Fibrosis and Fibrotic Gene Expression in Pediatric and Adult Patients With Idiopathic Dilated Cardiomyopathy.

BACKGROUND: Although fibrosis seems to be prognostic for adverse outcomes in adults with idiopathic dilated cardiomyopathy (IDC), little is known about the prevalence and development of fibrosis in pediatric IDC hearts. We hypothesized that there is less activation of fibrosis at a molecular level in pediatric IDC hearts than in failing adult hearts. METHODS AND RESULTS: Pediatric hearts were analyzed histologically to determine the prevalence of fibrosis. Left ventricular tissue from adult and pediatric IDC hearts and adult and pediatric nonfailing (NF) hearts were subjected to quantitative reverse-transcription polymerase chain reaction to study the expression of important mRNAs that affect fibrosis. We found age-specific differences between IDC and NF hearts in the regulation of noncoding galectin-3, Corin, matrix metalloproteinase (MMP) 2, MMP-9, tissue inhibitor of metalloproteinase (TIMP) 2, and TIMP-3. We also found markers that were similarly altered in both adult and pediatric IDC hearts (interleukin-1 receptor-like 1 receptor, TIMP-1, and TIMP-4). Finally, microRNAs 29a-c were significantly decreased in the pediatric IDC patients. CONCLUSIONS: Pediatric IDC patients demonstrate age-specific differences in the molecular pathways implicated in fibrosis in the adult heart. At the ultrastructural level the unique gene expression pattern appears to limit fibrosis in the failing pediatric heart.

Basal wall hypercontraction of Takotsubo cardiomyopathy in a patient who had been diagnosed with dilated cardiomyopathy: a case report.

BACKGROUND: Takotsubo cardiomyopathy is characterized by the basal hypercontractility and apical ballooning of the left ventriculum and T-wave inversion in the electrocardiogram. It has been suggested that Takotsubo cardiomyopathy might underlie the pathogenesis of persistent cardiac dysfunction; however, few reports are present demonstrating the advent of Takotsubo cardiomyopathy in patients with idiopathic cardiomyopathy. CASE PRESENTATION: A 64-year-old women was admitted due to dyspnea on effort and lower extremity edema. She had been diagnosed with idiopathic dilated cardiomyopathy 2.5 years before owing to the reduced left ventricular ejection fraction (24%), normal coronary artery, and interstitial fibrosis of the myocardial samples. On admission, her electrocardiogram showed giant negative T wave in II, III, aVF, and precordial leads. Echocardiography showed dyskinesis of the left ventricular apex and hypercontraction of the basal wall, which had not been observed in the previous examinations. Coronary angiography showed normal coronary arteries, and apical ballooning and basal hypercontractility was confirmed by left ventriculography. On day 15 of admission, contraction of apical wall was recovered, and basal hypercontraction was disappeared. CONCLUSION: The present case is the first report demonstrating appearance the transient basal wall hypercontraction along with the advent of Takotsubo cardiomyopathy in a patient diagnosed with dilated cardiomyopathy. Whether such findings are indicative of fair prognosis and have the utility of understanding the pathogenesis of dilated cardiomyopathy needs further investigation.

The Impact of Known Heart Disease on Long-Term Outcomes of Catheter Ablation in Patients with Atrial Fibrillation and Left Ventricular Systolic Dysfunction: A Multicenter International Study.

BACKGROUND: Catheter ablation for AF is an effective treatment for patients with AF and systolic LV dysfunction; however, the clinical outcome is variable. We evaluated the impact of cardiomyopathy etiology on long-term outcomes post-catheter ablation. METHODS: Patients undergoing AF ablation across 3 centers (2 Australian, 1 UK) from 2002 to 2014, with LVEF<45% were evaluated. Patients were stratified into those with known heart disease as a cause of cardiomyopathy (KHD), and those with idiopathic dilated cardiomyopathy (IDCM). RESULTS: One hundred and one patients (IDCM = 77, KHD = 24) with AF and LVEF <45% underwent AF ablation. The KHD group (ischemic HD in 67%) were older (61 ± 7 vs. 55 ± 11 years, P = 0.005), with a higher CHADS2 score (2.0 ± 0.8 vs. 1.6 ± 0.7, P = 0.016), but otherwise well matched. After mean follow-up of 36 ± 23 months, AF control was greater in the IDCM group (82% vs. 50% in KHD, P < 0.001). On multivariate analysis IDCM was associated with long-term AF control (P = 0.033). The IDCM group had less functional impairment at follow-up (NYHA class 1.5 ± 0.7 vs. 2.0 ± 0.8, P = 0.005) and improved LVEF (50 ± 11% vs. 38 ± 10%, P < 0.001). Super responders (EF improvement >15%) were overwhelmingly in the IDCM group (94% vs. 6%, P < 0.001) with greater AF control (89% vs. 61%, P < 0.001). All-cause mortality was significantly higher in the KHD group (17% vs. 1.3%, P = 0.002). CONCLUSION: IDCM was associated with greater AF control, and improvement in symptoms and LVEF compared to patients with KHD post-AF ablation. AF is an important reversible cause of HF in patients with an unexplained CM and catheter ablation an effective treatment option.

Efficacy and Safety of Coenzyme Q10 Supplementation in Neonates, Infants and Children: An Overview.

To date, there have been no review articles specifically relating to the general efficacy and safety of coenzyme Q10 (CoQ10) supplementation in younger subjects. In this article, we therefore reviewed the efficacy and safety of CoQ10 supplementation in neonates (less than 1 month of age), infants (up to 1 year of age) and children (up to 12 years of age). As there is no rationale for the supplementation of CoQ10 in normal younger subjects (as there is in otherwise healthy older subjects), all of the articles in the medical literature reviewed in the present article therefore refer to the supplementation of CoQ10 in younger subjects with a variety of clinical disorders; these include primary CoQ10 deficiency, acyl CoA dehydrogenase deficiency, Duchenne muscular dystrophy, migraine, Down syndrome, ADHD, idiopathic cardiomyopathy and Friedreich's ataxia.

T-Cell Subpopulations Exhibit Distinct Recruitment Potential, Immunoregulatory Profile and Functional Characteristics in Chagas versus Idiopathic Dilated Cardiomyopathies.

Chronic Chagas cardiomyopathy (CCC) is one of the deadliest cardiomyopathies known and the most severe manifestation of Chagas disease, which is caused by infection with the parasite Trypanosoma cruzi. Idiopathic dilated cardiomyopathies (IDC) are a diverse group of inflammatory heart diseases that affect the myocardium and are clinically similar to CCC, often causing heart failure and death. While T-cells are critical for mediating cardiac pathology in CCC and IDC, the mechanisms underlying T-cell function in these cardiomyopathies are not well-defined. In this study, we sought to investigate the phenotypic and functional characteristics of T-cell subpopulations in CCC and IDC, aiming to clarify whether the inflammatory response is similar or distinct in these cardiomyopathies. We evaluated the expression of systemic cytokines, determined the sources of the different cytokines, the expression of their receptors, of cytotoxic molecules, and of molecules associated with recruitment to the heart by circulating CD4+, CD8+, and CD4-CD8- T-cells from CCC and IDC patients, using multiparameter flow cytometry combined with conventional and unsupervised machine-learning strategies. We also used an in silico approach to identify the expression of genes that code for key molecules related to T-cell function in hearts of patient with CCC and IDC. Our data demonstrated that CCC patients displayed a more robust systemic inflammatory cytokine production as compared to IDC. While CD8+ T-cells were highly activated in CCC as compared to IDC, CD4+ T-cells were more activated in IDC. In addition to differential expression of functional molecules, these cells also displayed distinct expression of molecules associated with recruitment to the heart. In silico analysis of gene transcripts in the cardiac tissue demonstrated a significant correlation between CD8 and inflammatory, cytotoxic and cardiotropic molecules in CCC transcripts, while no correlation with CD4 was observed. A positive correlation was observed between CD4 and perforin transcripts in hearts from IDC but not CCC, as compared to normal tissue. These data show a clearly distinct systemic and local cellular response in CCC and IDC, despite their similar cardiac impairment, which may contribute to identifying specific immunotherapeutic targets in these diseases.

Phenotypic Disease Network-Based Multimorbidity Analysis in Idiopathic Cardiomyopathy Patients with Hospital Discharge Records.

BACKGROUND: Idiopathic cardiomyopathy (ICM) is a rare disease affecting numerous physiological and biomolecular systems with multimorbidity. However, due to the small sample size of uncommon diseases, the whole spectrum of chronic disease co-occurrence, especially in developing nations, has not yet been investigated. To grasp the multimorbidity pattern, we aimed to present a multidimensional model for ICM and differences among age groups. METHODS: Hospital discharge records were collected from a rare disease centre of ICM inpatients (n = 1036) over 10 years (2012 to 2021) for this retrospective analysis. One-to-one matched controls were also included. First, by looking at the first three digits of the ICD-10 code, we concentrated on chronic illnesses with a prevalence of more than 1%. The ICM and control inpatients had a total of 71 and 69 chronic illnesses, respectively. Second, to evaluate the multimorbidity pattern in both groups, we built age-specific cosine-index-based multimorbidity networks. Third, the associated rule mining (ARM) assessed the comorbidities with heart failure for ICM, specifically. RESULTS: The comorbidity burden of ICM was 78% larger than that of the controls. All ages were affected by the burden, although those over 50 years old had more intense interactions. Moreover, in terms of disease connectivity, central, hub, and authority diseases were concentrated in the metabolic, musculoskeletal and connective tissue, genitourinary, eye and adnexa, respiratory, and digestive systems. According to the age-specific connection, the impaired coagulation function was required for raising attention (e.g., autoimmune-attacked digestive and musculoskeletal system disorders) in young adult groups (ICM patients aged 20-49 years). For the middle-aged (50-60 years) and older (≥70 years) groups, malignant neoplasm and circulatory issues were the main confrontable problems. Finally, according to the result of ARM, the comorbidities and comorbidity patterns of heart failure include diabetes mellitus and metabolic disorder, sleeping disorder, renal failure, liver, and circulatory diseases. CONCLUSIONS: The main cause of the comorbid load is aging. The ICM comorbidities were concentrated in the circulatory, metabolic, musculoskeletal and connective tissue, genitourinary, eye and adnexa, respiratory, and digestive systems. The network-based approach optimizes the integrated care of patients with ICM and advances our understanding of multimorbidity associated with the disease.

Genetic analysis resolves differential diagnosis of a familial syndromic dilated cardiomyopathy: A new case of Alström syndrome.

BACKGROUND: Syndromic dilated cardiomyopathy (DCM) includes a group of complex disorders with a very heterogeneous genetic etiology, leading to delay in definitive diagnosis. Conversely, an early genetic diagnosis is very important in determining the disease course, the prognosis, and may guide personalized treatments and family counseling. METHODS: We analyzed two brothers with a multisystemic disorder, including dilated cardiomyopathy, diabetes, bilateral neurosensorial hearing loss, and optic atrophy, using different genetic approaches, namely mitochondrial DNA sequencing, comparative genomic hybridization-array (a-CGH) and whole exome sequencing (WES). RESULTS: Sequencing of the wide mitochondrial genome revealed, in both brothers, the known homoplasmic variant rs2853826 in the subunit 3 of the NADH dehydrogenase gene (MT-ND3), whose pathogenicity was conflicting. Comparative genomic hybridization-array analysis revealed in both patients and their father two heterozygous deletions in Phosphodiesterase 4d-Interacting Protein (PDE4DIP) and Protocadherin-related 15 (PCDH15) genes, respectively. The use of WES detected a pathogenetic mutation in ALMS1, enabling the definitive diagnosis of Alström syndrome. CONCLUSION: We demonstrated how the diagnosis of a complex heterogeneous disease may be difficult, due to several overlapping manifestations and the possible interaction of more genetic variants that could lead to a more severe and complex phenotype. This paper strongly evidences how genomics is revolutionizing the diagnosis of rare complex disease, representing one of the most essential steps to enable a definitive diagnosis and to establish the etiology for diseases, such as syndromic DCM.

Dilated cardiomyopathy in a pediatric population: etiology and outcome predictors - a single-center experience.

AIM: The aim of the study was to assess predictors of outcome in patients hospitalized for dilated cardiomyopathy (DCM) and severe left ventricular dysfunction. Patients & methods: 83 pediatric patients hospitalized for heart failure due to DCM with coexistent left ventricular dysfunction were enrolled. RESULTS: Overall, 5-year survival free from heart transplantation was 69.8%. Normalization of left ventricular function was achieved in 39.8% of patients during follow-up: younger age, less necessity of inotropic support and other than idiopathic DCM predicted left ventricular function, while familial history for cardiac disease or sudden death and inotropic support during hospitalization were associated with poorer outcome. CONCLUSION: Almost 40% of patients with DCM experienced a complete normalization of cardiac function. Outcome was extremely variable according to the type of DCM.

The Association between Hypertensive Disorders of Pregnancy and Peripartum Cardiomyopathy.

Peripartum cardiomyopathy (PPCM) is a diagnosis of exclusion and a heterogeneous disorder that presents during the last month of pregnancy or the first five months postpartum. It is a rare but potentially life-threatening illness. A lot of work has been done trying to discover the causes of this condition, and several risk factors have been identified, including hypertension during pregnancy (HDP), ethnicity, advanced age, and multiple gestations. HDP affects 40% of cases of PPCM, and the strength of the association increases with increasing severity of hypertension. Among PPCM patients, there is a 1.5 times higher prevalence of HDP and a four-fold higher prevalence of preeclampsia (PE). Besides, the risk of PPCM markedly increases among women with HDP (5-21 times) compared with normotensive women. The experimental work done in animal models has provided support for the angiogenic-imbalance theory proposed regarding the association between these two conditions. The presence of the same risk factors also supports the prevalence of the coexistence of PE and PPCM. During the last part of gestation, the placenta secretes more anti-angiogenic factors, which leads to the development of both PE and PPCM. However, not all patients with HDP develop PPCM. In fact, most PPCM patients do not show any signs of HDP. Further work in these patients elucidated that there is an underlying susceptibility in some women that predisposes them to develop this condition and results in a worse prognosis as compared with those PPCM patients who have HDP. Better provision of care, genetic variations, and association with HDP have been cited as some of the factors affecting prognosis. HDP has also been found to increase the risk of other forms of cardiomyopathies in the future. A lot of work still needs to be done to uncover all the pathologic mechanisms and genetic variations involved in this disorder. More intensive and focussed research may help in developing new therapies to better manage this condition and address all of its complications.

Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction: The CAMERA-MRI Study.

BACKGROUND: Atrial fibrillation (AF) and left ventricular systolic dysfunction (LVSD) frequently co-exist despite adequate rate control. Existing randomized studies of AF and LVSD of varying etiologies have reported modest benefits with a rhythm control strategy. OBJECTIVES: The goal of this study was to determine whether catheter ablation (CA) for AF could improve LVSD compared with medical rate control (MRC) where the etiology of the LVSD was unexplained, apart from the presence of AF. METHODS: This multicenter, randomized clinical trial enrolled patients with persistent AF and idiopathic cardiomyopathy (left ventricular ejection fraction [LVEF] ≤45%). After optimization of rate control, patients underwent cardiac magnetic resonance (CMR) to assess LVEF and late gadolinium enhancement, indicative of ventricular fibrosis, before randomization to either CA or ongoing MRC. CA included pulmonary vein isolation and posterior wall isolation. AF burden post-CA was assessed by using an implanted loop recorder, and adequacy of MRC was assessed by using serial Holter monitoring. The primary endpoint was change in LVEF on repeat CMR at 6 months. RESULTS: A total of 301 patients were screened; 68 patients were enrolled between November 2013 and October 2016 and randomized with 33 in each arm (accounting for 2 dropouts). The average AF burden post-CA was 1.6 ± 5.0% at 6 months. In the intention-to-treat analysis, absolute LVEF improved by 18 ± 13% in the CA group compared with 4.4 ± 13% in the MRC group (p < 0.0001) and normalized (LVEF ≥50%) in 58% versus 9% (p = 0.0002). In those undergoing CA, the absence of late gadolinium enhancement predicted greater improvements in absolute LVEF (10.7%; p = 0.0069) and normalization at 6 months (73% vs. 29%; p = 0.0093). CONCLUSIONS: AF is an underappreciated reversible cause of LVSD in this population despite adequate rate control. The restoration of sinus rhythm with CA results in significant improvements in ventricular function, particularly in the absence of ventricular fibrosis on CMR. This outcome challenges the current treatment paradigm that rate control is the appropriate strategy in patients with AF and LVSD. (Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction [CAMERA-MRI]; ACTRN12613000880741).

Metabolic profiles in heart failure due to non-ischemic cardiomyopathy at rest and under exercise.

AIMS: Identification of metabolic signatures in heart failure (HF) patients and evaluation of their diagnostic potential to discriminate HF patients from healthy controls during baseline and exercise conditions. METHODS: Plasma samples were collected from 22 male HF patients with non-ischemic idiopathic cardiomyopathy and left ventricular systolic dysfunction and 19 healthy controls before (t0), at peak (t1) and 1 h after (t2) symptom-limited cardiopulmonary exercise testing. Two hundred fifty-two metabolites were quantified by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography (LC)-MS/MS-based metabolite profiling. RESULTS: Plasma metabolite profiles clearly differed between HF patients and controls at t0 (P < 0.05). The metabolic signature of HF was characterized by decreased levels of complex lipids and fatty acids, notably phosphatidylcholines, cholesterol, and sphingolipids. Moreover, reduced glutamine and increased glutamate plasma levels, significantly increased purine degradation products, as well as signs of impaired glucose metabolism were observed. The metabolic differences increased strongly according to New York Heart Association functional class and the addition of three metabolites further improved prediction of exercise capacity (Q2 = 0.24 to 0.35). Despite a high number of metabolites changing significantly with exercise (30.2% at t1/t0), the number of significant alterations between HF and controls was almost unchanged at t1 and t2 (30.7 and 29.0% vs. 31.3% at t0) with a similar predictive group separation (Q2 = 0.50 for t0, 0.52 for t1, and 0.56 for t2, respectively). CONCLUSIONS: Our study identified a metabolic signature of non-ischemic HF with prominent changes in complex lipids including phosphatidylcholines, cholesterol, and sphingolipids. The metabolic changes were already evident at rest and largely preserved under exercise.