scholarly journals Interleukin-1 and Systemic Sclerosis: Getting to the Heart of Cardiac Involvement

2021 ◽  
Vol 12 ◽  
Author(s):  
Giacomo De Luca ◽  
Giulio Cavalli ◽  
Corrado Campochiaro ◽  
Cosimo Bruni ◽  
Alessandro Tomelleri ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Myocardial Fibrosis ◽  
Cardiac Involvement ◽  
Interleukin 1 ◽  
Inflammasome Activation ◽  
High Morbidity ◽  
Prognostic Features ◽  
Heart Involvement ◽  
Targeted Inhibition

Systemic sclerosis (SSc) is rare, severe connective tissue disease characterized by endothelial and vascular damage, immune activation, and resulting in inflammation and fibrosis of skin and internal organs, including the heart. SSc is associated with high morbidity and mortality. Cardiac involvement is frequent in SSc patients, even though often asymptomatic at early stages, and represents one of the major causes of SSc-related mortality. Heart involvement has a variable clinical presentation, and its pathogenesis is not completely understood. Myocardial fibrosis is traditionally considered the immunopathologic hallmark of heart involvement in SSc. This unique histological feature is paralleled by distinctive clinical and prognostic features. The so-called “vascular hypothesis” represents the most credited hypothesis to explain myocardial fibrosis. More recently, the prominent role of an inflammatory myocardial process has been identified as a cardinal event in the evolution to fibrosis, thus also delineating an “inflammation-driven pathway to fibrosis”. The pro-inflammatory cytokine interleukin (IL)-1 has an apical and cardinal role in the myocardial inflammatory cascade and in cardiac dysfunction. The primary aim of this perspective article is: to present the emerging evidence on the role of IL-1 and inflammasome in both SSc and heart inflammation, to review the complex interplay between cellular metabolism and inflammasome activation, and to discuss the rationale for targeted inhibition of IL-1 for the treatment of SSc-heart involvement, providing preliminary experimental and clinical data to support this hypothesis.

Subclinical progression of systemic sclerosis-related cardiomyopathy

2020 ◽  
Vol 27 (17) ◽  
pp. 1876-1886
Author(s):  
Giulia Stronati ◽  
Lucia Manfredi ◽  
Alessia Ferrarini ◽  
Lucia Zuliani ◽  
Marco Fogante ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Systemic Sclerosis ◽  
Speckle Tracking ◽  
Cardiac Involvement ◽  
Global Longitudinal Strain ◽  
Prospective Longitudinal Study ◽  
Heart Involvement ◽  
Increased Risk ◽  
Prospective Longitudinal

Aims Cardiac involvement in patients with systemic sclerosis (SSc) is frequent and represents a negative prognostic factor. Recent studies have described subclinical heart involvement of both the right ventricle (RV) and left ventricle (LV) via speckle-tracking-derived global longitudinal strain (GLS). It is currently unknown if SSc-related cardiomyopathy progresses through time. Our aim was to assess the progression of subclinical cardiac involvement in patients with SSc via speckle-tracking-derived GLS. Methods This was a prospective longitudinal study enrolling 72 consecutive patients with a diagnosis of SSc and no structural heart disease nor pulmonary hypertension. A standard echocardiographic exam and GLS calculations were performed at baseline and at follow-up. Results Traditional echocardiographic parameters did not differ from baseline to 20-month follow-up. LV GLS, despite being already impaired at baseline, worsened significantly during follow-up (from –19.8 ± 3.5% to –18.7 ± 3.5%, p = .034). RV GLS impairment progressed through the follow-up period (from –20.9 ± 6.1% to –18.7 ± 5.4%, p = .013). The impairment was more pronounced for the endocardial layers of both LV (from –22.5 ± 3.9% to –21.4 ± 3.9%, p = .041) and RV (–24.2 ± 6.2% to –20.6 ± 5.9%, p = .001). A 1% worsening in RV GLS was associated with an 18% increased risk of all-cause death or major cardiovascular event ( p = .03) and with a 55% increased risk of pulmonary hypertension ( p = .043). Conclusion SSC-related cardiomyopathy progresses over time and can be detected by speckle-tracking GLS. The highest progression towards reduced deformation was registered for the endocardial layers, which supports the hypothesis that microvascular dysfunction is the main determinant of heart involvement in SSc patients and starts well before overt pulmonary hypertension.

FRI0439 The Role of the Myeloid Inflammatory Bone Marrow Compartment in Onset and Progression of Myocardial Fibrosis in Systemic Sclerosis

2015 ◽  
Vol 74 (Suppl 2) ◽  
pp. 586.1-586
Author(s):  
V. Haunerdinger ◽  
E. Pachera ◽  
R. Dobrota ◽  
P. Blyszczuk ◽  
O. Distler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Systemic Sclerosis ◽  
Myocardial Fibrosis

scholarly journals Myocardial native T1 mapping and correlations with clinical and CMR parameters in patients with systemic sclerosis

2021 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
A Meloni ◽  
L Gargani ◽  
C Bruni ◽  
C Cavallaro ◽  
M Gobbo ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Myocardial Fibrosis ◽  
Healthy Subjects ◽  
T1 Mapping ◽  
Cardiac Involvement ◽  
Left Ventricular ◽  
Volume Index ◽  
Imaging Protocol ◽  
Native T1 ◽  
Spin Echo Sequence

Abstract Funding Acknowledgements Type of funding sources: None. Background Systemic sclerosis (SSc) is a connective tissue disease characterized by diffuse vascular lesions and fibrosis, also affecting the heart. Cardiovascular magnetic resonance (CMR) can detect replacement myocardial fibrosis by late gadolinium enhancement (LGE) and interstitial myocardial fibrosis/edema by T1 mapping techniques. Purpose To evaluate the prevalence of cardiac involvement by native T1 mapping and its correlation with clinical and CMR parameters in SSc patients. Methods Fifty-one consecutive SSc patients (mean age 51.8 ± 13.7 years, 42 females) and 51 healthy subjects matched for age and sex underwent clinical, bio-humoral assessment, and CMR at 1.5T (Signa Artist, GE Healthcare ). The imaging protocol included: cine, T1 mapping by MOLLI, T2 mapping by multi-echo fast-spin-echo sequence, LGE, and STIR T2-weighted sequences. Native T1 and T2 values were assessed in all 16 myocardial segments and the global value was the mean. Results. Global native T1 values were significantly higher in SSc patients than in healthy subjects (1076.4 ± 50.7 vs 1033.3 ± 31.9 ms; P < 0.0001). As in healthy subjects, in patients native T1 values were significantly lower in males than in females (1033.4 ± 38.3 vs 1085.6 ± 48.6 ms; P = 0.004) and inversely correlated with age (R=-0415; P = 0.002). Twenty-three (45.1%) patients had an increased global heart T1 value (>1060 ms in males and >1085 ms in females). Of them, 14 patients (60.9 %) showed positive LGE. Frequency of cardiovascular risk factors, indices of disease activity and chronicity, biochemical parameters, and cardio-active therapy were comparable between patients with normal and elevated T1. Compared to patients with normal T1 value, patients with elevated T1 had significantly higher left ventricular (LV) end-diastolic volume index (76.8 ± 13.3 vs 69.2 ± 11.8, P = 0.050), LV stroke volume index (49.7 ± 6.4 vs 44.4 ± 6.9 ml/m2; P = 0.010), LV cardiac output (3.6 ± 0.5  vs 3.0 ± 0.6 l/min /m2; P < 0.0001), and global heart T2 values (60.1 ± 3.6 vs 55.7 ± 3.1 ms; P < 0.0001). Replacement myocardial fibrosis was detected in 24 (47.1%) patients and they showed significantly higher global heart native T1 values (Figure 1A). Positive T2-weighted images for myocardial oedema were found in 5 (9.8%) patients, all with increased global heart native T1 value. Patients with oedema had significantly higher native global heart T1 values (Figure 1B). Conclusion Elevated native T1 values measured by CMR are frequent in SSc patients and they are associated with inflammation, replacement fibrosis, and increased LV dimension. CMR T1 mapping seems to be a sensitive parameter to include in the routine clinical assessment of SSc patients for detecting earlier pejorative cardiac involvement, although prospective data are recommended. Abstract Figure.

scholarly journals Early detection of ventricular dysfunction in juvenile systemic sclerosis by speckle tracking echocardiography

Rheumatology ◽  
2020 ◽  
Vol 60 (1) ◽  
pp. 103-107
Author(s):  
Giovanni Civieri ◽  
Biagio Castaldi ◽  
Giorgia Martini ◽  
Alessandra Meneghel ◽  
Ornella Milanesi ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Speckle Tracking ◽  
Cardiac Involvement ◽  
Ventricular Dysfunction ◽  
Speckle Tracking Echocardiography ◽  
Global Longitudinal Strain ◽  
Laboratory Data ◽  
Left Ventricular ◽  
Juvenile Systemic Sclerosis

Abstract Objective Cardiac involvement is the most important cause of mortality in juvenile systemic sclerosis (JSSc). Recent reports in adult patients underline that traditional techniques of imaging are inadequate to assess the subclinical cardiac involvement, while speckle tracking echocardiography (STE) is able to identify ventricular dysfunctions in the early stages. The aim of our study was to assess the role of STE in JSSc. Methods Demographic, clinical and laboratory data were collected from patients with JSSc. Cardiac investigations performed at baseline (T0) and 18 (T18) and 36 months (T36) follow-up included electrocardiography, conventional echocardiography with measurement of the ejection fraction (EF) and STE with assessment of left and right ventricular global longitudinal strain (LV-GLS and RV-GLS). Cardiac parameters have been compared with demographic characteristics and disease severity, assessed by the Juvenile Systemic Sclerosis Severity Score (J4S). Results A total of 18 patients, 12 (67%) females, entered the study. At T0, electrocardiography was abnormal in three patients, EF was reduced in one, LV-GLS was abnormal in three (16.7%) and RV-GLS was abnormal in five (27.8%). At T18, EF remained stable while at T36 the result decreased in seven of nine patients. At the same time, LV-GLS also worsened (from −21.6% to −18.2%, P = 0.01). LV-GLS and RV-GLS at baseline showed a significant correlation with J4S (P = 0.012 and P = 0.02, respectively). Conclusion STE is more sensitive than standard echocardiography to identify cardiac involvement in JSSc. Over time, we observed a gradual worsening of LV-GLS, a sign of left ventricular dysfunction, that anticipated by several months the decrease of EF.

scholarly journals Nonessential Role for the NLRP1 Inflammasome Complex in a Murine Model of Traumatic Brain Injury

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Thomas Brickler ◽  
Kisha Gresham ◽  
Armand Meza ◽  
Sheryl Coutermarsh-Ott ◽  
Tere M. Williams ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Murine Model ◽  
Motor Behavior ◽  
Interleukin 1 ◽  
Inflammasome Activation ◽  
Wild Type ◽  
Nucleotide Binding Domain

Traumatic brain injury (TBI) elicits the immediate production of proinflammatory cytokines which participate in regulating the immune response. While the mechanisms of adaptive immunity in secondary injury are well characterized, the role of the innate response is unclear. Recently, the NLR inflammasome has been shown to become activated following TBI, causing processing and release of interleukin-1β(IL-1β). The inflammasome is a multiprotein complex consisting of nucleotide-binding domain and leucine-rich repeat containing proteins (NLR), caspase-1, and apoptosis-associated speck-like protein (ASC). ASC is upregulated after TBI and is critical in coupling the proteins during complex formation resulting in IL-1βcleavage. To directly test whether inflammasome activation contributes to acute TBI-induced damage, we assessed IL-1β, IL-18, and IL-6 expression, contusion volume, hippocampal cell death, and motor behavior recovery inNlrp1−/−,Asc−/−, and wild type mice after moderate controlled cortical impact (CCI) injury. Although IL-1βexpression is significantly attenuated in the cortex ofNlrp1−/−andAsc−/−mice following CCI injury, no difference in motor recovery, cell death, or contusion volume is observed compared to wild type. These findings indicate that inflammasome activation does not significantly contribute to acute neural injury in the murine model of moderate CCI injury.

Systemic sclerosis myocarditis has unique clinical, histological and prognostic features: a comparative histological analysis

Rheumatology ◽  
2020 ◽  
Vol 59 (9) ◽  
pp. 2523-2533 ◽  
Author(s):  
Giacomo De Luca ◽  
Corrado Campochiaro ◽  
Maria De Santis ◽  
Silvia Sartorelli ◽  
Giovanni Peretto ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Magnetic Resonance ◽  
Systemic Sclerosis ◽  
Magnetic Resonance ◽  
Myocardial Fibrosis ◽  
Endomyocardial Biopsy ◽  
Cardiac Complications ◽  
Prognostic Features ◽  
Number Of Patients

Abstract Objective To outline the clinical, histological and prognostic features of systemic sclerosis (SSc) endomyocardial biopsy-proven myocarditis with respect to those of diverse endomyocardial biopsy-proven virus-negative myocarditis (VNM). Methods We retrospectively analysed data from three cohorts of endomyocardial biopsy-proven myocarditis: SSc-related VNM (SSc-VNM); isolated VNM (i-VNM); and VNM related to other systemic autoimmune diseases (a-VNM). The degree of myocardial fibrosis was expressed as relative percentage and fibrotic score (0–3). Clinical data, cardiac enzymes, echocardiogram, 24 h ECG Holter and cardiac magnetic resonance were obtained at baseline and during follow-up. Non-parametric tests were used. Results We enrolled 12 SSc-VNM [11 females, mean age 49.3 (14.2) years; seven diffuse-SSc, five early-SSc], 12 i-VNM [12 females, mean age 47.7 (10.8) years] and 10 a-VNM [four females, mean age 48.4 (16.3) years] patients. SSc patients had higher degrees of myocardial fibrosis as assessed by both percentage [SSc-VNM: 44.8 (18.8)%; a-VNM: 28.6 (16.5)%; i-VNM: 24.9 (10.3)%; P = 0.019] and score [SSc-VNM: 2.3 (0.8); a-VNM: 1.4 (1.1); i-VNM: 1.2 (0.7); P = 0.002]. Myocardial fibrosis directly correlated with skin score (r = 0.625, P = 0.03) and number of ventricular ectopic beats on 24 h ECG Holter in SSc patients (r = 0.756, P = 0.01). Dyspnoea class was higher at presentation in SSc-VNM patients (P = 0.041) and we found heart failure only in SSc patients (25%) (P = 0.05). At cardiac magnetic resonance, myocardial oedema was nearly undetectable in SSc-VNM patients compared with others (P = 0.02). All patients received immunosuppressive treatment. The number of patients who died during follow-up due to cardiac complications was significantly higher in SSc-VNM patients (50%), as compared with a-VNM (0%) and i-VNM (8.3%) patients (P = 0.006). Patients who died during follow-up had higher degrees of myocardial fibrosis [52.2 (11.6)% vs 27.5 (12.9)%, P = 0.024; fibrotic score: 2.83 (0.41) vs 1.4 (0.9), P < 0.001]. Conclusion SSc has unique clinical and histological features, as it tends to present more frequently with heart failure and a higher dyspnoea class and to show higher degrees of myocardial fibrosis. These specific features are paralleled by a worse cardiac prognosis.

scholarly journals AB0575 THE ROLE OF LONG-TERM AND INTENSIVE IV ILOPROST TREATMENT IN REDUCTION OF PULMONARY ARTERY PRESSURE AND PRO-BRAIN NATRIURETIC PEPTIDE (PBNP) IN SCLERODERMA PATIENTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1584.3-1584
Author(s):  
R. Foti ◽  
E. Visalli ◽  
G. Amato ◽  
A. Benenati ◽  
S. Bellofiore ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Cardiac Involvement ◽  
Alveolar Volume ◽  
Skin Score ◽  
Pulmonary Arterial

Background:Systemic sclerosis (SSc) is a chronic immune-mediated connective tissue disease with heterogeneous organ involvement that reduces the life expectancy of this patients. In particular cardiopulmonary manifestations, such as pulmonary arterial hypertension (PAH), are currently the primary cause of death and stabilizing this condiction may represent an important therapeutic goal (1,2). An increased NT-proBNP is predictors of PAH in SSc and use this markers should result in improved PAH risk stratification (3)Some studies have suggested the role of intravenous iloprost in preventing the incidence of most severe vascular complications in long term treated patients (4).Objectives:The aim of our study is to evaluate the evolution of the disease, with particular focus on cardiopulmonary function, in a group of consecutive patients chronically treated with iloprost at the Rheumatology Unit of Catania Hospital, Italy, from 2006 to 2019.Methods:68 SSc patients (58F, 52.88 ± 12.6 years). At baseline, 67.6%, 25% and 5.9% had a limited, diffuse and early scleroderma type respectively and 20,6% had interstitial lung disease. The follow-up period of the study was of 9.9 ± 2.9 years. Iloprost was administered with a regimen of 6 infusions per month (6 hours/day, 0.5-2.0 ng/kg/min) to treat secondary Raynaud’s phenomenon (RP), diagnosed at an average age of 46.6 ± 13.7 years. We evaluated: skin score (SS), systolic pulmonary arterial pressure (PAPs), plane tricuspid annular systolic excursion (TAPSE), lung diffusing capacity of carbon monoxide (DLCO), forced vital capacity (FVC), alveolar volume (VA), DLCO/VA, pro-brain natriuretic peptide (pBNP), and NYHA class.We analyzed the patients as a whole group (68 subjects), as a group who continued the treatment (57 subjects) and as a group who stopped the treatment during the follow-up (11 patients).Results:After the long follow up period in the study (almost 10 years) in the whole group of patients, PAPs and pBNP showed statistically significant improvement from baseline (30.91 ± 6.4 vs 27.36 ± 7.1 and 97.20 ± 69.3 vs 66.65 ± 44.3 respectively, p < 0.0001 for both) while the other parameters showed no significant changes: SS (4.70 ± 5.3 vs 3.86 ± 4.2 mm), TAPSE (22.07 ± 2.4 vs 22.06 ± 3.8 mm), DLCO (83.68 ± 13.5 vs 77.70 ± 14.6 mmol/kPa.min), FVC (107.09 ± 14.5 vs 107.72 ± 18.7 liters), VA (91.12 ± 13 vs 90.30 ± 14.4 liters), DLCO/VA (88.48 ± 13.5 vs 89.5 ± 16.3) and NYHA class (1.0 ± 0.0 vs 1.0 ± 0.0). A subgroup analysis indicated a significant improvement in addition to PAPs and pBNP also for skin score for 57 patients who continued the treatment (5.09 ± 5.7 vs 3.30± 4.2, p < 0.0001) and a significant worsening of this parameter as early as the first year of suspension (p <0.05 year 1, p<0.01 year 2 and 3) in 11 patients who stopped the treatment.Conclusion:Cardiac involvement is recognised as a poor prognostic factor among systemic sclerosis (SSc) patients, significantly to mortality and N-TproBNP peptide may represent a surrogate marker for cardiac involvement in SSc, selectively identifying patients with severe impairment of cardiac function. Our intensive (6 infusions/month) and chronic regimen of iv iloprost administration seems improve the long-term evolution of disease in SSc patients, as suggested by the improvement of cardiopulmonary parameters and the significant improvement of SS.References:[1]Rheumatology 51, 1027-36 2) Best Pract Res Clin Rheumatol.32, 223-240 3) Arthritis Rheum. 2008 58, 284-9 4) Rheumatol Int 2012;32:1933-8.Disclosure of Interests:Rosario Foti Consultant of: lilly, sanofi, MSD, Janssen, Abbvie, BMS, celgene, roche, Speakers bureau: lilly, sanofi, MSD, Janssen, Abbvie, BMS, celgene, roche, elisa visalli Consultant of: lilly, sanofi, MSD, Janssen, Abbvie, BMS, celgene, roche, Speakers bureau: lilly, sanofi, MSD, Janssen, Abbvie, BMS, celgene, roche, Giorgio Amato: None declared, Alessia Benenati: None declared, Salvatore Bellofiore: None declared, Massimiliano Mule’: None declared, Marcella Di Gangi: None declared

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