Editorial

3 pages, 205 KiB

Open AccessEditorial

Dilated Cardiomyopathy: A Paradigm of Revolution in Medicine

by Marco Merlo, Antonio Cannatà and Gianfranco Sinagra

J. Clin. Med. 2020, 9(11), 3385; https://doi.org/10.3390/jcm9113385 - 22 Oct 2020

Cited by 5 | Viewed by 1665

Dilated Cardiomyopathy (DCM) has a straightforward and apparently “simple” definition: a heart muscle disease characterized by left ventricular (LV) or biventricular dilation and systolic dysfunction in the absence of either pressure or volume overload or coronary artery disease sufficient enough to explain the [...] Read more.

Dilated Cardiomyopathy (DCM) has a straightforward and apparently “simple” definition: a heart muscle disease characterized by left ventricular (LV) or biventricular dilation and systolic dysfunction in the absence of either pressure or volume overload or coronary artery disease sufficient enough to explain the dysfunction [...] Full article

(This article belongs to the Special Issue Characterization and Clinical Management of Dilated Cardiomyopathy)

Research

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16 pages, 1275 KiB

Open AccessArticle

Characterization of Left Ventricular Non-Compaction Cardiomyopathy

by Rebeca Lorca, María Martín, Isaac Pascual, Aurora Astudillo, Beatriz Díaz Molina, Helena Cigarrán, Elías Cuesta-Llavona, Pablo Avanzas, José Julían Rodríguez Reguero, Eliecer Coto, César Morís and Juan Gómez

J. Clin. Med. 2020, 9(8), 2524; https://doi.org/10.3390/jcm9082524 - 05 Aug 2020

Cited by 13 | Viewed by 3648

Abstract

Left ventricle non-compaction cardiomyopathy (LVNC) has gained great interest in recent years, being one of the most controversial cardiomyopathies. There are several open debates, not only about its genetic heterogeneity, or about the possibility to be an acquired cardiomyopathy, but also about its [...] Read more.

Left ventricle non-compaction cardiomyopathy (LVNC) has gained great interest in recent years, being one of the most controversial cardiomyopathies. There are several open debates, not only about its genetic heterogeneity, or about the possibility to be an acquired cardiomyopathy, but also about its possible overdiagnosis based on imaging techniques. In order to better understand this entity, we identified 38 LVNC patients diagnosed by cardiac MRI (CMRI) or anatomopathological study that could underwent NGS-sequencing and clinical study. Anatomopathological exam was performed in eight available LVNC hearts. The genetic yield was 34.2%. Patients with negative genetic testing had better left ventricular ejection fraction (LVEF) or it showed a tendency to improve in follow-up, and a possible trigger factor for LVNC was identified in 1/3 of them. Nonetheless, cerebrovascular accidents occurred in similar proportions in both groups. We conclude that in LVNC there seem to be different ways to achieve the same final phenotype. Genetic testing has a good genetic yield and provides valuable information. LVNC without an underlying genetic cause may have a better prognosis in terms of LVEF evolution. However, anticoagulation to prevent cerebrovascular accident (CVA) should be carefully evaluated in all patients. Larger series with pathologic examination are needed to help better understand this entity. Full article

(This article belongs to the Special Issue Characterization and Clinical Management of Dilated Cardiomyopathy)

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11 pages, 1205 KiB

Open AccessArticle

Sex-Specific Prognostic Implications in Dilated Cardiomyopathy After Left Ventricular Reverse Remodeling

by Antonio Cannata, Paolo Manca, Vincenzo Nuzzi, Caterina Gregorio, Jessica Artico, Piero Gentile, Carola Pio Loco, Federica Ramani, Giulia Barbati, Marco Merlo and Gianfranco Sinagra

J. Clin. Med. 2020, 9(8), 2426; https://doi.org/10.3390/jcm9082426 - 29 Jul 2020

Cited by 10 | Viewed by 3324

Abstract

Background. Women affected by Dilated Cardiomyopathy (DCM) experience better outcomes compared to men. Whether a more pronounced Left Ventricular Reverse Remodelling (LVRR) might explain this is still unknown. Aim. We investigated the relationship between LVRR and sex and its long-term outcomes. Methods. A [...] Read more.

Background. Women affected by Dilated Cardiomyopathy (DCM) experience better outcomes compared to men. Whether a more pronounced Left Ventricular Reverse Remodelling (LVRR) might explain this is still unknown. Aim. We investigated the relationship between LVRR and sex and its long-term outcomes. Methods. A cohort of 605 DCM patients with available follow-up data was consecutively enrolled. LVRR was defined, at 24-month follow-up evaluation, as an increase in left ventricular ejection fraction (LVEF) ≥ 10% or a LVEF > 50% and a decrease ≥ 10% in indexed left ventricular end-diastolic diameter (LVEDDi) or an LVEDDi ≤ 33 mm/m². Outcome measures were a composite of all-cause mortality/heart transplantation (HTx) or ventricular assist device (VAD) and a composite of Sudden Cardiac Death (SCD) or Major Ventricular Arrhythmias (MVA). Results. 181 patients (30%) experienced LVRR. The cumulative incidence of LVRR at 24-months evaluation was comparable between sexes (33% vs. 29%; p = 0.26). During a median follow-up of 149 months, women experiencing LVRR had the lowest rate of main outcome measure (global p = 0.03) with a 71% relative risk reduction compared to men with LVRR, without significant difference between women without LVRR and males. A trend towards the same results was found regarding SCD/MVA (global p = 0.06). Applying a multi-state model, male sex emerged as an independent adverse prognostic factor even after LVRR completion. Conclusions. Although the rate of LVRR was comparable between sexes, females experiencing LVRR showed the best outcomes in the long term follow up compared to males and females without LVRR. Further studies are advocated to explain this difference in outcomes between sexes. Full article

(This article belongs to the Special Issue Characterization and Clinical Management of Dilated Cardiomyopathy)

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15 pages, 1921 KiB

Open AccessArticle

Left Ventricular Geometry and Replacement Fibrosis Detected by cMRI Are Associated with Major Adverse Cardiovascular Events in Nonischemic Dilated Cardiomyopathy

by Bianca Olivia Cojan-Minzat, Alexandru Zlibut, Ioana Danuta Muresan, Carmen Cionca, Dalma Horvat, Eva Kiss, Radu Revnic, Mira Florea, Razvan Ciortea and Lucia Agoston-Coldea

J. Clin. Med. 2020, 9(6), 1997; https://doi.org/10.3390/jcm9061997 - 25 Jun 2020

Cited by 9 | Viewed by 2910

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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18 pages, 7776 KiB

Open AccessArticle

Epigenetic Regulation of Alternative mRNA Splicing in Dilated Cardiomyopathy

by Weng-Tein Gi, Jan Haas, Farbod Sedaghat-Hamedani, Elham Kayvanpour, Rewati Tappu, David Hermann Lehmann, Omid Shirvani Samani, Michael Wisdom, Andreas Keller, Hugo A. Katus and Benjamin Meder

J. Clin. Med. 2020, 9(5), 1499; https://doi.org/10.3390/jcm9051499 - 16 May 2020

Cited by 12 | Viewed by 3730

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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16 pages, 1530 KiB

Open AccessArticle

Can Circulating Cardiac Biomarkers Be Helpful in the Assessment of LMNA Mutation Carriers?

by Przemyslaw Chmielewski, Ewa Michalak, Ilona Kowalik, Maria Franaszczyk, Malgorzata Sobieszczanska-Malek, Grazyna Truszkowska, Malgorzata Stepien-Wojno, Elzbieta Katarzyna Biernacka, Bogna Foss-Nieradko, Michal Lewandowski, Artur Oreziak, Maria Bilinska, Mariusz Kusmierczyk, Frédérique Tesson, Jacek Grzybowski, Tomasz Zielinski, Rafal Ploski and Zofia T. Bilinska

J. Clin. Med. 2020, 9(5), 1443; https://doi.org/10.3390/jcm9051443 - 12 May 2020

Cited by 9 | Viewed by 2347

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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19 pages, 2907 KiB

Open AccessArticle

Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction

by Miloš Kubánek, Tereza Schimerová, Lenka Piherová, Andreas Brodehl, Alice Krebsová, Sandra Ratnavadivel, Caroline Stanasiuk, Hana Hansíková, Jiří Zeman, Tomáš Paleček, Josef Houštěk, Zdeněk Drahota, Hana Nůsková, Jana Mikešová, Josef Zámečník, Milan Macek, Jr., Petr Ridzoň, Jana Malusková, Viktor Stránecký, Vojtěch Melenovský, Hendrik Milting and Stanislav Kmoch Show full author list Hide full author list

J. Clin. Med. 2020, 9(4), 937; https://doi.org/10.3390/jcm9040937 - 29 Mar 2020

Cited by 22 | Viewed by 5443

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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15 pages, 1012 KiB

Open AccessArticle

Left Ventricular Noncompaction and Congenital Heart Disease Increases the Risk of Congestive Heart Failure

by Keiichi Hirono, Yukiko Hata, Nariaki Miyao, Mako Okabe, Shinya Takarada, Hideyuki Nakaoka, Keijiro Ibuki, Sayaka Ozawa, Naoki Yoshimura, Naoki Nishida, Fukiko Ichida and LVNC study collaborators

J. Clin. Med. 2020, 9(3), 785; https://doi.org/10.3390/jcm9030785 - 13 Mar 2020

Cited by 22 | Viewed by 3617

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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13 pages, 1459 KiB

Open AccessArticle

Tachycardiomyopathy in Patients without Underlying Structural Heart Disease

by Giulia Stronati, Federico Guerra, Alessia Urbinati, Giuseppe Ciliberti, Laura Cipolletta and Alessandro Capucci

J. Clin. Med. 2019, 8(9), 1411; https://doi.org/10.3390/jcm8091411 - 08 Sep 2019

Cited by 11 | Viewed by 4037

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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18 pages, 947 KiB

Open AccessReview

Duchenne Dilated Cardiomyopathy: Cardiac Management from Prevention to Advanced Cardiovascular Therapies

by Rachele Adorisio, Erica Mencarelli, Nicoletta Cantarutti, Camilla Calvieri, Liliana Amato, Marianna Cicenia, Massimo Silvetti, Adele D’Amico, Maria Grandinetti, Fabrizio Drago and Antonio Amodeo

J. Clin. Med. 2020, 9(10), 3186; https://doi.org/10.3390/jcm9103186 - 01 Oct 2020

Cited by 23 | Viewed by 6854

Abstract

Duchenne muscular dystrophy (DMD) cardiomyopathy (DCM) is characterized by a hypokinetic, dilated phenotype progressively increasing with age. Regular cardiac care is crucial in DMD care. Early recognition and prophylactic use of angiotensin converting enzyme inhibitors (ACEi) are the main stay therapeutic strategy to [...] Read more.

Duchenne muscular dystrophy (DMD) cardiomyopathy (DCM) is characterized by a hypokinetic, dilated phenotype progressively increasing with age. Regular cardiac care is crucial in DMD care. Early recognition and prophylactic use of angiotensin converting enzyme inhibitors (ACEi) are the main stay therapeutic strategy to delay incidence of DMD-DCM. Pharmacological treatment to improve symptoms and left ventricle (LV) systolic function, have been widely implemented in the past years. Because of lack of DMD specific drugs, actual indications for established DCM include current treatment for heart failure (HF). This review focuses on current HF strategies to identify, characterize, and treat DMD-DCM. Full article

(This article belongs to the Special Issue Characterization and Clinical Management of Dilated Cardiomyopathy)

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17 pages, 2088 KiB

Open AccessReview

Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure

by Charles Tharp, Luisa Mestroni and Matthew Taylor

J. Clin. Med. 2020, 9(9), 2770; https://doi.org/10.3390/jcm9092770 - 26 Aug 2020

Cited by 16 | Viewed by 9532

Abstract

Titin is the largest human protein and an essential component of the cardiac sarcomere. With multiple immunoglobulin(Ig)-like domains that serve as molecular springs, titin contributes significantly to the passive tension, systolic function, and diastolic function of the heart. Mutations leading to early termination [...] Read more.

Titin is the largest human protein and an essential component of the cardiac sarcomere. With multiple immunoglobulin(Ig)-like domains that serve as molecular springs, titin contributes significantly to the passive tension, systolic function, and diastolic function of the heart. Mutations leading to early termination of titin are the most common genetic cause of dilated cardiomyopathy. Modifications of titin, which change protein length, and relative stiffness affect resting tension of the ventricle and are associated with acquired forms of heart failure. Transcriptional and post-translational changes that increase titin’s length and extensibility, making the sarcomere longer and softer, are associated with systolic dysfunction and left ventricular dilation. Modifications of titin that decrease its length and extensibility, making the sarcomere shorter and stiffer, are associated with diastolic dysfunction in animal models. There has been significant progress in understanding the mechanisms by which titin is modified. As molecular pathways that modify titin’s mechanical properties are elucidated, they represent therapeutic targets for treatment of both systolic and diastolic dysfunction. In this article, we review titin’s contribution to normal cardiac physiology, the pathophysiology of titin truncation variations leading to dilated cardiomyopathy, and transcriptional and post-translational modifications of titin. Emphasis is on how modification of titin can be utilized as a therapeutic target for treatment of heart failure. Full article

(This article belongs to the Special Issue Characterization and Clinical Management of Dilated Cardiomyopathy)

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32 pages, 2718 KiB

Open AccessReview

Dysregulation of Calcium Handling in Duchenne Muscular Dystrophy-Associated Dilated Cardiomyopathy: Mechanisms and Experimental Therapeutic Strategies

by Michelle L. Law, Houda Cohen, Ashley A. Martin, Addeli Bez Batti Angulski and Joseph M. Metzger

J. Clin. Med. 2020, 9(2), 520; https://doi.org/10.3390/jcm9020520 - 14 Feb 2020

Cited by 48 | Viewed by 6880

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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14 pages, 3673 KiB

Open AccessReview

Improved Left Atrial Function in CRT Responders: A Systematic Review and Meta-Analysis

by Ibadete Bytyçi, Gani Bajraktari, Per Lindqvist and Michael Y. Henein

J. Clin. Med. 2020, 9(2), 298; https://doi.org/10.3390/jcm9020298 - 21 Jan 2020

Cited by 6 | Viewed by 3825

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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8 pages, 3072 KiB

Open AccessPerspective

Cardiac Sodium Channel Dysfunction and Dilated Cardiomyopathy: A Contemporary Reappraisal of Pathophysiological Concepts

by Babken Asatryan

J. Clin. Med. 2019, 8(7), 1029; https://doi.org/10.3390/jcm8071029 - 12 Jul 2019

Cited by 13 | Viewed by 3727

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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