Loeffler's Endocarditis- A cause of endomyocardial fibrosis in a patient of juvenile idiopathic arthritis: A Case Report.

Endomyocardial fibrosis secondary to hyper-eosinophilic syndrome also known as Loeffler's Endocarditis is a rare cause of restrictive cardiomyopathy. If left untreated, it carries a very high morbidity and mortality rate. The case of a 20 years old girl, a known case of polyarticular juvenile idiopathic arthritis since the age of 13 years was reported at Federal Government Polyclinic Hospital, Islamabad on 14th May 2022. She presented with an acute history of shortness of breath and cough for two weeks. Her initial echocardiogram showed suspicion of Loeffler's Endocarditis, which is attributed to be an adverse effect of etanercept- a tumour necrosis factor (TNF) inhibitor, which she had been prescribed for her arthritis. The patient is currently being managed with high doses of steroids, therapeutic anticoagulation with rivaroxaban, carvedilol for tachycardia and mycophenolate mofetil as an immunosuppressant.

Endomyocardial Fibrosis: an Update After 70 Years.

PURPOSE OF REVIEW: This review aims at highlighting the need to better understand the pathogenesis and natural history of endomyocardial fibrosis when set against its changing endemicity and disease burden, improvements in diagnosis, and new options for clinical management. RECENT FINDINGS: Progress in imaging diagnostic techniques and availability of new targets for drug and surgical treatment of heart failure are contributing to earlier diagnosis and may lead to improvement in patient survival. Endomyocardial fibrosis was first described in Uganda by Davies more than 70 years ago (1948). Despite its poor prognosis, the etiology of this neglected tropical restrictive cardiomyopathy still remains enigmatic nowadays. Our review reflects on the journey of scientific discovery and construction of the current guiding concepts on this mysterious and fascinating condition, bringing to light the contemporary knowledge acquired over these years. Here we describe novel tools for diagnosis, give an overview of the improvement in clinical management, and finally, suggest research themes that can help improve patient outcomes focusing (whenever possible) on novel players coming into action.

Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype.

Aims: Acute myocardial infarction (MI) is the leading cause of mortality worldwide. Anti-inflammatory strategies to reduce neutrophil-driven acute post-MI injury have been shown to limit acute cardiac tissue damage. On the other hand, whether neutrophils are required for resolving post-MI inflammation and repair is unknown. Methods and Results: We show that neutrophil-depleted mice subjected to MI had worsened cardiac function, increased fibrosis, and progressively developed heart failure. Flow cytometry of blood, lymphoid organs and digested hearts revealed reduced numbers of Ly6Chigh monocytes in infarcts of neutrophil-depleted mice, whereas the number of macrophages increased, which was paralleled by reduced splenic Ly6Chigh monocyte mobilization but enhanced proliferation of cardiac macrophages. Macrophage subtype analysis revealed reduced cardiac expression of M1 markers, whereas M2 markers were increased in neutrophil-depleted mice. Surprisingly, we found reduced expression of phagocytosis receptor myeloid-epithelial-reproductive tyrosine kinase, a marker of reparative M2c macrophages which mediate clearance of apoptotic cells. In agreement with this finding, neutrophil-depleted mice had increased numbers of TUNEL-positive cells within infarcts. We identified neutrophil gelatinase-associated lipocalin (NGAL) in the neutrophil secretome as a key inducer of macrophages with high capacity to engulf apoptotic cells. The cardiac macrophage phenotype in neutrophil-depleted mice was restored by administration of neutrophil secretome or NGAL. Conclusion: Neutrophils are crucially involved in cardiac repair after MI by polarizing macrophages towards a reparative phenotype. Therapeutic strategies to reduce acute neutrophil-driven inflammation after MI should be carefully balanced as they might interfere with the healing response and cardiac remodelling.

Endocardial Fibrotic Lesions Have a Greater Effect on Peak Longitudinal Strain than Epicardial Fibrotic Lesions in Hypertrophic Cardiomyopathy Patients.

Peak longitudinal strain (PLS) of the left ventricular (LV) myocardium by transthoracic echocardiogram (TTE) is useful to detect LV myocardial damage. We hypothesized that myocardial fibrosis (MF) in the LV myocardium may influence PLS. Eighteen hypertrophic cardiomyopathy (HCM) patients (14 males; 58 ± 17 years old) underwent 1.5 Tesla cardiac magnetic resonance (CMR) and TTE. Patients with previous myocardial infarction were excluded. We used TTE to assess whole-layer PLS in an American Heart Association-defined 17-segment LV model. Whole-layer PLS was calculated using Echo PAC, version 113 (GE Healthcare). MF was assessed by T1-weighted CMR of the LV endocardial layer, the LV epicardial layer, or both the LV endocardial and epicardial layers for each lesion. Of the 306 segments, MF was detected in the LV endocardial layer only (13 segments), in the LV epicardial layer only (9 segments), or in both LV endocardial and epicardial layers (59 segments). PLS values were significantly lower in segments with MF affecting only the LV endocardial layer (7% ± 4%) (P < 0.05) and where MF was observed in both the LV endocardial and epicardial layers (9% ± 5%) (P = 0.001) compared with segments without MF (13% ± 7%). No significant difference in PLS values was detected between the MF segments for the LV epicardial layer only (10% ± 6%) and those without MF (13% ± 7%) (P > 0.05). In HCM patients, fibrotic lesions in the LV endocardium have a greater adverse effect on PLS than those in the LV epicardium. Our results are significant for HCM patients with fibrotic lesions within the LV endocardium.

Relationship Between Ventricular Arrhythmias, Conduction Disorders, and Myocardial Fibrosis in Patients With Systemic Sclerosis.

BACKGROUND: Delayed-enhancement magnetic resonance imaging (DE-MRI) is a noninvasive diagnostic tool able to identify myocardial fibrosis. In patients with scleroderma, its relationship with arrhythmias and conduction disorders has not been fully explored. OBJECTIVES: The aim of this study was to evaluate the possible correlations between ventricular arrhythmias, conduction disorders, and myocardial fibrosis in patients with systemic sclerosis. METHODS: Thirty-six patients with diffuse or limited cutaneous scleroderma underwent 12-lead electrocardiogram (ECG), 24-hour Holter ECG monitoring, transthoracic echocardiography, and cardiac DE-MRI, with gadolinium administration in 33 patients. RESULTS: High-quality DE-MRI scans were obtained in 30 patients. Myocardial fibrosis was detected in 25 patients (83.3%). Eighteen patients (60%) had ventricular arrhythmias or conduction disorders. There was no significant difference in ventricular arrhythmia burden (the total number of premature ventricular contractions [PVCs]/24 hours) (48 ± 304 vs. 69 ± 236, P = 0.97), ventricular arrhythmia severity (couplets, triplets, runs) on Holter ECG, or in the presence of conduction disorders (36% vs. 40%, P = 0.86) between patients with and without myocardial fibrosis. In univariate analysis, diffuse fibrosis was weakly associated with the number of PVCs/24 hours (R = 0.157, P = 0.03). A number of at least 597 PVCs/24 hours had a sensitivity of 60% and a specificity of 92% in predicting the presence of diffuse fibrosis on DE-MRI (area under the curve = 0.640). CONCLUSIONS: Delayed-enhancement magnetic resonance imaging can identify myocardial fibrosis in a high percentage of scleroderma patients. Its presence does not seem to influence the ventricular arrhythmia burden and severity or the presence of conduction disorders, with the exception of diffuse myocardial fibrosis, which modestly influences the total number of PVCs/24 hours.

Role of TGF Beta and PPAR Alpha Signaling Pathways in Radiation Response of Locally Exposed Heart: Integrated Global Transcriptomics and Proteomics Analysis.

Epidemiological data from patients undergoing radiotherapy for thoracic tumors clearly show the damaging effect of ionizing radiation on cardiovascular system. The long-term impairment of heart function and structure after local high-dose irradiation is associated with systemic inflammatory response, contraction impairment, microvascular damage, and cardiac fibrosis. The goal of the present study was to investigate molecular mechanisms involved in this process. C57BL/6J mice received a single X-ray dose of 16 Gy given locally to the heart at the age of 8 weeks. Radiation-induced changes in the heart transcriptome and proteome were investigated 40 weeks after the exposure. The omics data were analyzed by bioinformatics tools and validated by immunoblotting. Integrated network analysis of transcriptomics and proteomics data elucidated the signaling pathways that were similarly affected at gene and protein level. Analysis showed induction of transforming growth factor (TGF) beta signaling but inactivation of peroxisome proliferator-activated receptor (PPAR) alpha signaling in irradiated heart. The putative mediator role of mitogen-activated protein kinase cascade linking PPAR alpha and TGF beta signaling was supported by data from immunoblotting and ELISA. This study indicates that both signaling pathways are involved in radiation-induced heart fibrosis, metabolic disordering, and impaired contractility, a pathophysiological condition that is often observed in patients that received high radiation doses in thorax.

Baicalin Attenuates Cardiac Dysfunction and Myocardial Remodeling in a Chronic Pressure-Overload Mice Model.

BACKGROUND/AIMS: Baicalin has been shown to be effective for various animal models of cardiovascular diseases, such as pulmonary hypertension, atherosclerosis and myocardial ischaemic injury. However, whether baicalin plays a role in cardiac hypertrophy remains unknown. Here we investigated the protective effects of baicalin on cardiac hypertrophy induced by pressure overload and explored the potential mechanisms involved. METHODS: C57BL/6J-mice were treated with baicalin or vehicle following transverse aortic constriction or Sham surgery for up to 8 weeks, and at different time points, cardiac function and heart size measurement and histological and biochemical examination were performed. RESULTS: Mice under pressure overload exhibited cardiac dysfunction, high mortality, myocardial hypertrophy, increased apoptosis and fibrosis markers, and suppressed cardiac expression of PPARα and PPARß/δ. However, oral administration of baicalin improved cardiac dysfunction, decreased mortality, and attenuated histological and biochemical changes described above. These protective effects of baicalin were associated with reduced heart and cardiomyocyte size, lower fetal genes expression, attenuated cardiac fibrosis, lower expression of profibrotic markers, and decreased apoptosis signals in heart tissue. Moreover, we found that baicalin induced PPARα and PPARß/δ expression in vivo and in vitro. Subsequent experiments demonstrated that long-term baicalin treatment presented no obvious cardiac lipotoxicity. CONCLUSIONS: The present results demonstrated that baicalin attenuates pressure overload induced cardiac dysfunction and ventricular remodeling, which would be due to suppressed cardiac hypertrophy, fibrosis, apoptosis and metabolic abnormality.

Endogenous assessment of diffuse myocardial fibrosis in patients with T1ρ -mapping.

PURPOSE: Recently, it was shown that a significantly higher T1ρ is found in compact myocardial fibrosis after chronic myocardial infarction. In this study, we investigated the feasibility of native T1ρ -mapping for the detection of diffuse myocardial fibrosis in patients with dilated cardiomyopathy (DCM). MATERIALS AND METHODS: T1ρ -mapping was performed on three explanted hearts from DCM patients at 3 Tesla (T). Histological fibrosis quantification was performed, and compared with the T1ρ -relaxation times in the heart. Furthermore, twenty DCM patients underwent an MRI at 1.5T. Native T1ρ -maps, native T1 -maps, and extracellular volume (ECV)-maps were acquired. Additionally, eight healthy volunteers were scanned for reference values. RESULTS: A significant correlation (Pearson r = 0.49; P = 0.005) was found between ex vivo T1ρ -values and fibrosis fraction from histology. Additionally, a significantly higher T1ρ -relaxation time (55.2 ± 2.7 ms) was found in DCM patients compared with healthy control subjects (51.5 ± 1.2 ms) (P = 0.0024). The relation between in vivo T1ρ -values and ECV-values was significant (Pearson r = 0.66). No significant relation was found between native T1 - and ECV-values in this study (P = 0.89). CONCLUSION: This study showed proof of principle for the endogenous detection of diffuse myocardial fibrosis with T1ρ -MRI. Ex vivo and in vivo experiments showed promising results that T1ρ -MRI can be used to measure the extent of diffuse myocardial fibrosis in the myocardium. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:132-138.

Association of EGF Receptor and NLRs signaling with Cardiac Inflammation and Fibrosis in Mice Exposed to Fine Particulate Matter.

ЄAmbient fine particulate matter (PM2.5 ) could induce cardiovascular diseases (CVD), but the mechanism remains unknown. To investigate the roles of epidermal growth factor receptor (EGFR) and NOD-like receptors (NLRs) in PM2.5 -induced cardiac injury, we set up a BALB/c mice model of PM2.5 -induced cardiac inflammation and fibrosis with intratracheal instillation of PM2.5 suspension (4.0 mg/kg b.w.) for 5 consecutive days (once per day). After exposure, we found that mRNA levels of CXCL1, interleukin (IL)-6, and IL-18 were elevated, but interestingly, mRNA level of NLRP12 was significant decreased in heart tissue from PM2.5 -induced mice compared with those of saline-treated mice using real-time PCR. Protein levels of phospho-EGFR (Tyr1068), phospho-Akt (Thr308), NLRP3, NF-κB-p52/p100, and NF-κB-p65 in heart tissue of PM2.5 -exposed mice were all significantly increased using immunohistochemistry or Western blotting. Therefore, PM2.5 exposure could induce cardiac inflammatory injury in mice, which may be involved with EGFR/Akt signaling, NLRP3, and NLRP12.

Endomyocardial fibrosis and mural thrombus in a 4-year-old girl due to idiopathic hypereosinophilia syndrome described with serial cardiac magnetic resonance imaging.

We present the case of a 4-year-old girl with idiopathic hypereosinophilia syndrome, endomyocardial fibrosis, and mural thrombus. This condition is rarely seen in children outside the tropics. Myocardial biopsy is historically the standard for diagnosis. Reports in adult literature, however, have shown the utility of cardiac MRI as a non-invasive tool for diagnosis, prognosis, and monitoring. To our knowledge, this is the first reported case with serial cardiac MRI in a child.

No Additional Effect of DPP-4 Inhibitor on Preventing Atrial Fibrosis in Streptozotocin-Induced Diabetic Rat as Compared With Sulfonylurea.

Chronic inflammation is known to occur in diabetes mellitus (DM) and contributes to atrial fibrosis, possible substrates for atrial fibrillation. We tested the hypothesis that dipeptidyl peptidase (DPP)-4 inhibitors prevent the formation of atrial fibrosis through their anti-inflammatory activity, beyond the effects of controlling blood glucose.DM models obtained by administration of streptozotocin (STZ) were divided into 3 groups: with PKF275-055, a DPP-4 inhibitor in group D, glibenclamide in group SU, and no additional drug in group P. At 8 weeks after STZ administration, the heart was subjected to Masson trichrome staining and immunohistochemistry with anti-ED2, ED3, and smooth muscle actin antibody.The % area of fibrosis in atria of group P accounted for 14.7% ± 4.1%, showing a significant increase in fibrosis when compared with the control group. In group SU, the % area accounted for 7.9% ± 2.9%, indicating significant deceased fibrosis by sulfonylurea. Meanwhile, we could not find significant differences in group D when compared to group P or group SU. While ED3-positive cells increased in group P (1.12% ± 0.24%), they were significantly decreased in groups D and SU (0.41% ± 0.22% and 0.55% ± 0.29%, respectively). Between group D and SU, however, there were no significant differences in the amount of cells positive to ED2, ED3, and smooth muscle actin antibodies.In STZ-induced DM rats, administration of sulfonylurea and DPP-4 inhibitors inhibited inflammation and fibrosis of the atria. However, no significant differences were observed between the 2 antidiabetic drugs.

Rapamycin inhibits the mTOR/p70S6K pathway and attenuates cardiac fibrosis in adriamycin-induced dilated cardiomyopathy.

BACKGROUND: The objective of the present study was to investigate whether mTOR is involved in cardiac fibrosis evident in dilated cardiomyopathy, and whether rapamycin provides therapeutic potential for cardiac fibrosis. METHODS: Forty-five rats were divided into three groups. Fifteen rats in the Adriamycin group underwent 8 weeks of Adriamycin treatment (2.5 mg/kg, twice per week; i.v.) to induce cardiac fibrosis and dilated cardiomyopathy. Fifteen rats in the rapamycin group received rapamycin (2 mg/kg, per day, orally) and i.v. Adriamycin simultaneously for 8 weeks. Fifteen untreated rats served as controls. Cardiac morphology and function were quantified using echocardiography. mTOR and p70S6K1 mRNA expression were assessed using reverse transcription-PCR. RESULTS: Collagen volume fraction (CVF) was significantly elevated in the adriamycin group (3.36 ± 0.75) compared with controls (1.51 ± 0.31), whereas mTOR and p70S6K mRNA expression were significantly increased in the adriamycin group (0.68 ± 0.03 and 0.69 ± 0.03) compared with controls (0.38 ± 0.03 and 0.34 ± 0.02). The Adriamycin group was associated with cardiac dilation and decreased contractile function. The rapamycin group showed significantly decreased CVF (1.87 ± 0.45), accompanied with a significant decrease in mTOR and p70S6K mRNA expression (0.42 ± 0.05 and 0.45 ± 0.04) relative to the Adriamycin group. In addition, treatment with rapamycin recovered impairments in cardiac morphology and function. CONCLUSION: The mTOR/p70S6K pathway plays an important role in adriamycin-induced cardiac fibrosis resulting from dilated cardiomyopathy. Rapamycin is a potential therapeutic treatment that can be used to attenuate cardiac fibrosis and improve cardiac function.

Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice.

Mineralocorticoid receptor antagonists (MRAs) improve survival and reduce morbidity in patients with heart failure, reduced ejection fraction (HF-REF), and mild-to-severe symptoms, and in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction. These clinical benefits are observed in addition to those of angiotensin converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers. The morbidity and mortality benefits of MRAs may be mediated by several proposed actions, including antifibrotic mechanisms that slow heart failure progression, prevent or reverse cardiac remodelling, or reduce arrhythmogenesis. Both eplerenone and spironolactone have demonstrated survival benefits in individual clinical trials. Pharmacologic differences exist between the drugs, which may be relevant for therapeutic decision making in individual patients. Although serious hyperkalaemia events were reported in the major MRA clinical trials, these risks can be mitigated through appropriate patient selection, dose selection, patient education, monitoring, and follow-up. When used appropriately, MRAs significantly improve outcomes across the spectrum of patients with HF-REF.

Frequency of fragmented QRS in ankylosing spondylitis : a prospective controlled study.

OBJECTIVES: Since inflammatory diseases may also cause fibrosis, we hypothesized that patients with ankylosing spondylitis (AS) may have frequent fragmented QRS complexes (fQRS) when compared to a control group. PATIENTS AND METHODS: In this prospective study, 71 patients with AS (group 1) were compared with 42 age- and gender-matched individuals without rheumatic disease (group 2, control). fQRS was described as the presence of an additional R wave (R') or R or S wave bridging, or the presence of fragmentation on two consecutive derivations that correspond to the major coronary artery regions. RESULTS: The mean ages of groups 1 and 2 were 37.67 ± 9.17 and 40.43 ± 11.09 years, respectively (p = 0.270). fQRS was detected in 23 AS patients (32.4%), whereas 3 patients in the control group had fQRS (7.14%). Age, gender, medication, and echocardiography results were comparable. The disease duration score was 101.37 ± 59.96 months in fQRS(+) patients; in contrast, it was 57.93 ± 30.95 months in fQRS(-) patients. This difference was of statistical significance (p = 0.046). A statistically significant difference was not determined between the fQRS(+) and fQRS(-) groups when evaluated in terms of HLAB27 (p = 0.739). In the fQRS(+) group, the mean lumbar Schober score was 2.91 ± 1.52; in patients without fQRS, it was 4.10 ± 1.40. The mean thoracic expansion test scores in the fQRS(+) and fQRS(-) groups were 1.44 ± 0.66 and 2.69 ± 1.22, respectively. CONCLUSION: Given the higher frequency of fQRS detected in electrocardiography studies in AS patients than in the control group, cardiac fibrosis is thought to be more likely to occur in AS patients without cardiovascular disease. The presence of fQRS may be a simple and cost-effective method for predicting cardiac fibrosis in AS patients. fQRS can be a predictive marker for fibrosis in patients with AS.

[Influence of the long-term administration of torasemide on morphometric characteristics of cardiac muscle under conditions of developed experimental postinfarction cardiosclerosis].

The possible antifibrotic effect of torasemide used for the treatment of model chronic heart failure (CHF) has been studied in rats aged 12 months with developed postinfarction cardiosclerosis (PICS). The antifibrotic effect was evaluated of the course of torasemide administration in a daily dose of 0.13 mg/kg. A comparative analysis showed that torasemide did not affect the state of connective tissues in cardiac muscles of both intact rats and those with PICS. It was concluded that manifestations of the antifibrotic effect of torasemide can be related to the nosological form of CHF.

Cyclophilin A affects inflammation, virus elimination and myocardial fibrosis in coxsackievirus B3-induced myocarditis.

Extracellular cyclophilin A (CyPA) and its receptor Extracellular Matrix Metalloproteinase Inducer (EMMPRIN, CD147) modulate inflammatory processes beyond metalloproteinase (MMP) activity. Recently, we have shown that CyPA and CD147 are upregulated in patients with inflammatory cardiomyopathy. Here we investigate the role of CyPA and CD147 in murine coxsackievirus B3 (CVB3)-induced myocarditis. CVB3-infected CyPA(-/-) mice (129S6/SvEv) revealed a significantly reduced T-cell and macrophage recruitment at 8 days p.i. compared to wild-type mice. In A.BY/SnJ mice, treatment with the cyclophilin-inhibitor NIM811 was associated with a reduction of inflammatory lesions and MMP-9 expression but with enhanced virus replication 8 days p.i. At 28 days p.i. the extent of lesion areas was not affected bei NIM811, whereas the collagen content was reduced. Initiation of NIM811-treatment on day 12 (after an effective virus defense) resulted in an even more pronounced reduction of myocardial fibrosis. In conclusion, in CVB3-induced myocarditis CyPA is important for macrophage and T cell recruitment and effective virus defense and may represent a pharmacological target to modulate myocardial remodeling in myocarditis.

Coenzyme Q10 attenuates diastolic dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis in the db/db mouse model of type 2 diabetes.

AIMS/HYPOTHESIS: An increase in the production of reactive oxygen species is commonly thought to contribute to the development of diabetic cardiomyopathy. This study aimed to assess whether administration of the antioxidant coenzyme Q(10) would protect the diabetic heart against dysfunction and remodelling, using the db/db mouse model of type 2 diabetes. Furthermore, we aimed to compare the efficacy of coenzyme Q(10) to that of the ACE inhibitor ramipril. METHODS: Six-week-old non-diabetic db/+ mice and diabetic db/db mice received either normal drinking water or water supplemented with coenzyme Q(10) for 10 weeks. Endpoint cardiac function was assessed by echocardiography and catheterisation. Ventricular tissue was collected for histology, gene expression and protein analysis. RESULTS: Untreated db/db diabetic mice exhibited hyperglycaemia, accompanied by diastolic dysfunction and adverse structural remodelling, including cardiomyocyte hypertrophy, myocardial fibrosis and increased apoptosis. Systemic lipid peroxidation and myocardial superoxide generation were also elevated in db/db mice. Coenzyme Q(10) and ramipril treatment reduced superoxide generation, ameliorated diastolic dysfunction and reduced cardiomyocyte hypertrophy and fibrosis in db/db mice. Phosphorylation of Akt, although depressed in untreated db/db mice, was restored with coenzyme Q(10) administration. We postulate that preservation of cardioprotective Akt signalling may be a mechanism by which coenzyme Q(10)-treated db/db mice are protected from pathological cardiac hypertrophy. CONCLUSIONS/INTERPRETATION: These data demonstrate that coenzyme Q(10) attenuates oxidative stress and left ventricular diastolic dysfunction and remodelling in the diabetic heart. Addition of coenzyme Q(10) to the current therapy used in diabetic patients with diastolic dysfunction warrants further investigation.