±25.3	77.3±24.2	0.60	0.88
Ejection Fraction, %	61.7±5.3	61.0±6.9	0.37	62.6±5.2	59.9±5.5	0.02	0.49
GLS, %	18.7±4.4	19.0±3.4	0.61	19.8±3.8	19.2±3.8	0.34	0.31
GCS, %	26.4±7.1	25.7±6.8	0.49	24.5±7.7	25.2±6.1	0.54	0.29
Left Atrium
Volume index, ml/m²	24.7±8.3	24.2±7.2	0.64	24.8±6.6	25.2±10.9	0.88	0.95
Septal mitral annular e’ velocity, cm/sec	10.1±3.0	9.3±2.8	0.01	9.2±2.0	8.4±2.2	0.25	0.22
Lateral mitral annular e’ velocity, cm/sec	12.2±3.4	11.5±3.4	0.03	11.8±2.5	10.4±2.3	0.09	0.64
Transmitral Doppler E/A ratio	1.4±0.5	1.2±0.4	0.01	1.3±0.3	1.4±0.4	0.66	0.57
E/e’	8.0±2.4	8.3±2.6	0.30	8.2±1.6	10.3±3.1	0.04	0.73
Stiffness index	0.24±0.12	0.18±0.08	<0.01	0.21±0.07	0.29±0.19	0.06	0.21
Reservoir strain, %	35.9±8.7	47.8±11.4	<0.01	43.2±12.5	40.9±11.3	0.31	<0.01
Right Atrium
Right atrial area, cm²	13.3±3.8	13.4±4.5	0.78	12.6±4.1	13.6±3.8	0.20	0.45
Right Ventricle
Basal diameter, cm	3.6±1.1	3.4±0.6	0.13	3.5±0.7	3.7±0.7	0.36	0.78
End-diastolic area, cm²	16.7±5.5	17.5±4.9	0.01	18.1±5.6	19.2±4.4	0.31	0.34
End-systolic area, cm²	9.6±3.9	9.7±3.7	0.21	10.9±3.4	11.7±3.6	0.26	0.16
Fractional area change, %	43.0±11.8	44.8±11.0	0.25	39.2±8.4	39.9±9.7	0.79	0.17
TAPSE, cm	2.2±0.4	2.1±0.4	<0.01	2.4±0.6	2.3±0.6	0.26	0.13
Tricuspid annular S’ velocity, cm/sec	12.8±1.9	12.0±2.2	<0.01	12.2±2.4	13.0±2.9	0.91	0.27
TR velocity, cm/sec	2.4±0.4	2.3± 0.6	0.31	2.6±0.5	2.9±0.8	0.22	0.05
Pericardial effusion, No. (%)	12 (14)	10 (11)	0.62	2 (10)	4 (20)	0.63	0.66
GLS, %	18.1±3.9	20.0±4.5	<0.01	19.9±4.5	19.5±4.9	0.73	0.07
Free Wall Strain, %	20.7±5.3	23.2±5.6	<0.01	23.2±5.4	23.1±5.3	0.97	0.07
Free Wall Strain Segments
Basal, %	27.9±9.4	28.0 ± 7.9	0.94	29.0±7.7	28.5±9.7	0.76	0.63
Mid, %	20.4±9.5	23.7 ± 8.0	0.04	23.0±7.0	22.2±5.3	0.62	0.27
Apical, %	15.3±8.6	20.9 ± 9.0	<0.01	15.7±8.7	18.0±10.0	0.42	0.89
Clinical outcome measures
mRSS, median (IQR)	21 (13-34)	9 (4-20)	<0.01	14 (10-25)	10 (8-23)	0.01	0.01

Abbreviations: A: late diastolic mitral inflow velocity; E: early diastolic mitral inflow velocity; e’: early diastolic mitral annulus velocity; FWS: free wall strain; GCS: global circumferential strain; GLS: global longitudinal strain; IVS: interventricular septum; mRSS: modified Rodnan skin score; TAPSE: tricuspid annular plane systolic excursion; TR: tricuspid regurgitation.

¹Paired t-test, McNemar’s test or Wilcoxon sum rank test as appropriate comparing baseline and follow-up measures of the HSCT group.

²Paired t-test, McNemar’s test or Wilcoxon sum rank test as appropriate comparing baseline and follow-up measures of the non-HSCT group.

³Two-sample t-test or chi-squared test as appropriate comparing baseline measures of the HSCT and non-HSCT group.

Comparison of echocardiographic changes between HSCT and non-HSCT patients

Among participants who received HSCT, there was a 9.70 (95% CI [3.80, 15.61], p<0.01) unit increase in LA reservoir strain at follow-up compared to those who did not receive HSCT after controlling for baseline measures. After additional adjustment for age, sex, race, and comorbidities, HSCT therapy remained significantly associated with an improvement in LA reservoir strain at follow-up. There were no significant between-group differences observed for changes in RV and LV strain (Table 3 and Figure 2).

Strain parameters and clinical outcomes

Among the HSCT recipients, mRSS decreased, reflecting an improvement in symptom burden (21 [13-34] at baseline to 9 [4-20] follow up, p<0.01). Among participants who did not undergo HSCT and were only treated with conventional immunosuppressant therapies, mRSS was lower at baseline compared to the HSCT recipients, but still improved at follow up (14 [10-25] at baseline to 10 [8-23] follow up, p=0.01, Table 2). However, the between-group analysis demonstrated that there was an improvement of a 6 (95% CI [2.36, 9.61], p<0.01) unit reduction in mRSS at follow up in participants who received HSCT compared to those who did not after adjustment for baseline mRSS (Table 3). There was no significant correlation between change in strain parameters and change in mRSS (Supplemental Table 3).

Table 3. Association between treatment status and change in mRSS or strain parameters.

	Baseline Strain		HSCT Treatment
	β coefficient (95% CI)	P-value	β coefficient (95% CI)	P-value
ANCOVA¹
mRSS	-0.34 (-0.46, -0.22)	<0.01	-5.98 (-9.61, -2.36)	<0.01
LVGLS	-0.61 (-0.76, -0.47)	<0.01	0.25 (-1.31, 1.80)	0.75
LVGCS	-0.64 (-0.80, -0.47)	<0.01	-0.15 (-3.23, 2.93)	0.92
RVGLS	-0.68 (-0.90, -0.47)	<0.01	1.17 (-1.05, 3.39)	0.30
RVFWS	-0.72 (-0.92, -0.52)	<0.01	0.81 (-1.91, 3.52)	0.56
LA reservoir strain	-0.67 (-0.91, -0.44)	<0.01	9.70 (3.80, 15.61)	<0.01
Demographic Adjusted²
mRSS	-0.33 (-0.46, -0.20)	<0.01	-6.38 (-11.16, -1.60)	0.01
LVGLS	-0.63 (-0.78, -0.47)	<0.01	0.52 (-1.33, 2.37)	0.58
LVGCS	-0.65 (-0.83, -0.48)	<0.01	1.44 (-2.15, 5.02)	0.43
RVGLS	-0.67 (-0.91, -0.44)	<0.01	1.17 (-1.43, 3.77)	0.37
RVFWS	-0.70 (-0.91, -0.49)	<0.01	1.22 (-1.97, 4.40)	0.45
LA reservoir strain	-0.66 (-0.90, -0.42)	<0.01	8.03 (1.15, 14.90)	0.02

Abbreviations: FWS: free wall strain; GCS: global circumferential strain; GLS: global longitudinal strain; LA: left atrium; LV: left ventricle; mRSS: modified Rodnan skin score; RV: right ventricle.

¹ANCOVA models evaluate the effect of HSCT on the change in strain adjusted for baseline measures.

²Demographic adjusted models were additionally adjusted for age, gender, race and comorbidities.

In this study of SSc participants without SSc-associated PAH, we found a significant improvement in RV and LA reservoir strain post-HSCT among SSc participants who underwent HSCT. This improvement did not occur in those who did not undergo HSCT. On further analysis, improvement in LA reservoir strain was independently associated with HSCT after adjustment for baseline strain, age, gender, race, and comorbidities. To our knowledge, this is the first study to investigate the effects of HSCT on cardiac function in patients with SSc.

Myocardial strain characteristics in SSc

Myocardial strain is a more sensitive marker than conventional parameters of cardiac function and is more conducive to study in SSc with its high prevalence of subclinical cardiac disease. Previous studies have shown abnormal strain metrics in SSc patients despite normal conventional 2DE measures of LV, RV, and LA size and function. The baseline LVGLS and LA reservoir strain in our study cohort are similar to prior studies, which are lower than in healthy controls [6, 7, 9-11]. In previous studies, the reported average RVFWS has ranged from 17-19% [7, 11],however, our study cohort had an average RVFWS that was more robust (20.7±5.3% among the HSCT recipients and 23.2±5.4% among the non-HSCT group at baseline). This could potentially be explained by nuanced selection criteria for HSCT, variabilities in vendor platforms for strain analysis and a shorter disease course of our study cohort (a median disease duration of 2.7 years in our study versus an average of 6-15 years in previous studies) [7, 11].

Cardiac mechanics post-HSCT among HSCT recipients

Our study showed that HSCT was associated with significant improvement in RVGLS and RVFWS among the HSCT recipients despite no clinically significant changes in conventional 2DE parameters of RV function. There is a predominant focus on RV involvement in SSc particularly in the context of SSc-associated PAH [26]. However, global RV systolic function can be impaired in SSc patients even in the absence of PAH. Our results add to the mounting evidence for occult, intrinsic RV myocardial dysfunction in SSc patients with normal pulmonary pressure [1, 11, 26]and offers HSCT as a potentially disease-modifying therapy [27].

There are likely regional differences in ventricular involvement in SSc. Mukherjee et al. identified a heterogenous pattern of RV dysfunction with RVFWS being preserved in the basal segment and diminished in the mid and apical segments and hypothesized that the basal segment of the RV free wall may initially serve as the primary vector of RV contraction [11]. They also found augmentation in the mid and apical segments, but not in the basal segment, with exercise in SSc patients, demonstrating myocardial reserve in these segments [28]. Our study complemented these findings by showing preferential improvement in strain in the mid and apical segments of the RV free wall following HSCT. This might also explain the overall improvement in RV strain despite the decrease in conventional 2DE RV function parameters such as TAPSE and S’ which only measure the basal segment of the RV. Strain provided a more nuanced assessment of myocardial activity than conventional 2DE measures.

Our results also showed a significant improvement in LA reservoir strain associated with HSCT despite no significant change in LA volumes or echocardiographic estimates of LV filling pressure. This is consistent with previous studies examining echocardiographic changes in patients with SSc where LA reservoir strain was diminished despite normal LA volumes [9]. This, again, reflects the sensitivity of strain imaging to identify subclinical disease and myocardial alterations that might occur with therapeutic interventions.

Despite the significant improvement in RV and LA strain measures associated with HSCT in our study cohort, we did not observe a significant change in LV strain measures after HSCT. While there were significant changes in some conventional measures of LV function, the absolute changes were small and not clinically significant. The absence in improvement in LV function may be explained by minimal LV involvement in this carefully selected cohort as demonstrated by normal left-sided filling pressures, normal LVGLS and LVGCS at baseline, and normal cardiac biomarker profiles. Porpaczy et al found that LVGLS became impaired only after disease duration approached 7 years [10]. This is also supported by data from MRI studies that have identified an association between disease duration and degree of late gadolinium enhancement (LGE, a marker of myocardial fibrosis) within the LV myocardium [29]. Our study cohort has a distinctly shorter disease duration and may thus only harbor subclinical LV involvement in its earliest stages that has not reached a threshold for a treatment effect to manifest.

Participants who did not undergo HSCT did not have improved strain

There was no improvement in any strain measures among participants who did not undergo HSCT in the same time frame. Both cohorts have comparable baseline strain measures except that participants who did not undergo HSCT had a significantly higher baseline LA reservoir strain. In the between-group analysis after adjustment for baseline strain, we observed a significant association between HSCT and the improvement in LA reservoir strain at follow-up, but no associations were observed between HSCT and RV or LV strain. This offers the possibility that HSCT was associated with improved LA mechanics that were not achieved by immunotherapies alone.

Potential mechanistic explanation for improved myocardial strain post-HSCT

We propose that reduction in the burden of myocardial fibrosis and improvement in myocardial performance as a potential mechanistic explanation for improved RV and LA strain measures post-HSCT. Tedford and colleagues have previously described in- and ex-vivo sarcomeric dysfunction in the RV in SSc-associated PAH and it is possible HSCT may aid in reversing these pathologic processes [26, 30]. In our study, improvement in LA reservoir strain was accompanied by improvement in LA stiffness among HSCT recipients, which was not observed in those who did not receive HSCT. Since myocardial fibrosis is the hallmark for the pathogenesis of SSc [31, 32], we hypothesize that this could represent a direct reduction in LA fibrosis and subclinical reverse atrial remodeling with HSCT. The absence of LV improvement post-HSCT may also represent the subtle changes in fibrosis were more apparent in thin-walled RV and LA than the thicker LV. Further research of myocardial fibrosis post-HSCT, for example, with the use of LGE imaging, may provide further mechanistic insight.

Change in cardiac mechanics are not associated with clinical outcome

There was no significant association between myocardial strain and clinical outcome as measured by the mRSS score. It is not surprising that the improvement in subclinical cardiac abnormalities in these patients is not directly associated with the decrease in skin fibrosis. Further study is needed to examine whether the improvement in cardiac mechanics is associated with improved quality of life and/or a decrease in adverse cardiac events.

Limitation

Our study has several limitations. First, this study was a case-control study of participants in a registry. Participants were not randomized by nature of this study design. Residual confounding may persist despite statistical adjustment and the associations identified in this study cannot prove causation. The HSCT group was carefully selected for receiving HSCT. HSCT was not pursued by the non-HSCT group due to physicians’ choice of alternative immunosuppressive therapy and patient refusal. As a result, there were some significant differences with the non-HSCT group in its baseline clinical and echocardiographic features. These differences could potentially limit the interpretation of between-group results due to selection bias. In addition, this is a single-center study. Although HSCT procedures are standard, each center follows a local protocol which can introduce potential inter-center variability. The ability to perform speckle-tracking analysis is largely dependent on 2D image quality and, while we were able to perform strain analysis on the majority of study participants (LVGLS, 89%; LVGCS, 93%; RV strain, 97%; LA strain, 98%), we had to exclude a few participants due to poor image quality. Additionally, there was limited follow-up for clinical outcomes in this study cohort as this was a referral population to our institution and we were thus unable to obtain longitudinal morbidity and mortality data for study participants. Regression to the mean must be considered when making inferences with our findings. Finally, our findings are not generalizable to SSc patients who have PAH or overt cardiac dysfunction.

Our study shows significant improvement in RV and LA cardiac mechanics following HSCT in patients with SSc. These results offer insight into processes that are operative in the absence of overt cardiac dysfunction and may serve as a future therapeutic target in this patient population.

2DE = 2D echocardiography

FWS = free wall strain

GCS = global circumferential strain

GLS = global longitudinal strain

HSCT = autologous hematopoietic stem cell transplant

mRSS = modified Rodnan skin score

PAH = pulmonary arterial hypertension

QOL = quality of life

SSc = systemic sclerosis

STE = speckle-tracking echocardiography

Author Contribution

C.C., A.N. and B.F. wrote the main manuscript text. C.C., A.N., E.L., W.S., J.G. performed primary data collection. C.C., A.N., and A.B. performed data analysis. All authors reviewed the manuscript.

Acknowledgement: none

Source of funding: none

Disclosures:

SJS is supported by research grants from the National Institutes of Health (U54 HL160273, R01 HL140731, R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GSK, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. There are no relationships with industry for all other authors.

Rangarajan V, Matiasz R, Freed BH: Cardiac complications of systemic sclerosis and management: recent progress. Curr Opin Rheumatol 2017, 29(6):574-584. DOI: 10.1097/BOR.0000000000000439
Champion HC: The heart in scleroderma. Rheum Dis Clin North Am 2008, 34(1):181-190; viii. DOI: 10.1016/j.rdc.2007.12.002
Ross L, Prior D, Proudman S, Vacca A, Baron M, Nikpour M: Defining primary systemic sclerosis heart involvement: A scoping literature review. Semin Arthritis Rheum 2019, 48(5):874-887. DOI: 10.1016/j.semarthrit.2018.07.008
Elhai M, Meune C, Boubaya M, Avouac J, Hachulla E, Balbir-Gurman A, Riemekasten G, Airo P, Joven B, Vettori S et al: Mapping and predicting mortality from systemic sclerosis. Ann Rheum Dis 2017, 76(11):1897-1905. DOI: 10.1136/annrheumdis-2017-211448
Dandel M, Lehmkuhl H, Knosalla C, Suramelashvili N, Hetzer R: Strain and strain rate imaging by echocardiography - basic concepts and clinical applicability. Curr Cardiol Rev 2009, 5(2):133-148. DOI: 10.2174/157340309788166642
Mele D, Censi S, La Corte R, Merli E, Lo Monaco A, Locaputo A, Ceconi C, Trotta F, Ferrari R: Abnormalities of left ventricular function in asymptomatic patients with systemic sclerosis using Doppler measures of myocardial strain. J Am Soc Echocardiogr 2008, 21(11):1257-1264. DOI: 10.1016/j.echo.2008.08.004
Karadag DTSTTSI, O. O.; Yazici A.; Eraldemir, F. C.; Cefle A.: Evaluation of left and right ventricle by two-dimensional speckle tracking echocardiography in systemic sclerosis patients without overt cardiac disease. Clin Rheumatol 2020, 39(1):37-48. DOI: 10.1007/s10067-019-04604-3
Thomas L, Marwick TH, Popescu BA, Donal E, Badano LP: Left Atrial Structure and Function, and Left Ventricular Diastolic Dysfunction: JACC State-of-the-Art Review. J Am Coll Cardiol 2019, 73(15):1961-1977. DOI: 10.1016/j.jacc.2019.01.059
Agoston G, Gargani L, Miglioranza MH, Caputo M, Badano LP, Moreo A, Muraru D, Mondillo S, Moggi Pignone A, Matucci Cerinic M et al: Left atrial dysfunction detected by speckle tracking in patients with systemic sclerosis. Cardiovasc Ultrasound 2014, 12:30. DOI: 10.1186/1476-7120-12-30
Porpaczy A, Nogradi A, Kehl D, Strenner M, Minier T, Czirjak L, Komocsi A, Faludi R: Impairment of Left Atrial Mechanics Is an Early Sign of Myocardial Involvement in Systemic Sclerosis. J Card Fail 2018, 24(4):234-242. DOI: 10.1016/j.cardfail.2018.02.012
Mukherjee MM, V.; Tedford, R. J.; Shah, A. A.; Hsu, S.; Mullin, C. J.; Sato, T.; Damico, R.; Kolb, T. M.; Mathai, S. C.; Hassoun, P. M.: Right ventricular longitudinal strain is diminished in systemic sclerosis compared with idiopathic pulmonary arterial hypertension. Eur Respir J 2017, 50(5). DOI: 10.1183/13993003.01436-2017
Burt RK, Shah SJ, Dill K, Grant T, Gheorghiade M, Schroeder J, Craig R, Hirano I, Marshall K, Ruderman E et al: Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet 2011, 378(9790):498-506. DOI: 10.1016/S0140-6736(11)60982-3
van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, Schuerwegh AJ, Marijt EW, Vonk MC, Schattenberg AV et al: Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA 2014, 311(24):2490-2498. DOI: 10.1001/jama.2014.6368
Sullivan KM, Goldmuntz EA, Keyes-Elstein L, McSweeney PA, Pinckney A, Welch B, Mayes MD, Nash RA, Crofford LJ, Eggleston B et al: Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma. N Engl J Med 2018, 378(1):35-47. DOI: 10.1056/nejmoa1703327
Burt RK, Han X, Quigley K, Arnautovic I, Shah SJ, Lee DC, Freed BH, Jovanovic B, Helenowski IB: Cardiac safe hematopoietic stem cell transplantation for systemic sclerosis with poor cardiac function: a pilot safety study that decreases neutropenic interval to 5 days. Bone Marrow Transplant 2021, 56(1):50-59. DOI: 10.1038/s41409-020-0978-2
Burt RK, Oliveira MC, Shah SJ, Moraes DA, Simoes B, Gheorghiade M, Schroeder J, Ruderman E, Farge D, Chai ZJ et al: Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: a retrospective analysis. Lancet 2013, 381(9872):1116-1124. DOI: 10.1016/S0140-6736(12)62114-X
Farge D, Burt RK, Oliveira MC, Mousseaux E, Rovira M, Marjanovic Z, de Vries-Bouwstra J, Del Papa N, Saccardi R, Shah SJ et al: Cardiopulmonary assessment of patients with systemic sclerosis for hematopoietic stem cell transplantation: recommendations from the European Society for Blood and Marrow Transplantation Autoimmune Diseases Working Party and collaborating partners. Bone Marrow Transplant 2017, 52(11):1495-1503. DOI: 10.1038/bmt.2017.56
Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980, 23(5):581-590. DOI: 10.1002/art.1780230510
van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger TA, Jr., Carreira PE et al: 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum 2013, 65(11):2737-2747. DOI: 10.1002/art.38098
Clements PJ, Lachenbruch PA, Seibold JR, Zee B, Steen VD, Brennan P, Silman AJ, Allegar N, Varga J, Massa M et al: Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol 1993, 20(11):1892-1896.
Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T et al: Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015, 28(1):1-39 e14. DOI: 10.1016/j.echo.2014.10.003
Badano LP, Kolias TJ, Muraru D, Abraham TP, Aurigemma G, Edvardsen T, D'Hooge J, Donal E, Fraser AG, Marwick T et al: Standardization of left atrial, right ventricular, and right atrial deformation imaging using two-dimensional speckle tracking echocardiography: a consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging. Eur Heart J Cardiovasc Imaging 2018, 19(6):591-600. DOI: 10.1093/ehjci/jey042
Kurt M, Wang J, Torre-Amione G, Nagueh SF: Left atrial function in diastolic heart failure. Circ Cardiovasc Imaging 2009, 2(1):10-15. DOI: 10.1161/CIRCIMAGING.108.813071
Pathan F, D'Elia N, Nolan MT, Marwick TH, Negishi K: Normal Ranges of Left Atrial Strain by Speckle-Tracking Echocardiography: A Systematic Review and Meta-Analysis. J Am Soc Echocardiogr 2017, 30(1):59-70 e58. DOI: 10.1016/j.echo.2016.09.007
Sugimoto T, Dulgheru R, Bernard A, Ilardi F, Contu L, Addetia K, Caballero L, Akhaladze N, Athanassopoulos GD, Barone D et al: Echocardiographic reference ranges for normal left ventricular 2D strain: results from the EACVI NORRE study. Eur Heart J Cardiovasc Imaging 2017, 18(8):833-840. DOI: 10.1093/ehjci/jex140
Tedford RJ, Mudd JO, Girgis RE, Mathai SC, Zaiman AL, Housten-Harris T, Boyce D, Kelemen BW, Bacher AC, Shah AA et al: Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension. Circ Heart Fail 2013, 6(5):953-963. DOI: 10.1161/CIRCHEARTFAILURE.112.000008
van Rhijn-Brouwer FCC, Spierings J, van Laar JM: Autologous hematopoietic stem cell transplantation in systemic sclerosis: A reset to tolerance? Immunol Lett 2018, 195:88-96. DOI: 10.1016/j.imlet.2017.11.005
Mukherjee M, Mercurio V, Hsu S, Mayer SA, Mathai SC, Hummers LK, Kass DA, Hassoun PM, Wigley FM, Tedford RJ et al: Assessment of right ventricular reserve utilizing exercise provocation in systemic sclerosis. Int J Cardiovasc Imaging 2021, 37(7):2137-2147. DOI: 10.1007/s10554-021-02237-9
Tzelepis GE, Kelekis NL, Plastiras SC, Mitseas P, Economopoulos N, Kampolis C, Gialafos EJ, Moyssakis I, Moutsopoulos HM: Pattern and distribution of myocardial fibrosis in systemic sclerosis: a delayed enhanced magnetic resonance imaging study. Arthritis Rheum 2007, 56(11):3827-3836. DOI: 10.1002/art.22971
Hsu S, Kokkonen-Simon KM, Kirk JA, Kolb TM, Damico RL, Mathai SC, Mukherjee M, Shah AA, Wigley FM, Margulies KB et al: Right Ventricular Myofilament Functional Differences in Humans With Systemic Sclerosis-Associated Versus Idiopathic Pulmonary Arterial Hypertension. Circulation 2018, 137(22):2360-2370. DOI: 10.1161/CIRCULATIONAHA.117.033147
Belloli L, Carlo-Stella N, Ciocia G, Chiti A, Massarotti M, Marasini B: Myocardial involvement in systemic sclerosis. Rheumatology (Oxford) 2008, 47(7):1070-1072. DOI: 10.1093/rheumatology/ken186
Ntusi NA, Piechnik SK, Francis JM, Ferreira VM, Rai AB, Matthews PM, Robson MD, Moon J, Wordsworth PB, Neubauer S et al: Subclinical myocardial inflammation and diffuse fibrosis are common in systemic sclerosis--a clinical study using myocardial T1-mapping and extracellular volume quantification. J Cardiovasc Magn Reson 2014, 16(1):21. DOI: 10.1186/1532-429X-16-21

No competing interests reported.

SupplementalMaterial.docx

The Effect of Hematopoietic Stem Cell Transplantation on Cardiac Mechanics in Systemic Sclerosis

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusions

Figures

Introduction

Methods

Study Design and Patient Population

Clinical Characteristics

Transthoracic Echocardiography

Statistical Analysis

Results

Baseline clinical characteristics

Baseline echocardiographic characteristics

Follow-up echocardiographic findings

Comparison of echocardiographic changes between HSCT and non-HSCT patients

Strain parameters and clinical outcomes

Discussion

Myocardial strain characteristics in SSc

Cardiac mechanics post-HSCT among HSCT recipients

Participants who did not undergo HSCT did not have improved strain

Potential mechanistic explanation for improved myocardial strain post-HSCT

Change in cardiac mechanics are not associated with clinical outcome

Limitation

Conclusion

Abbreviations

Declarations

Author Contribution

References

Additional Declarations

Supplementary Files

Status:

Version 1