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Fractalkine/CXCR1 in Dilated Cardiomyopathy: A Potential Future Target for Immunomodulatory Therapy?Cells Sep 2023Dilated cardiomyopathy (DCM) is a cardiac condition with structural and functional impairment, where either the left ventricle or both ventricular chambers are enlarged,... (Review)
Review
Dilated cardiomyopathy (DCM) is a cardiac condition with structural and functional impairment, where either the left ventricle or both ventricular chambers are enlarged, coinciding with reduced systolic pump function (reduced ejection fraction, rEF). The prevalence of DCM is more than 1:250 individuals, and mortality largely due to heart failure in two-third of cases, and sudden cardiac death in one-third of patients. Damage to the myocardium, whether from a genetic or environmental cause such as viruses, triggers inflammation and recruits immune cells to the heart to repair the myocardium. Examination of myocardial biopsy tissue often reveals an inflammatory cell infiltrate, T lymphocyte (T cell) infiltration, or other activated immune cells. Despite medical therapy, adverse outcomes for DCM remain. The evidence base and existing literature suggest that upregulation of CXCR1, migration of immune cells, together with cytomegalovirus (CMV) seropositivity is associated with worse outcomes in patients with dilated cardiomyopathy. We hypothesise that this potentially occurs through cardiac inflammation and fibrosis, resulting in adverse remodelling. Immune modulators to target this pathway may potentially improve outcomes above and beyond current guideline-recommended therapy.
Topics: Humans; Cardiomyopathy, Dilated; CX3C Chemokine Receptor 1; Chemokine CX3CL1; Inflammation; Immunomodulation; Receptors, Complement 3b
PubMed: 37830591
DOI: 10.3390/cells12192377 -
Circulation Apr 2024Exercise-induced cardiac remodeling can be profound, resulting in clinical overlap with dilated cardiomyopathy, yet the significance of reduced ejection fraction (EF) in...
BACKGROUND
Exercise-induced cardiac remodeling can be profound, resulting in clinical overlap with dilated cardiomyopathy, yet the significance of reduced ejection fraction (EF) in athletes is unclear. The aim is to assess the prevalence, clinical consequences, and genetic predisposition of reduced EF in athletes.
METHODS
Young endurance athletes were recruited from elite training programs and underwent comprehensive cardiac phenotyping and genetic testing. Those with reduced EF using cardiac magnetic resonance imaging (defined as left ventricular EF <50%, or right ventricular EF <45%, or both) were compared with athletes with normal EF. A validated polygenic risk score for indexed left ventricular end-systolic volume (LVESVi-PRS), previously associated with dilated cardiomyopathy, was assessed. Clinical events were recorded over a mean of 4.4 years.
RESULTS
Of the 281 elite endurance athletes (22±8 years, 79.7% male) undergoing comprehensive assessment, 44 of 281 (15.7%) had reduced left ventricular EF (N=12; 4.3%), right ventricular EF (N=14; 5.0%), or both (N=18; 6.4%). Reduced EF was associated with a higher burden of ventricular premature beats (13.6% versus 3.8% with >100 ventricular premature beats/24 h; =0.008) and lower left ventricular global longitudinal strain (-17%±2% versus -19%±2%; <0.001). Athletes with reduced EF had a higher mean LVESVi-PRS (0.57±0.13 versus 0.51±0.14; =0.009) with athletes in the top decile of LVESVi-PRS having an 11-fold increase in the likelihood of reduced EF compared with those in the bottom decile (=0.034). Male sex and higher LVESVi-PRS were the only significant predictors of reduced EF in a multivariate analysis that included age and fitness. During follow-up, no athletes developed symptomatic heart failure or arrhythmias. Two athletes died, 1 from trauma and 1 from sudden cardiac death, the latter having a reduced right ventricular EF and a LVESVi-PRS >95%.
CONCLUSIONS
Reduced EF occurs in approximately 1 in 6 elite endurance athletes and is related to genetic predisposition in addition to exercise training. Genetic and imaging markers may help identify endurance athletes in whom scrutiny about long-term clinical outcomes may be appropriate.
REGISTRATION
URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374976&isReview=true; Unique identifier: ACTRN12618000716268.
Topics: Humans; Male; Cardiomyopathy, Dilated; Female; Athletes; Stroke Volume; Adult; Young Adult; Physical Endurance; Adolescent; Genetic Predisposition to Disease; Ventricular Remodeling; Ventricular Function, Left
PubMed: 38109351
DOI: 10.1161/CIRCULATIONAHA.122.063777 -
Medicina (Kaunas, Lithuania) Aug 2023Dilated cardiomyopathy (DCM), a primary myocardial disease, is characterized by dilation of the left or both ventricles and systolic dysfunction with or without... (Review)
Review
Dilated cardiomyopathy (DCM), a primary myocardial disease, is characterized by dilation of the left or both ventricles and systolic dysfunction with or without congestive heart failure. DCM per se is a well-recognized risk factor for sudden cardiac death and poor surgical outcomes following noncardiac surgery. Surgical trauma/stress represents unique challenges for DCM patient management. Unfortunately, there is a big knowledge gap in managing DCM patients undergoing non-cardiac surgery. Therefore, the aim of our review is to provide basic facts and current advances in DCM, as well as a practical guideline to perioperative care providers, for the management of surgical patients with DCM, who are quite rare compared with the general surgical population. This review summarizes recent advances in the medical management of DCM as well as perioperative assessment and management strategies for DCM patients undergoing noncardiac surgery. Optimal surgical outcomes depend on multiple-disciplinary care to minimize perioperative cardiovascular disturbances.
Topics: Humans; Cardiomyopathy, Dilated; Anesthetics; Heart Failure; Heart Ventricles; Knowledge
PubMed: 37763685
DOI: 10.3390/medicina59091567 -
Scientific Reports May 2022Dilated cardiomyopathy (DCM) is a primary myocardial disease of unclear mechanism and poor prevention. The purpose of this study is to explore the potential molecular...
Dilated cardiomyopathy (DCM) is a primary myocardial disease of unclear mechanism and poor prevention. The purpose of this study is to explore the potential molecular mechanisms and targets of DCM via bioinformatics methods and try to diagnose and prevent disease progression early. We screened 333 genes differentially expressed between DCM and normal heart samples from GSE141910, and further used Weighted correlation network analysis to identify 197 DCM-related genes. By identifying the key modules in the protein-protein interaction network and Least Absolute Shrinkage and Selection Operator regression analysis, seven hub DCM genes (CX3CR1, AGTR2, ADORA3, CXCL10, CXCL11, CXCL9, SAA1) were identified. Calculating the area under the receiver's operating curve revealed that these 7 genes have an excellent ability to diagnose and predict DCM. Based on this, we built a logistic regression model and drew a nomogram. The calibration curve showed that the actual incidence is basically the same as the predicted incidence; while the C-index values of the nomogram and the four external validation data sets are 0.95, 0.90, 0.96, and 0.737, respectively, showing excellent diagnostic and predictive ability; while the decision curve indicated the wide applicability of the nomogram is helpful for clinicians to make accurate decisions.
Topics: Cardiomyopathy, Dilated; Computational Biology; Humans; Nomograms; Protein Interaction Maps; Regression Analysis
PubMed: 35618744
DOI: 10.1038/s41598-022-13135-y -
Frontiers in Bioscience (Landmark... Sep 2023Macrophages expressing CC chemokine receptor 2 (CCR2) possess characteristics and performance akin to M1 polarized macrophages, which promote inflammation. Advanced...
BACKGROUND
Macrophages expressing CC chemokine receptor 2 (CCR2) possess characteristics and performance akin to M1 polarized macrophages, which promote inflammation. Advanced heart failure (HF) patients with higher abundance of CCR2+ macrophages are more likely to experience adverse remodeling. The precise mechanism of CCR2+ macrophages in how they affect the progression of dilated cardiomyopathy remains unknown.
METHODS
Cardiac biopsy samples from dilated cardiomyopathy patients (DCM) were used for immunohistochemistry and immunofluorescence staining. PCR is employed to identify the , , , , , , , , , , , , , , and mRNA expression of CCR2+ monocytes/macrophages from the peripheral blood of DCM patients. Seahorse was used to evaluate the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of CCR2+ monocytes/macrophages. 2-DG was used to simulate a lack of glucose. Lentivirus containing GLUT1 inhibitory sequence was used to knockdown GLUT1 gene expression of CCR2+ monocytes/macrophages. Western Blot and immunofluorescence staining was used to evaluate the expression of NLRP3.
RESULTS
Immunostaining results of cardiac biopsy tissue from dilated cardiomyopathy (DCM) patients demonstrated that the progression to HF was associated with an increase in the number of CCR2+ macrophages. PCR results demonstrated that CCR2 monocytes and macrophages derived from the blood of DCM patients expressed elevated levels of inflammatory factors and up regulation of glycolysis related genes. In addition, OCR and glucose uptake experiments confirmed that increased glucose uptake of these cells was associated with greater inflammation and correlated with a worsening of cardiac function. limiting the glucose supply to CCR2+ monocytes and macrophages, or suppressing the activity of glucose transporter 1 (GLUT1) could reduce inflammation levels.
CONCLUSIONS
These results suggest that CCR2+ monocytes and macrophages rely on metabolic reprogramming to trigger inflammatory response and contribute to myocardial injury and the progression of DCM.
Topics: Humans; Monocytes; Receptors, CCR2; Cardiomyopathy, Dilated; Glucose Transporter Type 1; Macrophages; Inflammation; Glucose
PubMed: 37796701
DOI: 10.31083/j.fbl2809223 -
Journal of the American College of... Sep 2022Although genotyping allows family screening and influences risk-stratification in patients with nonischemic dilated cardiomyopathy (DCM) or isolated left ventricular...
BACKGROUND
Although genotyping allows family screening and influences risk-stratification in patients with nonischemic dilated cardiomyopathy (DCM) or isolated left ventricular systolic dysfunction (LVSD), its result is negative in a significant number of patients, limiting its widespread adoption.
OBJECTIVES
This study sought to develop and externally validate a score that predicts the probability for a positive genetic test result (G+) in DCM/LVSD.
METHODS
Clinical, electrocardiogram, and echocardiographic variables were collected in 1,015 genotyped patients from Spain with DCM/LVSD. Multivariable logistic regression analysis was used to identify variables independently predicting G+, which were summed to create the Madrid Genotype Score. The external validation sample comprised 1,097 genotyped patients from the Maastricht and Trieste registries.
RESULTS
A G+ result was found in 377 (37%) and 289 (26%) patients from the derivation and validation cohorts, respectively. Independent predictors of a G+ result in the derivation cohort were: family history of DCM (OR: 2.29; 95% CI: 1.73-3.04; P < 0.001), low electrocardiogram voltage in peripheral leads (OR: 3.61; 95% CI: 2.38-5.49; P < 0.001), skeletal myopathy (OR: 3.42; 95% CI: 1.60-7.31; P = 0.001), absence of hypertension (OR: 2.28; 95% CI: 1.67-3.13; P < 0.001), and absence of left bundle branch block (OR: 3.58; 95% CI: 2.57-5.01; P < 0.001). A score containing these factors predicted a G+ result, ranging from 3% when all predictors were absent to 79% when ≥4 predictors were present. Internal validation provided a C-statistic of 0.74 (95% CI: 0.71-0.77) and a calibration slope of 0.94 (95% CI: 0.80-1.10). The C-statistic in the external validation cohort was 0.74 (95% CI: 0.71-0.78).
CONCLUSIONS
The Madrid Genotype Score is an accurate tool to predict a G+ result in DCM/LVSD.
Topics: Cardiomyopathy, Dilated; Cohort Studies; Genotype; Humans; Risk Factors; Ventricular Dysfunction, Left
PubMed: 36109106
DOI: 10.1016/j.jacc.2022.06.040 -
European Journal of Pediatrics Jan 2022Acute myocarditis is an inflammatory disease of the myocardium, and it can present as severe heart failure in children. Differential diagnosis with genetic...
Acute myocarditis is an inflammatory disease of the myocardium, and it can present as severe heart failure in children. Differential diagnosis with genetic cardiomyopathy can be difficult. The objective of this study is to identify patterns of clinical presentation and to assess invasive and non-invasive measures to differentiate patients with acute myocarditis from patients with dilated genetic cardiomyopathy. We performed a retrospective descriptive study of all paediatric patients (0-16 years old) that presented with new-onset heart failure with left ventricle ejection fraction < 35% in whom we performed an endomyocardial biopsy (EMB) during the period from April 2007 to December 2020. The patients were classified into two groups: Group 1 included 18 patients with myocarditis. Group 2 included 9 patients with genetic cardiomyopathy. Findings favouring a diagnosis of myocarditis included a fulminant or acute presentation (77.8% vs 33.3%, p = 0.01), higher degree of cardiac enzyme elevation (p = 0.011), lower left ventricular dimension z-score (2.2 vs 5.4, p = 0.03) increase of ventricular wall thickness (88.8% vs 33.3%, p = 0.03) and oedema in the EMB. Seven (77.8%) patients with genetic cardiomyopathy had inflammation in the endomyocardial biopsy fulfilling the diagnostic criteria of inflammatory cardiomyopathy.Conclusion: Differentiating patients with a myocarditis from those with genetic cardiomyopathy can be challenging, even performing an EMB. Some patients with genetic cardiomyopathy fulfil the diagnostic criteria of inflammatory cardiomyopathy. Using invasive and non-invasive measures may be useful to develop a predictive model to differentiate myocarditis from genetic cardiomyopathy. What is Known: • Acute myocarditis could present with cardiogenic shock in paediatric patients. • Parvovirus B19 is the main cause of myocarditis in this population. What is New: • Current diagnostic criteria for myocarditis have limited use in paediatric patients presenting with new-onset heart failure. • Some patients with a genetic cardiomyopathy and a new-onset heart failure fulfill the diagnostic criteria of inflammatory cardiomyopathy.
Topics: Adolescent; Biopsy; Cardiomyopathy, Dilated; Child; Child, Preschool; Humans; Infant; Infant, Newborn; Myocarditis; Myocardium; Retrospective Studies; Stroke Volume
PubMed: 34286374
DOI: 10.1007/s00431-021-04175-z -
ESC Heart Failure Jun 2023Dilated cardiomyopathy (DCM) belongs to the common types of cardiomyopathies. The pathogenesis remains unclear despite the fact that various genes have been found...
AIMS
Dilated cardiomyopathy (DCM) belongs to the common types of cardiomyopathies. The pathogenesis remains unclear despite the fact that various genes have been found associated with DCM. MMP2 is a zinc-dependent and calcium-containing secreted endoproteinases, which could cleave a broad spectrum of substrates including extracellular matrix components and cytokines. It has proved to play an important role in the cardiovascular diseases. This study aimed to investigate the potential role of MMP2 gene polymorphisms in DCM susceptibility and prognosis in a Chinese Han population.
METHODS AND RESULTS
A total of 600 idiopathic DCM patients and 700 healthy controls were enrolled. Patients with contact information were followed up for a median period of 28 months. Three tagged single nucleotide polymorphisms (rs243865, rs2285052, and rs2285053) in the promoter of MMP2 gene were genotyped. A series of function analysis were conducted to illuminate the underlying mechanism. The frequency of rs243865-C allele was increased in DCM patients when compared with healthy controls (P = 0.001). Genotypic frequencies of rs243865 were associated with the susceptibility of DCM in the codominant, dominant, and overdominant models (P < 0.05). Besides, rs243865-C allele presented a correlation with the poor prognosis of DCM patients in both dominant (HR = 2.0, 95% confidence interval [CI] = 1.14-3.57, P = 0.017) and additive (HR = 1.85, 95% CI = 1.09-3.13, P = 0.02) model. The statistical significance remained after adjustment for sex, age, hypertension, diabetes, hyperlipidaemia, and smoking status. There were significant differences in left ventricular end-diastolic diameter and left ventricular ejection fraction between rs243865-CC and CT genotypes. Functional analysis indicated that rs243865-C allele increased luciferase activity and the mRNA expression level of MMP2 by facilitating ZNF354C binding.
CONCLUSIONS
Our study suggested that MMP2 gene polymorphisms were associated with DCM susceptibility and prognosis in the Chinese Han population.
Topics: Humans; Cardiomyopathy, Dilated; Stroke Volume; Matrix Metalloproteinase 2; East Asian People; Ventricular Function, Left; Polymorphism, Single Nucleotide; Repressor Proteins
PubMed: 36866790
DOI: 10.1002/ehf2.14333 -
Orphanet Journal of Rare Diseases May 2022There are scarce publications regarding the presentation and outcome of Becker muscular dystrophy in adulthood when idiopathic dilated cardiomyopathy is the initial... (Review)
Review
There are scarce publications regarding the presentation and outcome of Becker muscular dystrophy in adulthood when idiopathic dilated cardiomyopathy is the initial disease manifestation. We performed a systematic review using Medline, Embase, Cochrane, and Scopus to identify cases of adults with idiopathic dilated cardiomyopathy who were subsequently diagnosed with Becker muscular dystrophy from inception through August 2020. Six cases were found. We identified young males (Median age: 26 years) with Becker muscular dystrophy who first presented with dilated cardiomyopathy. Most patients initially presented with congestive heart failure symptoms (5/6, 83%), and had a median left ventricular ejection fraction of 23%. One case did have calf pseudohypertrophy. Musculoskeletal symptoms later appeared one to six years after the initial dilated cardiomyopathy presentation. Heart transplantation was the most common management strategy (4/6, 67%). A left ventricular assist device was used in one case as a bridge to heart transplant. Dilated cardiomyopathy can be the initial presentation of Becker muscular dystrophy in the third to fourth decades of life in adult patients, and musculoskeletal symptoms can be subclinical.
Topics: Adult; Cardiomyopathy, Dilated; Heart Failure; Humans; Male; Muscular Dystrophy, Duchenne; Stroke Volume; Ventricular Function, Left
PubMed: 35549971
DOI: 10.1186/s13023-022-02346-1 -
Journal of Cardiovascular Magnetic...
Topics: Humans; Cardiomyopathy, Dilated; Predictive Value of Tests; Prognosis; Fractals; Image Interpretation, Computer-Assisted; Ventricular Function, Left; Magnetic Resonance Imaging; Reproducibility of Results
PubMed: 38309580
DOI: 10.1016/j.jocmr.2024.101004