Special Issue "Characterization and Clinical Management of Dilated Cardiomyopathy"

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Cardiology".

Deadline for manuscript submissions: 31 July 2020.

Special Issue Editor

Prof. Dr. Marco Merlo
Website
Guest Editor
Energy Department, Politecnico di Milano, Milano, Italy
Interests: heart failure; dilated cardiomyopathy; myocarditis; genetics; non-ischemic cardiomyopathy; cardiac magnetic resonance; long term survival; arrhythmic risk stratification; left ventricular reverse remodeling

Special Issue Information

Dear Colleagues,

Dilated cardiomyopathy (DCM) is a particular phenotype of non-ischemic systolic heart failure, frequently recognizing a genetic background and affecting relatively young patients with few comorbidities. Nowadays, long-term survival of DCM patients has been markedly improved due to an early diagnosis, and the uninterrupted and tailored follow-up under constant optimal medical and non-pharmacological evidence-based treatments. Nevertheless, DCM is still one of the most common causes of heart transplantation in the Western World. Clinical management requires an integrated and systematic use of diagnostic tools and a deeper investigation of the basic mechanisms underlying the disease. However, several emerging issues remain still debated. Specifically, the genotype-phenotype correlation, the role of advanced imaging techniques and genetic testing, the lack of appropriate risk stratification models, the need of multiparametric and multidisciplinary approach for device implantation, and a continuous reclassification of the disease during follow-up remain challenging issues in clinical practice.

Therefore, the aim of this special issue is to shed the light on the most recent advancements in characterization and clinical management of DCM, in order to unveil the conundrum of this particular disease.

Prof. Dr. Marco Merlo
Guest Editor

Manuscript Submission Information

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Keywords

  • dilated cardiomyopathy
  • non-ischemic cardiomyopathy
  • heart failure with reduced ejection fraction
  • genetics
  • cardiac magnetic resonance
  • long term survival
  • arrhythmic risk stratification

Published Papers (9 papers)

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Research

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Open AccessArticle
Left Ventricular Geometry and Replacement Fibrosis Detected by cMRI Are Associated with Major Adverse Cardiovascular Events in Nonischemic Dilated Cardiomyopathy
J. Clin. Med. 2020, 9(6), 1997; https://doi.org/10.3390/jcm9061997 - 25 Jun 2020
Abstract
To investigate the relationship between left ventricular (LV) long-axis strain (LAS) and LV sphericity index (LVSI) and outcomes in patients with nonischemic dilated cardiomyopathy (NIDCM) and myocardial replacement fibrosis confirmed by late gadolinium enhancement (LGE) using cardiac magnetic resonance imaging (cMRI), we conducted [...] Read more.
To investigate the relationship between left ventricular (LV) long-axis strain (LAS) and LV sphericity index (LVSI) and outcomes in patients with nonischemic dilated cardiomyopathy (NIDCM) and myocardial replacement fibrosis confirmed by late gadolinium enhancement (LGE) using cardiac magnetic resonance imaging (cMRI), we conducted a prospective study on 178 patients (48 ± 14.4 years; 25.2% women) with first NIDCM diagnosis. The evaluation protocol included ECG monitoring, echocardiography and cMRI. LAS and LVSI were cMRI-determined. Major adverse cardiovascular events (MACEs) were defined as a composite outcome including heart failure (HF), ventricular arrhythmias (VAs) and sudden cardiac death (SCD). After a median follow-up of 17 months, patients with LGE+ had increased risk of MACEs. Kaplan-Meier curves showed significantly higher rate of MACEs in patients with LGE+ (p < 0.001), increased LVSI (p < 0.01) and decreased LAS (p < 0.001). In Cox analysis, LAS (HR = 1.32, 95%CI (1.54–9.14), p = 0.001), LVSI [HR = 1.17, 95%CI (1.45–7.19), p < 0.01] and LGE+ (HR = 1.77, 95%CI (2.79–12.51), p < 0.0001) were independent predictors for MACEs. In a 4-point risk scoring system based on LV ejection fraction (LVEF) < 30%, LGE+, LAS > −7.8% and LVSI > 0.48%, patients with 3 and 4 points had a significantly higher risk for MACEs. LAS and LVSI are independent predictors of MACEs and provide incremental value beyond LVEF and LGE+ in patients with NIDCM and myocardial fibrosis. Full article
(This article belongs to the Special Issue Characterization and Clinical Management of Dilated Cardiomyopathy)
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Open AccessArticle
Epigenetic Regulation of Alternative mRNA Splicing in Dilated Cardiomyopathy
J. Clin. Med. 2020, 9(5), 1499; https://doi.org/10.3390/jcm9051499 - 16 May 2020
Abstract
In recent years, the genetic architecture of dilated cardiomyopathy (DCM) has been more thoroughly elucidated. However, there is still insufficient knowledge on the modifiers and regulatory principles that lead to the failure of myocardial function. The current study investigates the association of epigenome-wide [...] Read more.
In recent years, the genetic architecture of dilated cardiomyopathy (DCM) has been more thoroughly elucidated. However, there is still insufficient knowledge on the modifiers and regulatory principles that lead to the failure of myocardial function. The current study investigates the association of epigenome-wide DNA methylation and alternative splicing, both of which are important regulatory principles in DCM. We analyzed screening and replication cohorts of cases and controls and identified distinct transcriptomic patterns in the myocardium that differ significantly, and we identified a strong association of intronic DNA methylation and flanking exons usage (p < 2 × 10−16). By combining differential exon usage (DEU) and differential methylation regions (DMR), we found a significant change of regulation in important sarcomeric and other DCM-associated pathways. Interestingly, inverse regulation of Titin antisense non-coding RNA transcript splicing and DNA methylation of a locus reciprocal to TTN substantiate these findings and indicate an additional role for non-protein-coding transcripts. In summary, this study highlights for the first time the close interrelationship between genetic imprinting by DNA methylation and the transport of this epigenetic information towards the dynamic mRNA splicing landscape. This expands our knowledge of the genome–environment interaction in DCM besides simple gene expression regulation. Full article
(This article belongs to the Special Issue Characterization and Clinical Management of Dilated Cardiomyopathy)
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Open AccessArticle
Can Circulating Cardiac Biomarkers Be Helpful in the Assessment of LMNA Mutation Carriers?
J. Clin. Med. 2020, 9(5), 1443; https://doi.org/10.3390/jcm9051443 - 12 May 2020
Abstract
Mutations in the lamin A/C gene are variably phenotypically expressed; however, it is unclear whether circulating cardiac biomarkers are helpful in the detection and risk assessment of cardiolaminopathies. We sought to assess (1) clinical characteristics including serum biomarkers: high sensitivity troponin T (hsTnT) [...] Read more.
Mutations in the lamin A/C gene are variably phenotypically expressed; however, it is unclear whether circulating cardiac biomarkers are helpful in the detection and risk assessment of cardiolaminopathies. We sought to assess (1) clinical characteristics including serum biomarkers: high sensitivity troponin T (hsTnT) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) in clinically stable cardiolaminopathy patients, and (2) outcome among pathogenic/likely pathogenic lamin A/C gene (LMNA) mutation carriers. Our single-centre cohort included 53 patients from 21 families. Clinical, laboratory, follow-up data were analysed. Median follow-up was 1522 days. The earliest abnormality, emerging in the second and third decades of life, was elevated hsTnT (in 12% and in 27% of patients, respectively), followed by the presence of atrioventricular block, heart failure, and malignant ventricular arrhythmia (MVA). In patients with missense vs. other mutations, we found no difference in MVA occurrence and, surprisingly, worse transplant-free survival. Increased levels of both hsTnT and NT-proBNP were strongly associated with MVA occurrence (HR > 13, p ≤ 0.02 in both) in univariable analysis. In multivariable analysis, NT-proBNP level > 150 pg/mL was the only independent indicator of MVA. We conclude that assessment of circulating cardiac biomarkers may help in the detection and risk assessment of cardiolaminopathies. Full article
(This article belongs to the Special Issue Characterization and Clinical Management of Dilated Cardiomyopathy)
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Open AccessArticle
Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction
J. Clin. Med. 2020, 9(4), 937; https://doi.org/10.3390/jcm9040937 - 29 Mar 2020
Cited by 1
Abstract
Background: The pleomorphic clinical presentation makes the diagnosis of desminopathy difficult. We aimed to describe the prevalence, phenotypic expression, and mitochondrial function of individuals with putative disease-causing desmin (DES) variants identified in patients with an unexplained etiology of cardiomyopathy. Methods: A total of [...] Read more.
Background: The pleomorphic clinical presentation makes the diagnosis of desminopathy difficult. We aimed to describe the prevalence, phenotypic expression, and mitochondrial function of individuals with putative disease-causing desmin (DES) variants identified in patients with an unexplained etiology of cardiomyopathy. Methods: A total of 327 Czech patients underwent whole exome sequencing and detailed phenotyping in probands harboring DES variants. Results: Rare, conserved, and possibly pathogenic DES variants were identified in six (1.8%) probands. Two DES variants previously classified as variants of uncertain significance (p.(K43E), p.(S57L)), one novel DES variant (p.(A210D)), and two known pathogenic DES variants (p.(R406W), p.(R454W)) were associated with characteristic desmin-immunoreactive aggregates in myocardial and/or skeletal biopsy samples. The individual with the novel DES variant p.(Q364H) had a decreased myocardial expression of desmin with absent desmin aggregates in myocardial/skeletal muscle biopsy and presented with familial left ventricular non-compaction cardiomyopathy (LVNC), a relatively novel phenotype associated with desminopathy. An assessment of the mitochondrial function in four probands heterozygous for a disease-causing DES variant confirmed a decreased metabolic capacity of mitochondrial respiratory chain complexes in myocardial/skeletal muscle specimens, which was in case of myocardial succinate respiration more profound than in other cardiomyopathies. Conclusions: The presence of desminopathy should also be considered in individuals with LVNC, and in the differential diagnosis of mitochondrial diseases. Full article
(This article belongs to the Special Issue Characterization and Clinical Management of Dilated Cardiomyopathy)
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Open AccessArticle
Left Ventricular Noncompaction and Congenital Heart Disease Increases the Risk of Congestive Heart Failure
J. Clin. Med. 2020, 9(3), 785; https://doi.org/10.3390/jcm9030785 - 13 Mar 2020
Abstract
Background: Left ventricular noncompaction (LVNC) is a hereditary cardiomyopathy that is associated with high morbidity and mortality rates. Recently, LVNC was classified into several phenotypes including congenital heart disease (CHD). However, although LVNC and CHD are frequently observed, the role and clinical significance [...] Read more.
Background: Left ventricular noncompaction (LVNC) is a hereditary cardiomyopathy that is associated with high morbidity and mortality rates. Recently, LVNC was classified into several phenotypes including congenital heart disease (CHD). However, although LVNC and CHD are frequently observed, the role and clinical significance of genetics in these cardiomyopathies has not been fully evaluated. Therefore, we aimed to evaluate the impact on the perioperative outcomes of children with concomitant LVNC and CHD using next-generation sequencing (NGS). Methods: From May 2000 to August 2018, 53 Japanese probands with LVNC (25 males and 28 females) were enrolled and we screened 182 cardiomyopathy-associated genes in these patients using NGS. Results: The age at diagnosis of the enrolled patients ranged from 0 to 14 years (median: 0.3 months). A total of 23 patients (43.4%) were diagnosed with heart failure, 14 with heart murmur (26.4%), and 6 with cyanosis (11.3%). During the observation period, 31 patients (58.5%) experienced heart failure and 13 (24.5%) developed arrhythmias such as ventricular tachycardia, supraventricular tachycardia, and atrioventricular block. Moreover, 29 patients (54.7%) had ventricular septal defects (VSDs), 17 (32.1%) had atrial septal defects, 10 had patent ductus arteriosus (PDA), and 7 (13.2%) had Ebstein’s anomaly and double outlet right ventricle. Among the included patients, 30 underwent surgery, 19 underwent biventricular repair, and 2 underwent pulmonary artery banding, bilateral pulmonary artery banding, and PDA ligation. Overall, 30 genetic variants were identified in 28 patients with LVNC and CHD. Eight variants were detected in MYH7 and two in TPM1. Echocardiography showed lower ejection fractions and more thickened trabeculations in the left ventricle in patients with LVNC and CHD than in age-matched patients with VSDs. During follow-up, 4 patients died and the condition of 8 worsened postoperatively. The multivariable proportional hazards model showed that heart failure, LV ejection fraction of < 24%, LV end-diastolic diameter z-score of > 8.56, and noncompacted-to-compacted ratio of the left ventricular apex of > 8.33 at the last visit were risk factors for survival. Conclusions: LVNC and CHD are frequently associated with genetic abnormalities. Knowledge of the association between CHD and LVNC is important for the awareness of clinical implications during the preoperative and postoperative periods to identify the populations who are at an increased risk of additional morbidity. Full article
(This article belongs to the Special Issue Characterization and Clinical Management of Dilated Cardiomyopathy)
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Open AccessArticle
Tachycardiomyopathy in Patients without Underlying Structural Heart Disease
J. Clin. Med. 2019, 8(9), 1411; https://doi.org/10.3390/jcm8091411 - 08 Sep 2019
Cited by 1
Abstract
Tachycardiomyopathy (TCM) is an underestimated cause of reversible left ventricle dysfunction. The aim of this study was to identify the predictors of recurrence and incidence of major cardiovascular events in TCM patients without underlying structural heart disease (pure TCM). The prospective, observational study [...] Read more.
Tachycardiomyopathy (TCM) is an underestimated cause of reversible left ventricle dysfunction. The aim of this study was to identify the predictors of recurrence and incidence of major cardiovascular events in TCM patients without underlying structural heart disease (pure TCM). The prospective, observational study enrolled all consecutive pure TCM patients. The diagnosis was suspected in patients admitted for heart failure (HF) with a reduced ejection fraction and concomitant persistent arrhythmia. Pure TCM was confirmed after the clinical and echocardiographic recovery during follow-up. From 107 pure TCM patients (9% of all HF admission, the median follow-up 22.6 months), 17 recurred, 51 were hospitalized for cardiovascular reasons, two suffered from thromboembolic events and one died. The diagnosis of obstructive sleep apnoea syndrome (OSAS, hazard ratio (HR) 5.44), brain natriuretic peptide on admission (HR 1.01 for each pg/mL) and the heart rate at discharge (HR 1.05 for each bpm) were all independent predictors of TCM recurrence. The left ventricular ejection fraction at discharge (HR 0.96 for each%) and the heart rate at discharge (HR 1.02 for each bpm) resulted as independent predictors of cardiovascular-related hospitalization. Pure TCM is more common than previously thought and associated with a good long-term survival but recurrences and hospitalizations are frequent. Reversing OSAS and controlling the heart rate could prevent TCM-related complications. Full article
(This article belongs to the Special Issue Characterization and Clinical Management of Dilated Cardiomyopathy)
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Review

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Open AccessReview
Dysregulation of Calcium Handling in Duchenne Muscular Dystrophy-Associated Dilated Cardiomyopathy: Mechanisms and Experimental Therapeutic Strategies
J. Clin. Med. 2020, 9(2), 520; https://doi.org/10.3390/jcm9020520 - 14 Feb 2020
Abstract
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease resulting in the loss of dystrophin, a key cytoskeletal protein in the dystrophin-glycoprotein complex. Dystrophin connects the extracellular matrix with the cytoskeleton and stabilizes the sarcolemma. Cardiomyopathy is prominent in adolescents and young adults [...] Read more.
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease resulting in the loss of dystrophin, a key cytoskeletal protein in the dystrophin-glycoprotein complex. Dystrophin connects the extracellular matrix with the cytoskeleton and stabilizes the sarcolemma. Cardiomyopathy is prominent in adolescents and young adults with DMD, manifesting as dilated cardiomyopathy (DCM) in the later stages of disease. Sarcolemmal instability, leading to calcium mishandling and overload in the cardiac myocyte, is a key mechanistic contributor to muscle cell death, fibrosis, and diminished cardiac contractile function in DMD patients. Current therapies for DMD cardiomyopathy can slow disease progression, but they do not directly target aberrant calcium handling and calcium overload. Experimental therapeutic targets that address calcium mishandling and overload include membrane stabilization, inhibition of stretch-activated channels, ryanodine receptor stabilization, and augmentation of calcium cycling via modulation of the Serca2a/phospholamban (PLN) complex or cytosolic calcium buffering. This paper addresses what is known about the mechanistic basis of calcium mishandling in DCM, with a focus on DMD cardiomyopathy. Additionally, we discuss currently utilized therapies for DMD cardiomyopathy, and review experimental therapeutic strategies targeting the calcium handling defects in DCM and DMD cardiomyopathy. Full article
(This article belongs to the Special Issue Characterization and Clinical Management of Dilated Cardiomyopathy)
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Open AccessReview
Improved Left Atrial Function in CRT Responders: A Systematic Review and Meta-Analysis
J. Clin. Med. 2020, 9(2), 298; https://doi.org/10.3390/jcm9020298 - 21 Jan 2020
Abstract
Cardiac resynchronization therapy (CRT) is associated with reverse left atrial (LA) remodeling. The aim of this meta-analysis was to assess the relationship between clinical response to CRT and LA function changes. We conducted a systematic search of all electronic databases up to September [...] Read more.
Cardiac resynchronization therapy (CRT) is associated with reverse left atrial (LA) remodeling. The aim of this meta-analysis was to assess the relationship between clinical response to CRT and LA function changes. We conducted a systematic search of all electronic databases up to September 2019 which identified 488 patients from seven studies. At (mean) 6 months follow-up, LA systolic strain and emptying fraction (EF) were increased in CRT responders, with a −5.70% weighted mean difference (WMD) [95% confidence interval (CI) −8.37 to −3.04, p < 0.001 and a WMD of −8.98% [CI −15.1 to −2.84, p = 0.004], compared to non-responders. The increase in LA strain was associated with a fall in left ventricle (LV) end-systolic volume (LVESV) r = −0.56 (CI −0.68 to −0.40, p < 0.001) and an increase in the LV ejection fraction (LVEF) r = 0.58 (CI 0.42 to 0.69, p < 0.001). The increase in LA EF correlated with the fall in LVESV r = −0.51 (CI −0.63 to −0.36, p < 0.001) and the increase in the LVEF r = 0.48 (CI 0.33 to 0.61, p = 0.002). The increase in LA strain correlated with the increase in the LA EF, r = 0.57 (CI 0.43 to 0.70, p < 0.001). Thus, the improvement of LA function in CRT responders reflects LA reverse remodeling and is related to its ventricular counterpart. Full article
(This article belongs to the Special Issue Characterization and Clinical Management of Dilated Cardiomyopathy)
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Other

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Open AccessPerspective
Cardiac Sodium Channel Dysfunction and Dilated Cardiomyopathy: A Contemporary Reappraisal of Pathophysiological Concepts
J. Clin. Med. 2019, 8(7), 1029; https://doi.org/10.3390/jcm8071029 - 12 Jul 2019
Cited by 2
Abstract
A key emerging theme in translational cardiovascular medicine is the need to identify specific causes of arrhythmias and heart failure, defined by phenotype and/or genotype that will respond to a particular intervention. Unlike other genes implicated in hereditary arrhythmias and cardiomyopathies, pathogenic/likely pathogenic [...] Read more.
A key emerging theme in translational cardiovascular medicine is the need to identify specific causes of arrhythmias and heart failure, defined by phenotype and/or genotype that will respond to a particular intervention. Unlike other genes implicated in hereditary arrhythmias and cardiomyopathies, pathogenic/likely pathogenic variants in the cardiac sodium channel alpha subunit gene (SCN5A) produce a remarkably diverse set of electrical and structural phenotypes, one of them being dilated cardiomyopathy. There has been debate about whether left ventricular remodeling is a bona fide phenotypic feature of cardiac sodium channel dysfunction, or a consequence of tachyarrhythmias or conduction disturbances. In light of recent findings, a critical digest of the available experimental and medical literature is necessary. This paper provides a critical appraisal of the evidence linking a dysfunctional cardiac sodium channel to ventricular dysfunction, and discusses the potential mechanisms involved in shaping this phenotype along with implications for precision therapy. Full article
(This article belongs to the Special Issue Characterization and Clinical Management of Dilated Cardiomyopathy)
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