Progression Of Myocardial Fibrosis Research Articles

Signature network-based survey of the effects of a traditional Chinese medicine on heart failure

Ethnopharmacological relevanceHeart failure (HF) after myocardial infarction (MI) is one of the most common disabling and painful diseases. A traditional Chinese medicine (TCM) formula, Shengmaisan, is known as a multitarget medicine that is widely used clinically to treat heart failure (HF) in Asian countries. However, its mechanism has not been comprehensively demonstrated. Aim of the studyTo use a prediction network to figure out which disease link SMZ mainly alleviates in HF and find biomarkers related to myocardial fibrosis in the serum for clinical reference. Materials and methodsIn this article, we collected a large amount of actual measurement data and our own proteomics data, along with the biomarkers of heart failure staging under study to establish a precise network. Then, we tested and verified the medicinal effect of SMZ in treatment of HF after MI by Measurement of left ventricular wall thickness and ejection fraction by echocardiography. Then we tested the serum level of the potential targets of SMZ predicting by the network we developed using ELISA.Results: the cardiac ejection fraction and retarding the thinning of the anterior wall of the left ventricle increased after treating with SMZ. The serum level of EGFR and MAPK1 decreased in the groups treated with SMZ. ConclusionSMZ can improve the cardiac function of rats with MI by increasing the cardiac ejection fraction and retarding the thinning of the anterior wall of the left ventricle. In addition, SMZ could delay heart failure mainly by inhibiting the progression of myocardial fibrosis through decreasing the EGFR and MAPK1 levels.

Mechanisms of cardiac protection by pirfenidone in the post-myocardial infarction setting

Abstract Background A high proportion of patients with ST-segment elevation myocardial infarction (STEMI) experience adverse left ventricular (LV) remodelling despite guideline-recommended therapy. An excessive and dysregulated fibrotic response is involved in LV remodelling, and could be targeted by anti-fibrotic drugs such as pirfenidone, which is an approved treatment for idiopathic pulmonary fibrosis. Methods We evaluated the mechanisms of action of pirfenidone in the post-MI setting through sampling method-based mathematical models, enriched with transcriptomic data of swine experimental models of MI translated to the human proteome. Results The analysis of proteins modulated by pirfenidone shows that pirfenidone has a strong impact on several pathways involved in post-MI remodeling (Figure). The inhibition of p38γ-MAPK12 and furin displays the most prominent role on post-MI remodeling when compared to the other pirfenidone targets (PAI-1 and GLI2). p38γ-MAPK12 blockade inhibits cardiomyocyte apoptosis mediated by BCL2 and BAX. Myocardial hypertrophy and inflammation might be modulated by pirfenidone through the regulation of proteins downstream to p38γ-MAPK12, such as the NFATC1/NFATC2/NFATC3 pathway, and the transcription factors FOXO1, FOXO3 and NFκB, which are involved in TNFα regulation. The transcription factor AP-1 (homo-heterodimers of c-JUN/c-FOS), also downstream to p38γ-MAPK12, regulate the expression of genes involved in hypertrophy, fibrosis and inflammation (for example, IFNγ) By blocking both p38γ-MAPK12 and furin, pirfenidone can modulate extracellular matrix remodelling and cardiac fibrosis by targeting the TGFβ1-SMAD2/3 pathway, known to be highly involved in the progression of myocardial fibrosis, and other effector proteins such as MMP2 and MMP14 metalloproteases, PDGFA/B, and IGF1, many found to be involved also in myocardial fibrosis, impaired myocyte contractility and cell hypertrophic response. Conclusions We have identified several possible mechanisms of action of pirfenidone with beneficial effects in the post-MI LV remodelling. These findings support future research regarding pirfenidone's clinical benefit in post-MI patients. Funding Acknowledgement Type of funding sources: None.

Changes in Intestinal Flora Structure and Metabolites Are Associated With Myocardial Fibrosis in Patients With Persistent Atrial Fibrillation.

Background: The occurrence of atrial fibrillation is often accompanied by myocardial fibrosis. An increasing number of studies have shown that intestinal flora is involved in the occurrence and development of a variety of cardiovascular diseases. This study explores the relationship between changes in the structure and function of intestinal flora and the progression of myocardial fibrosis in patients with persistent atrial fibrillation.Methods: Serum and stool samples were collected from 10 healthy people and 10 patients with persistent atrial fibrillation (PeAF), and statistical analyses were performed on the subjects' clinical baseline conditions. ELISA was used to measure the levels of carboxy-terminal telopeptide of type I collagen (CTX-I), propeptide of type I procollagen (PICP), procollagen III N-terminal propeptide (PIIINP), fibroblast growth factor-23 (FGF-23), and transforming growth factor-beta 1 (TGF-β1) in serum. Through 16S rRNA sequencing technology, the structural composition of the intestinal flora was detected and analyzed. In addition, metabolomics data were analyzed to determine the differences in the metabolites produced by the intestinal flora of the subjects.Results: By comparing the baseline data of the subjects, it was found that compared with those of the control group, the levels of creatinine (CRE) and serum uric acid (SUA) in the serum of PeAF patients were significantly increased. In addition, we found that the levels of CTX-I, PICP, PIIINP, and TGF-β1 in the serum of PeAF patients were significantly higher than those of the control group subjects. Although the control and PeAF groups exhibited no significant differences in the α diversity index, there were significant differences in the β diversity indexes (Bray-Curtis, weighted UniFrac and Anosim). At the phylum, family and species levels, the community structure and composition of the intestinal flora of the control group and those of the PeAF group showed significant differences. In addition, the compositions of the intestinal metabolites in the two different groups of people were significantly different. They were correlated considerably with PIIINP and specific communities in the intestinal flora.Conclusion: Pathologically, PeAF patients may have a higher risk of myocardial fibrosis. Systematically, abnormal changes in the structure and composition of the intestinal flora in PeAF patients may lead to differences in intestinal metabolites, which are involved in the process of myocardial fibrosis through metabolite pathways.

2021 TSOC Expert Consensus on the Clinical Features, Diagnosis, and Clinical Management of Cardiac Manifestations of Fabry Disease.

Fabry disease (FD) is an X-linked, rare inherited lysosomal storage disease caused by α-galactosidase A gene variants resulting in deficient or undetectable α-galactosidase A enzyme activity. Progressive accumulation of pathogenic globotriaosylceramide and its deacylated form globotriaosylsphingosine in multiple cell types and organs is proposed as main pathophysiology of FD, with elicited pro-inflammatory cascade as alternative key pathological process. The clinical manifestations may present with either early onset and multisystemic involvement (cutaneous, neurological, nephrological and the cardiovascular system) with a progressive disease nature in classic phenotype, or present with a later-onset course with predominant cardiac involvement (non-classical or cardiac variant; e.g. IVS4+919G>A in Taiwan) from missense variants. In either form, cardiac involvement is featured by progressive cardiac hypertrophy, myocardial fibrosis, various arrhythmias, and heart failure known as Fabry cardiomyopathy with potential risk of sudden cardiac death. Several plasma biomarkers and advances in imaging modalities along with novel parameters, cardiac magnetic resonance (CMR: native T1/T2 mapping) for myocardial tissue characterization or echocardiographic deformations, have shown promising performance in differentiating from other etiologies of cardiomyopathy and are presumed to be helpful in assessing the extent of cardiac involvement of FD and in guiding or monitoring subsequent treatment. Early recognition from extra-cardiac red flag signs either in classic form or red flags from cardiac manifestations in cardiac variants, and awareness from multispecialty team work remains the cornerstone for timely managements and beneficial responses from therapeutic interventions (e.g. oral chaperone therapy or enzyme replacement therapy) prior to irreversible organ damage. We aim to summarize contemporary knowledge based on literature review and the gap or future perspectives in clinical practice of FD-related cardiomyopathy in an attempt to form a current expert consensus in Taiwan.

Temporal Evolution of Diffuse Myocardial Fibrosis in Sickle Cell Anemia

▪Background: We recently demonstrated that diffuse myocardial fibrosis is a common and novel mechanism of heart disease in sickle cell anemia (SCA) that is strongly associated with diastolic dysfunction (Niss et al. Blood 2017). Diffuse myocardial fibrosis can be detected noninvasively by cardiac magnetic resonance imaging (CMR).The temporal evolution of diffuse myocardial fibrosis in SCA has not been studied before.Methods: This is an ongoing, prospective, longitudinal study to characterize the cardiomyopathy of SCA (NCT02410811). We used CMR measurements of native T1 and extracellular volume fraction (ECV) to detect and quantify diffuse myocardial fibrosis. ECV was calculated from pre- and post-gadolinium T1 measurements of blood and myocardium. Focal myocardial fibrosis was detected by late gadolinium enhancement (LGE). Diastolic function was assessed by echocardiography. We compared paired CMR studies from study entry and 1-year follow-up.Results: We studied 25 individuals with SCA who were 23±11 years of age (mean±SD). All had markedly increased ECV at baseline compared to controls (0.44±0.08 vs. 0.26±0.02, P<0.0001), indicating the presence of diffuse myocardial fibrosis; 1 also had LGE-defined focal myocardial fibrosis. At baseline, 8 (32%) had normal diastolic function, 17 (71%) had diastolic abnormalities, and 7 (29%) met the definition for diastolic dysfunction. The second (1-year follow-up) CMR was performed 12±0.4 months after the baseline. For all participants, the mean difference (year 1 - baseline) in ECV was -0.03 (95% CL: -0.08, 0.03; P=0.34), indicating general stability of the phenotype over 1 year. Similarly, the mean difference in native T1 values was 19 ms (95% CL: -10, 48; P=0.19). None developed new focal fibrosis. Participants with normal systolic and diastolic function at baseline (N=7) had median increases of 23% and 6% in ECV (Figure, Panel A, •) and native T1 (Figure, Panel B, •), respectively, at 1-year follow-up, compared to those with diastolic dysfunction at baseline (N=7) who had a median -0.46% decrease in ECV (Figure, Panel A, ♦; P=0.32) and 2% increase in native T1 (Figure, Panel B, ♦; P=0.45).Conclusions: Diffuse myocardial fibrosis is a common feature of SCA. Overall, the CMR measurements of diffuse fibrosis, native T1 and ECV, are stable over 1 year in SCA, demonstrating their utility to monitor anti-fibrotic or disease-modifying therapy for the cardiomyopathy of SCA. Individuals with normal heart function at baseline appear to be at risk of progressive myocardial fibrosis. [Display omitted] DisclosuresQuinn:Global Blood Therapeutics: Research Funding.

THE IMPACT OF SIROLIMUS AS A PRIMARY IMMUNOSUPPRESSANT ON MYOCARDIAL FIBROSIS AND DIASTOLIC FUNCTION FOLLOWING HEART TRANSPLANTATION

Purpose Myocardial fibrosis is an important contributor for development of diastolic dysfunction (DD) following heart transplantation (HT). Small studies have reported superiority of sirolimus (SRL) over calcineurin inhibitor (CNI) in mitigating DD assessed by echocardiography. However, data on invasive hemodynamic assessment is lacking, and the impact of SRL on myocardial fibrosis progression remains unclear. We aimed to investigate the impact of SRL on DD and fibrosis progression among HT recipients. Methods A cohort of 100 HT recipients who were either treated with CNI alone (n =51) or converted from CNI to SRL (n=49) as primary immunosuppression was analyzed. Diastolic function parameters were assessed using serial echocardiograms and right heart catheterizations (RHC). Myocardial fibrosis was quantified on serial myocardial biopsies by automated digital analysis, blinded to the type of therapy. Results After 3 years, left ventricular end diastolic diameter (LVEDD) increased in the SRL group (45.7 ± 5.1 to 48.3 ± 5.5 mm, paired p Conclusion Early conversion to SRL is associated with improvement in DD and LV filling pressures which can be partially explained by attenuation of myocardial fibrosis progression as compared to CNI therapy.

The Impact of Sirolimus as a Primary Immunosuppressant on Myocardial Fibrosis and Diastolic Function Following Heart Transplantation

Purpose Myocardial fibrosis is an important contributor for development of diastolic dysfunction (DD) following heart transplantation (HT). Small studies have reported superiority of sirolimus (SRL) over calcineurin inhibitor (CNI) in mitigating DD assessed by echocardiography. However, data on invasive hemodynamic assessment is lacking, and the impact of SRL on myocardial fibrosis progression remains unclear. We aimed to investigate the impact of SRL on DD and fibrosis progression among HT recipients. Methods A cohort of 100 HT recipients who were either treated with CNI alone (n =51) or converted from CNI to SRL (n=49) as primary immunosuppression was analyzed. Diastolic function parameters were assessed using serial echocardiograms and right heart catheterizations (RHC). Myocardial fibrosis was quantified on serial myocardial biopsies by automated digital analysis, blinded to the type of therapy. Results After 3 years, left ventricular end diastolic diameter (LVEDD) increased in the SRL group (45.7 ± 5.1 to 48.3 ± 5.5 mm, paired p Conclusion Early conversion to SRL is associated with improvement in DD and LV filling pressures which can be partially explained by attenuation of myocardial fibrosis progression as compared to CNI therapy.

Deletion of Smad3 protects against diabetic myocardiopathy in db/db mice

Diabetic cardiomyopathy (DCM) is a common diabetic complication characterized by diastolic relaxation abnormalities, myocardial fibrosis and chronic heart failure. Although TGF‐β/Smad3 signalling has been shown to play a critical role in chronic heart disease, the role and mechanisms of Smad3 in DCM remain unclear. We reported here the potential role of Smad3 in the development of DCM by genetically deleting the Smad3 gene from db/db mice. At the age of 32 weeks, Smad3WT‐db/db mice developed moderate to severe DCM as demonstrated by a marked increase in the left ventricular (LV) mass, a significant fall in the LV ejection fraction (EF) and LV fractional shortening (FS), and progressive myocardial fibrosis and inflammation. In contrast, db/db mice lacking Smad3 (Smad3KO‐db/db) were protected against the development of DCM with normal cardiac function and undetectable myocardial inflammation and fibrosis. Interestingly, db/db mice with deleting one copy of Smad3 (Smad3 ± db/db) did not show any cardioprotective effects. Mechanistically, we found that deletion of Smad3 from db/db mice largely protected cardiac Smad7 from Smurf2‐mediated ubiquitin proteasome degradation, thereby inducing IBα to suppress NF‐kB‐driven cardiac inflammation. In addition, deletion of Smad3 also altered Smad3‐dependent miRNAs by up‐regulating cardiac miR‐29b while suppressing miR‐21 to exhibit the cardioprotective effect on Smad3KO‐db/db mice. In conclusion, results from this study reveal that Smad3 is a key mediator in the pathogenesis of DCM. Targeting Smad3 may be a novel therapy for DCM.

Role of the Renin-Angiotensin-Aldosterone System in Dystrophin-Deficient Cardiomyopathy.

Dystrophin-deficient cardiomyopathy (DDC) is currently the leading cause of death in patients with dystrophinopathies. Targeting myocardial fibrosis (MF) has become a major therapeutic goal in order to prevent the occurrence of DDC. We aimed to review and summarize the current evidence about the role of the renin–angiotensin–aldosterone system (RAAS) in the development and perpetuation of MF in DCC. We conducted a comprehensive search of peer-reviewed English literature on PubMed about this subject. We found increasing preclinical evidence from studies in animal models during the last 20 years pointing out a central role of RAAS in the development of MF in DDC. Local tissue RAAS acts directly mainly through its main fibrotic component angiotensin II (ANG2) and its transducer receptor (AT1R) and downstream TGF-b pathway. Additionally, it modulates the actions of most of the remaining pro-fibrotic factors involved in DDC. Despite limited clinical evidence, RAAS blockade constitutes the most studied, available and promising therapeutic strategy against MF and DDC. Conclusion: Based on the evidence reviewed, it would be recommendable to start RAAS blockade therapy through angiotensin converter enzyme inhibitors (ACEI) or AT1R blockers (ARBs) alone or in combination with mineralocorticoid receptor antagonists (MRa) at the youngest age after the diagnosis of dystrophinopathies, in order to delay the occurrence or slow the progression of MF, even before the detection of any cardiovascular alteration.

Matrix metalloproteinase 3 regulates angiotensin II‑induced myocardial fibrosis cell viability, migration and apoptosis

Angiotensin II (AngII) is a central signaling molecule of the renin-angiotensin system that serves a vital role in myocardial fibrosis (MF). The present study aimed to investigate the effects of matrix metalloproteinase (MMP)3 on MF progression. To induce cellular fibrosis, H9C2 rat myocardial cells were treated with AngII for 24 h. Subsequently, cells were treated with levocarnitine, or transfected with small interfering (si)RNA-negative control or siRNA-MMP3 (1/2/3). Cell viability, apoptosis and migration were assessed by performing Cell Counting Kit-8, flow cytometry and Transwell assays, respectively. Reverse transcription-quantitative PCR (RT-qPCR) and western blotting were performed to determine the expression levels of MF biomarkers, including disease-, apoptosis- and oxidative stress-related genes. Compared with the control group, AngII significantly inhibited H9C2 cell viability and migration, and significantly increased H9C2 cell apoptosis (P<0.05). However, compared with AngII-treated H9C2 cells, MMP3 knockdown significantly inhibited fibrotic H9C2 cell viability and migration, but increased fibrotic H9C2 cell apoptosis (P<0.05). The RT-qPCR results demonstrated that MMP3 knockdown significantly downregulated the expression levels of AXL receptor tyrosine kinase, AngII receptor type 1, α-smooth muscle actin and Collagen I in AngII-treated H9C2 cells (P<0.05). Moreover, compared with AngII-treated cells, MMP3 knockdown significantly decreased Bcl-2 expression levels, but significantly increased caspase-3 and p53 expression levels in AngII-treated cells (P<0.05). Additionally, compared with AngII-treated cells, MMP3 knockdown significantly decreased MMP3, MMP9, STAT3, p22Phox and p47Phox expression levels in AngII-treated cells (P<0.05). The present study indicated that MMP3 knockdown altered myocardial fibroblast cell viability, migration and apoptosis by regulating apoptosis- and oxidative stress-related genes, thus delaying MF progression.

Impact of Sirolimus as a Primary Immunosuppressant on Myocardial Fibrosis and Diastolic Function Following Heart Transplantation.

BackgroundMyocardial fibrosis is an important contributor for development of diastolic dysfunction. We investigated the impact of sirolimus as primary immunosuppression on diastolic dysfunction and fibrosis progression among heart transplantation recipients.Methods and ResultsIn 100 heart transplantation recipients who were either treated with a calcineurin inhibitor (CNI) (n=51) or converted from CNI to sirolimus (n=49), diastolic function parameters were assessed using serial echocardiograms and right heart catheterizations. Myocardial fibrosis was quantified on serial myocardial biopsies. After 3 years, lateral e′ increased within the sirolimus group but decreased in the CNI group (0.02±0.04 versus −0.02±0.04 m/s delta change; P=0.003, respectively). Both pulmonary capillary wedge pressure and diastolic pulmonary artery pressure significantly decreased in the sirolimus group but remained unchanged in the CNI group (−1.50±2.59 versus 0.20±2.20 mm Hg/year; P=0.02; and −1.72±3.39 versus 0.82±2.59 mm Hg/year; P=0.005, respectively). A trend for increased percentage of fibrosis was seen in the sirolimus group (8.48±3.17 to 10.10±3.0%; P=0.07) as compared with marginally significant progression in the CNI group (8.76±3.87 to 10.56±4.34%; P=0.04). The percent change in fibrosis did not differ significantly between the groups (1.62±4.67 versus 1.80±5.31%, respectively; P=0.88).ConclusionsEarly conversion to sirolimus is associated with improvement in diastolic dysfunction and filling pressures as compared with CNI therapy. Whether this could be attributed to attenuation of myocardial fibrosis progression with sirolimus treatment warrants further investigation.

Abstract 14390: The Cardiac Myosin Inhibitor, Ck-3772271, Attenuates Cardiac Fibrosis and Diastolic Dysfunction in the Dahl/salt Sensitive Rat Model of Heart Failure With Preserved Ejection Fraction

Introduction: Heart failure with preserved ejection fraction (HFpEF) is characterized by underlying contractile dysfunction and progressive myocardial fibrosis and stiffness. CK-3772271 (CK-271) is a novel small molecule cardiac myosin inhibitor that reduces cardiac myosin ATPase activity and reduces cardiac contractility in unloaded isolated cardiomyocytes in vitro and in healthy rats and dogs in vivo . The effect of chronic CK-271 treatment on cardiac function and morphology was evaluated in the Dahl/Salt Sensitive (DSS) rat hypertension model of HFpEF. Methods: DSS male rats were fed either a control low salt (LS, 0.3% NaCl) or high salt (HS, 4% NaCl) diet to induce a hypertension-driven HFpEF disease phenotype. 6 weeks after HS diet treatment, DSS rats were randomized into two sub-groups: continued HS diet or a HS diet formulated with CK-271 (100 ppm) for an additional 6 weeks. Body mass, systolic blood pressure, and cardiac function were measured longitudinally. After 12 weeks of HS treatment, hearts were collected to assess cardiac fibrosis. Results: HS diet treatment increased systolic blood pressure (LS:132.2 ± 4.7 mm Hg vs. HS: 163.5 ± 4.0 mm Hg, mean ± SEM, p&lt; 0.001) and caused cardiac hypercontractility as evidenced by an increase in the end-systolic pressure-volume relationship (LS: 0.8 ± 0.17 vs. HS: 2.1 ± 0.46 mm Hg/ml). HS diet also increased isovolumic relaxation time (IVRT) (LS: 16.8 ± 0.6 vs. HS: 22.8 ± 0.6 ms, p&lt;0.0001), left atrial area (LS: 30.3 ± 0.8 vs. HS: 42.5 ± 2.2 mm 2 , p&lt;0.0001) and cardiac fibrosis (LS: 3.4 ± 0.4 vs. HS: 5.0 ± 0.6 %). 6 weeks of CK-271 treatment reduced fractional shortening (HS: 53.8 ± 1.4 vs. HS+CK-271: 42.7 ± 1.0 %, p&lt;0.0001) and reduced HS diet-induced diastolic dysfunction, including IVRT (HS: 22.8 ± 0.6 vs. HS+CK-271: 19.5 ± 0.5 ms, p&lt;0.0001) and left atrial area (HS: 42.5 ± 2.2 vs. HS+CK-271: 35.4 ± 0.8 mm 2 , p&lt;0.0001). Furthermore CK-271 reduced the development of cardiac fibrosis (HS: 5.0 ± 0.6 vs. HS+CK-271: 3.5 ± 0.3 %, p&lt;0.05) induced by HS diet. Conclusion: The small molecule cardiac myosin inhibitor, CK-3772271, attenuated the development of cardiac hypercontractility, diastolic dysfunction and fibrosis in the DSS rat model of HFpEF. Cardiac myosin inhibition may be a novel approach to mitigate the development of HFpEF.

Decreased global strains of the left ventricle in asymptomatic female carriers for duchenne muscular dystrophy gene using feature-tracking: a prospective study

Abstract Background Duchenne muscular dystrophy (DMD) is an X-linked recessive disease manifested in males predominantly by skeletal muscle wasting but also dilated myocardium. Heterozygous female carriers often have normal echocardiographic findings. Nevertheless, untreated could develop in 4th and 5th decade of life to cardiomyopathy, probably due to progressive myocardial fibrosis. CMR feature tracking (FT) is an innovative technique that measures the myocardial wall deformation and could help to detect the contractile dysfunction, even in its early stages, due to its high sensitivity. Thus, it could identify asymptomatic carriers at higher risk of developing cardiomyopathy later in life. Aim This prospective study aimed to assess left ventricular systolic function (LV) in DMD carriers using CMR-FT. Methodology Global longitudinal strain (GLS), global circumferential strain (GCS) and global radial strain (GRS) were evaluated by CMR-FT. End-systolic (ESV), end-diastolic (EDV) LV volumes and ejection fraction (EF) LV were also measured using CMR-FT. There were 37 carriers, and 20 healthy controls enrolled in the study. The measured parameters showed a Gaussian distribution and were compared using a t-test, followed by Benjamini-Hochberg correction. Results Groups carriers and controls did not differ in basic demographic data (age: 39.5±9.1 vs. 39.1±10.7 years). In contrast, there were found statistically significant differences in EF LV (56±5 vs. 60±3%), and all strain parameters (GLS (−19.4±2.4 vs. −22.3±2.2%), GCS (26.8±3.3 vs. 29.5±2.0%) and GRS (59.8±12.9 vs. 70.9±14.8%, all p&amp;lt;0.05)). Conclusion Carriers had significantly lower values of all strains compared to controls using CMR-FT, although they had preserved EF LV. CMR-FT could be beneficial for early diagnosis of the developing heart disease in asymptomatic patients with a genetic predisposition. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The work was supported by project no. LQ1605 from the National Program of Sustainability II (MEYS CR).This publication was written at Masaryk University as part of the project “Evaluation of left ventricular function using the feature tracking technique of Duchenne muscular dystrophy genes carriers” MUNI/A/1493/2018 with the support of the Specific University Research Grant, as provided by the Ministry of Education, Youth and Sports of the Czech Republic in the year 2018.

Hybrid CMR- and FDG-PET-imaging gives new insights into the relationship of myocardial metabolic activity and fibrosis in patients with Becker muscular dystrophy

Abstract Background Cardiac involvement in patients with Becker muscular dystrophy (BMD) is an important predictor of mortality. The cardiac phenotype of BMD patients is characterized by slowly progressive myocardial fibrosis that starts in the left ventricular (LV) free wall segments and extends into the septal wall during the disease course. Purpose Since the reason for this characteristic cardiac phenotype is unknown and comprehensive approaches using e.g. hybrid imaging combining cardiovascular magnetic resonance (CMR) with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) are limited, the present study addressed this issue by a comprehensive non-invasive imaging approach. Methods Hybrid CMR- and FDG-PET-imaging was performed in N=14 patients with BMD on a whole-body Biograph mMR system. The CMR protocol comprised cine- and late-gadolinium-enhancement (LGE)-imaging. Metabolism was assessed with FDG-PET after oral glucose loading to effect myocardial carbohydrate uptake. PET was acquired for 65 minutes starting with tracer injection. Uptake values from 60 to 65 minutes p.i. were divided by the area under the blood activity curve and reported as percentages relative to the segment with maximal myocardial FDG uptake. Results In the total study group, mean left ventricular (LV) ejection fraction (EF) was 55±5% and there were 6/14 patients with a reduced LV-EF &amp;lt;55%. A characteristic pattern of LGE in LV lateral wall was observed in 13/14 patients whereas an additional septal LGE pattern was documented in 6/14 patients only. Segmental FDG uptake was 88±6% in the LV lateral wall vs. 77±10% in the septal wall (p&amp;lt;0.001). There was a rather inverse relationship between segmental FDG activity compared to segmental LGE extent (r=−0.33, p=0.089). There were N=6 patients (= ΔFDG-high) with a segmental difference in FDG uptake of &amp;gt;15% in the LV lateral wall compared to the septal wall (lateral FDG = 91±3% vs. septal FDG = 69±8%; p&amp;lt;0.001) while the remaining N=8 patients (= ΔFDG-low) showed a segmental difference in FDG uptake of ≤15% (lateral FDG = 85±7% vs. septal FDG = 83±5%; p=0.37). Patients in the ΔFDG-high group showed a similar LV lateral wall vs. septal wall LGE extent of 12±6% vs. 7±15%, respectively, while those patients in the ΔFDG-low group demonstrated a large difference in LV lateral wall vs. septal wall LGE extent of 33±24% vs. 4±6%, respectively. Conclusions Segmental FDG uptake – reflecting myocardial metabolic activity – is in principal higher in the LV free wall of BMD patients – possibly due to a higher segmental work load. However, segmental metabolic activity seems to be dependent on and limited by the respective segmental extent of myocardial fibrosis as depicted by LGE-imaging. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Deutsche Gesellschaft für Kardiologie (DGK)

Treatment of Hypertensive Heart Disease by Targeting Smad3 Signaling in Mice

Transforming growth factor β (TGF-β)/Smad3 signaling plays a central role in chronic heart disease. Here, we report that targeting Smad3 with a Smad3 inhibitor SIS3 in an established mouse model of hypertension significantly improved cardiac dysfunctions by preserving the left ventricle (LV) ejection fraction (LVEF) and LV fractional shortening (LVFS), while reducing the LV mass. In addition, SIS3 treatment also halted the progression of myocardial fibrosis by blocking α-smooth muscle actin-positive (α-SMA+) myofibroblasts and collagen matrix accumulation, and inhibited cardiac inflammation by suppressing interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP1), intercellular cell adhesion molecule-1 (ICAM1) expression, and infiltration of CD3+ T cells and F4/80+ macrophages. Interestingly, treatment with SIS3 did not alter levels of high blood pressure, revealing a blood pressure-independent cardioprotective effect of SIS3. Mechanistically, treatment with SIS3 not only directly inactivated TGF-β/Smad3 signaling but also protected cardiac Smad7 from Smurf2-mediated proteasomal ubiquitin degradation. Because Smad7 functions as an inhibitor for both TGF-β/Smad and nuclear factor κB (NF-κB) signaling, increased cardiac Smad7 could be another mechanism through which SIS3 treatment blocked Smad3-mediated myocardial fibrosis and NF-κB-driven cardiac inflammation. In conclusion, SIS3 is a therapeutic agent for hypertensive heart disease. Results from this study demonstrate that targeting Smad3 signaling with SIS3 may be a novel and effective therapy for chronic heart disease.

The role of the cardiac lymphatic system in the development and progression of heart failure and novel therapeutic approaches for its management in post-infarction cardiac remodeling

Cardiac lymphatic vessels play a vital role in maintaining homeostasis in both physiological and pathological conditions, providing outflow of metabolites. It has been shown that myocardial infarction and postinfarction cardiac remodeling is accompanied by the lymphatic remodeling, which entails functional disorders and is of great importance in heart failure pathogenesis. As a result of progressive myocardial edema, hypoxia and fibrosis of the interstitial space increase, aggravating edema. Other pathways of additional myocardial damage and contractility reduction are triggered. Lymphatic efflux is associated with arrhythmias. Experimental models showed the positive effect of exogenous activation of lymphangiogenesis in relation to the prevention and treatment of heart failure, which can be further used to improve treatment regimens. This review discusses cardiac lymphatic remodeling after myocardial infarction, as well as the pathogenesis of related complications.

Novel Atrial Deformation Changes in Duchenne Cardiomyopathy

BACKGROUND: Although progressive myocardial fibrosis and worsening ventricular function is well characterized in Duchenne muscular dystrophy (DMD), changes in atrial mechanics are unknown. The objectives of this study are to evaluate changes in left atrial (LA) deformation and its association with left ventricular (LV) deformation, systolic function and fibrosis. METHODS: This is a retrospective (2004 to 2019) single …

Quercetin Dihydrate inhibition of cardiac fibrosis induced by angiotensin II in vivo and in vitro

Cardiac fibroblasts play a key role in the process of myocardial remodeling and myocardial fibrosis, which will eventually lead to heart failure. Quercetin Dihydrate has been studied in cardiovascular disease, but its effect on myocardial fibrosis is not clear. Here, cardiac remodeling was induced by infusion of Ang II (1000 ng/kg/min) for 2 weeks in mice. Quercetin Dihydrate was injected intraperitoneally for 25 mM/kg body weight (BW) once two days. We found that Quercetin Dihydrate significantly reduced cardiac contractile function, fibrosis, inflammation and myocardial hypertrophy induced by Ang II. Quercetin Dihydrate could inhibit the expression of Collagen I and Collagen III, which are the markers of fibroblast differentiation. We also verified the inhibitory effect of Quercetin Dihydrate on the proliferation and differentiation of fibroblasts induced by angiotensin II in vitro. Our results show that quercetin dihydrate plays a key role in the progression of myocardial fibrosis and suggests that Quercetin Dihydrate may be a promising drug for the treatment of myocardial fibrosis.

Compound LM9, a novel MyD88 inhibitor, efficiently mitigates inflammatory responses and fibrosis in obesity-induced cardiomyopathy.

Mechanisms of cardiomyopathy caused by obesity/hyperlipidemia are complicated. Obesity is usually associated with chronic low-grade inflammation and may lead to the onset and progression of myocardial fibrosis and remodeling. TLR4/MyD88 signaling pathway, as a key regulator of inflammation, plays an important role in the pathogenesis of obesity-induced cardiomyopathy. We previously demonstrated that LM9, a novel MyD88 inhibitor, attenuated inflammatory responses and fibrosis in obesity-induced cardiomyopathy by inhibiting the formation of TLR4/MyD88 complex. In this study, we investigated the protective effects of LM9 on obesity-induced cardiomyopathy in vitro and in vivo. We showed that LM9 (5, 10 μM) significantly attenuates palmitic acid (PA)-induced inflammation in mouse peritoneal macrophages, evidenced by decreased expression of proinflammatory genes including TNF-α, IL-6, IL-1β, and ICAM-1. In cardiac-derived H9C2 cells, LM9 treatment suppressed PA-induced inflammation, lipid accumulation, and fibrotic responses. In addition, LM9 treatment also inhibited PA-activated TLR4/MyD88/NF-κB signaling pathway. We further revealed in HEK293 cells that LM9 treatment blocked the TLR4/MyD88 binding and MyD88 homodimer formation. In HFD-fed mice, administration of LM9 (5, 10 mg/kg, ig, every other days for 8 weeks) dose-dependently alleviated inflammation and fibrosis in heart tissues and decreased serum lipid concentration. In conclusion, this study demonstrates that MyD88 inhibitor LM9 exerts protective effects against obesity-induced cardiomyopathy, suggesting LM9 to be a promising therapeutic candidate drug for the obesity-related cardiac complications.

Correlation between Serum Markers of Adverse Left Ventricular Remodelling and Gene Expression Levels Measured in the Myocardial Tissue of Patients with Chronic Primary Mitral Regurgitation

Abstract Background: Chronic primary mitral regurgitation (CPMR) is characterized by progressive myocardial hypertrophy, fibrosis and dilatation. Although molecular markers of adverse left ventricular (LV) remodelling have been identified in the progression from compensated to decompensated heart failure in these patients, serum markers that could guide the optimal timing of intervention in these patients are still needed. Here we describe the correlation between the levels of expression of several genes important in adverse LV remodelling in CPMR and the serum levels of these markers. Methods: We performed echocardiography, cardiac catheterization, endomyocardial biopsy (EMB) and serum analysis in patients with severe CPMR during the preoperative workup for mitral valve surgery. Serum levels of N-terminal-pro hormone B-type natriuretic peptide, suppression of tumourigenicity 2, tumour necrosis factor α, Interleukin 6, FS-7-associated surface antigen (FAS), FAS ligand, matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, tissue inhibitor of matrix metalloproteinases (TIMP)-1 and TIMP-4 were determined using commercially available enzyme-linked immunosorbent assays. Myocardial levels of expression of the genes encoding these proteins were determined by multiplex gene expression analysis. Results: Serum and EMBs were obtained from 12 patients with CPMR at the time of preoperative cardiac catheterization. Overall, there was no significant correlation between the serum levels and gene expression levels for the markers evaluated in this study. A non-significant inverse correlation between serum MMP-2 and myocardial MMP-2 was noted (r = −0.343, P = 0.263). Conclusion: We found a poor correlation between the myocardial gene expression levels of several markers of adverse LV remodelling in patients with CPMR and the serum levels of these markers sampled at the same time.