Advances in Cardiomyopathies


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Patients who received diltiazem showed stable LV diameter and mean thickness-to-dimension ratio compared with control patients who showed a decrease and an increase in LV diameter and mean thickness-to-dimension ratio, respectively There has been pre-clinical evidence of the potential benefit of renin-angiotensin axis inhibition in modifying the course of HCM in a randomized controlled trial that included patients with obstructive and non-obstructive cardiomyopathy, but the administration of losartan, though well tolerated, did not show significant difference when compared with placebo with regard to the primary endpoint change in LV mass as measured by computed tomography or cardiac magnetic resonance imaging 80 , The presence of LGE has been used to identify patients with Duchenne and Becker muscular dystrophies who have normal LVEF but who are at higher risk of developing cardiac dysfunction.

In this particular patient population, treatment with eplerenone Duchenne and angiotensin-converting enzyme inhibitor Duchenne and Becker delayed and attenuated adverse cardiac remodeling 82 , The value of moderate exercise training in selected patients with HCM has been recently evaluated in a pilot randomized trial.

After 16 weeks, patients randomly assigned to the unsupervised exercise protocol had a small but significant increase in exercise capacity as measured by cardiopulmonary exercise testing with no significant adverse events In non-ischemic dilated cardiomyopathy, myocardial blood flow at rest and after cold pressor test improved after 12 weeks of cardiac rehabilitation MYK, a small molecule which binds to myosin decreasing its ATPase activity in a dose-dependent manner and consequently sarcomere contractility, has been shown to prevent the development of the HCM phenotype in a murine model of HCM if administered early 8—15 weeks of age in the pre-hypertrophic stage, and it partially reversed structural abnormalities if administered once the hypertrophic phenotype became manifest The intravenous administration of MYK decreased contractility and eliminated systolic anterior motion of the mitral valve, relieving outflow obstruction in a feline model of HCM Initial experience in humans shows encouraging results with a dose-dependent reduction of contractility and abolition of LV outflow gradients in two patients.

Of note, one patient experienced asystole after receiving the highest dose studied, but it resolved without intervention A hyper-tyrosil phosphorylated form of protein-zero related PZR is present in the hearts of mice with those conditions. Yi et al. The LMNA gene encodes lamins C and A that are the major constituents of nuclear lamina, a proteinaceous meshwork that gives structural support to the nucleus and enables correct gene expression and DNA repair.

Lamins A and C are generated through alternative splicing Laminopathies are a diverse group of disorders caused by LMNA gene mutations and the most common one is dilated cardiomyopathy Current pathophysiological mechanisms of LMNA mutations include increased susceptibility to mechanical stress, altered gene expression, and accumulation of pre-lamin A 92 , The feasibility of alternative splicing modulation with antisense oligonucleotides to increase lamin C and decrease pre-lamin A accumulation has been successfully tested in fibroblasts of patients with Hutchinson-Gilford progeria syndrome and a mouse model Constitutive activation of mammalian target of rapamycin complex 1 MTOR-1 by tuberous sclerosis mutations is a recognized mechanism of tumor formation in this syndrome.

In a patient with tuberous sclerosis and cardiomyopathy in which phosphorylation of ribosomal protein S6 marker of MTOR-1 activation was detected in endomyocardial biopsy, the administration of everolimus MTOR inhibitor led to improvement in systolic function and LV dimensions Increased understanding of the molecular mechanisms of heart failure have led to the recognition of potential targets for gene therapy Nevertheless, the absence of significant adverse events is promising and has helped to enhance the interest in this therapeutic strategy A recent phase II trial has shown a significant increase in LVEF in patients who received intracoronary delivery of adenovirus hAC6 when compared with placebo There was no evidence of myocardial scar as measured by LGE in patients on maximal medical therapy In a previous article, trans-endocardial injection of allogenic mesenchymal stem cells was superior to auto-mesenchymal stem cells in terms of efficacy LVEF improvement and 6-minute walk test and safety with an extremely low risk of allosensitization Novel therapies that block abnormal protein synthesis such as small interfering RNA and antisense oligonucleotides are undergoing phase III clinical trial evaluation in transthyretin amyloidosis, the most common form of cardiac amyloidosis In light-chain amyloidosis, the use of an amyloid fibril-reactive chimeric monoclonal antibody is undergoing clinical trial evaluation.

This approach was shown to be safe in a phase I clinical trial that included six patients with refractory amyloidosis. Those three patients showed organ response: two cardiac and one gastrointestinal Inflammation is a key player in the development and progression of heart failure Anti- tumor necrosis factor therapy has been shown to be ineffective and even potentially harmful in this patient population in large randomized clinical trials Non-specific immunomodulation was also unsuccessful in reducing death from any cause and hospitalization from cardiovascular causes There is increasing interest in the manipulation of the innate immune system Toll-like receptors, which are the primary receptors of the innate immune system and related molecules for example, myeloid differentiation 1 , constitute attractive targets that are the subject of intense research , In addition, the recognition that embryonic-derived macrophages that have anti-inflammatory properties and promote tissue regeneration are replaced in heart failure with monocyte-derived macrophages that have pro-inflammatory properties may open a new pathway to cardiac recovery In HCM, surgical septal myectomy often resolves mitral regurgitation related to systolic anterior motion of the mitral valve; nevertheless, some patients need additional mitral valve procedures such as mitral valve repair or replacement A novel operative technique that consists of trans-aortic cutting of thickened secondary mitral valve chordae seems to be effective in relieving outflow tract obstruction in patients with HCM and mild septal thickness with the advantage of avoiding additional mitral valve procedures The number of patients affected by cardiomyopathies is increasing.

Given the strong genetic basis of many cardiomyopathies, a complete family history is mandatory. Judicious use of cardiac imaging is extremely useful in defining the morpho-functional phenotype, informing prognosis, and detecting subclinical disease. Genetic testing is being increasingly incorporated into clinical practice.

MOGES classification provides a good framework to facilitate communication and patient classification. The use of patient-specific pluripotent stem cell-derived cardiomyocytes for disease modeling and therapeutic testing is exciting and hopefully will be incorporated into clinical practice in the near future. Gene therapy, small molecules, small interfering RNA, and antisense oligonucleotides are being tested in clinical trials.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. F Faculty Reviews are commissioned from members of the prestigious F Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published.

The referees who approved the final version are listed with their names and affiliations but without their reports on earlier versions any comments will already have been addressed in the published version. National Center for Biotechnology Information , U.

Introduction

Journal List FRes v. Version 1. Published online Sep 7. Author information Article notes Copyright and License information Disclaimer. Competing interests: The authors declare that they have no competing interests. Accepted Sep 8. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract Cardiomyopathy is a disease of the heart muscle leading to abnormal structure or function in the absence of coronary artery disease, hypertension, or valvular or congenital heart disease. Keywords: cardiomyopathy, heart transplant, cardiomyocytes. Introduction Cardiomyopathy is a disease of the heart muscle leading to abnormal structure or function in the absence of coronary artery disease, hypertension, or valvular or congenital heart disease 1.

Open in a separate window. Figure 1.


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Detection of abnormal structure and function Non-invasive diagnostic modalities Echocardiography is often the first diagnostic modality used when cardiomyopathy is suspected. Invasive diagnostics Invasive hemodynamic evaluation is particularly useful to differentiate restriction from constriction. Genetic evaluation and testing Most cardiomyopathies are monogenic disorders.

Precision medicine and emerging therapeutic strategies Precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability genes, environmental factors, and lifestyle and is of particular relevance for cardiomyopathy Gene therapy in cardiomyopathy and heart failure Increased understanding of the molecular mechanisms of heart failure have led to the recognition of potential targets for gene therapy New developments in treating amyloidosis Novel therapies that block abnormal protein synthesis such as small interfering RNA and antisense oligonucleotides are undergoing phase III clinical trial evaluation in transthyretin amyloidosis, the most common form of cardiac amyloidosis Immune modulation in heart failure Inflammation is a key player in the development and progression of heart failure New surgical approaches In HCM, surgical septal myectomy often resolves mitral regurgitation related to systolic anterior motion of the mitral valve; nevertheless, some patients need additional mitral valve procedures such as mitral valve repair or replacement Conclusions The number of patients affected by cardiomyopathies is increasing.

Notes [version 1; referees: 2 approved]. References 1. J Am Coll Cardiol. Since its first description in the s, much progress has been made in elucidating the extremely heterogeneous genetic, morphogenic, diagnosis, and patient management. The goals of this chapter are to outline the symptoms, complication, and diagnosis of HCM; update published pathogenic variants; and discuss current treatment and efforts to study HCM by using induced pluripotent stem cell-derived cardiomyocytes, next-generation sequencing, and gene editing technologies.

HCM is a common inherited cardiomyopathy with a diverse clinical presentation. Most patients with HCM are asymptomatic and have a normal life span but some develop symptoms. The most frequent symptoms of HCM included chest pain, dizziness, shortness of breath, palpitations, fatigue, and inability to perform vigorous exercise. Furthermore, HCM is related with disease complications that may be profound, with the potential to result in disease progression or premature death [ 8 , 9 ].

Heart failure is another severe complication of HCM. Symptoms of chronic heart failure are frequent; however, the clinical profile of advanced heart failure varies between patients. In some, the thickened and stiff ventricle reduces the compliance of the heart muscle, decreases preload, and contributes to diastolic heart failure [ 6 ]. On the other end of the spectrum, typical DCM cases show chamber volume dilatation and thin walls, which reduces contractile force and causes systolic heart failure [ 13 ]. Myocardial ischemia: the other common pathologic features of HCM are the thickened and narrowed intramural coronary arteries and myocardial fibrosis by increased collagen deposition, leading to symptoms related to myocardial ischemia [ 14 ].

Accurate diagnosis is vital for the management of HCM patients. Echocardiography is the primary method of diagnosis of HCM by determination of left ventricular hypertrophy LVH [ 15 ], left ventricular outflow tract gradients [ 16 ], systolic and diastolic function, as well as mitral valve anatomy and function.

Cardiac magnetic resonance imaging MRI is becoming more widely used in diagnosis of HCM by determining the extent and location of LVH and the anatomic abnormalities of the mitral valve and papillary muscles [ 17 ]. Besides, genetic testing that is now commercially available is currently used most effectively in the identification of affected relatives in families known to have HCM.

Echocardiography echo was first used to aid diagnosis in HCM in [ 18 ]. Forty years later, echo is central to diagnosis and monitoring of HCM. However, in some cases, genetic and nongenetic disorders may present with a lesser degrees of wall thickening 13—14 mm ; for these patients, the diagnosis of HCM requires evaluation of other factors including electrocardiogram ECG abnormalities, laboratory tests, and MRI, as well as family history [ 19 ].

It is clinically important to distinguish between the obstructive and nonobstructive forms of HCM because management strategies are largely dependent on the presence or absence of symptoms caused by obstruction. Definition of dynamic left ventricular outflow tract obstruction [ 2 ]. Magnetic resonance imaging MRI and computed tomography imaging are being used increasingly to evaluate patients with HCM.

Cardiovascular magnetic resonance CMR , with its superior spatial resolution as well as tomographic imaging capability, has provided the opportunity to more accurately characterize the diverse phenotypic expression of HCM [ 21 ]. CMR is mainly used in the following situations: 1 the patients are suspected with HCM, but the echocardiogram is inconclusive, mostly because of suboptimal imaging from poor acoustic windows or when hypertrophy is localized to regions of the LV myocardium not well visualized by echocardiography [ 22 ].

Hypertrophic cardiomyopathy is a common genetic cardiovascular disease. Since the identification of the first locus for familial HCM and the first mutation in MYH7-encoded beta-myosin heavy chain 20 years ago [ 25 ], over causal mutations associated with HCM encode sarcomeric proteins have been revealed [ 26 ]. Recently, large genotype-phenotype analysis correlation studies established implications for septal morphology, disease onset, and prognosis of certain sarcomeric genes, which may further facilitate commercialized genetic testing.

On the other hand, unexplained left ventricular hypertrophies that mimic HCM appear in some syndromic diseases. These diseases are usually called phenocopies and may contain rare variants in metabolism genes. These mutations alter myocardial metabolism, resulting in increased wall thickness, cardiac storage abnormalities, and conduction irregularities second to multiple systematic disorders. HCM susceptibility genes [ 28 ].

Although more than mutations linked to hypertrophic cardiomyopathy, most of which are unique to individual families and less evident for pathogenicity. Multiple studies revealed that single or combined function of miRNAs is directly involved in the pathophysiology of cardiac hypertrophy, fibrosis, and electrical remodeling in vivo and in vitro [ 33 ].

Since miRNAs play a more and more important role in the development of HCM, they are being studied for potential diagnostic biomarkers and a promising therapeutics for HCM. The schematic shows the miRNAs and their targets involving in cellular hypertrophy, gene switching, electrical remodeling, as well as fibrosis during cardiac hypertrophy.

An upward or a downward arrow is used to represent the upregulation or downregulation of a specific miRNA, respectively. As is typical for many forms of CVD, many current therapeutic strategies for HCM try to alleviate symptoms and prevent complications. Due to contemporary management strategies and treatment interventions, including ICDs for SD prevention, a variety of available surgical HCM mortality rates have dropped to 0.

It has been clearly demonstrated that left ventricular outflow tract obstruction at rest in HCM patients is a strong, independent predictor of progression to severe symptoms of heart failure and of death [ 48 ]. Considering the mechanisms underlying myocardial contraction calcium ions binding to troponin C and excitation-contraction coupling , a number of medical regimens have been used in these patients with the goal of lessening or eliminating the LVOT gradient through negative inotropy [ 7 ].

Small and mostly retrospective studies suggest that oral propranolol can abolish or reduce resting and provocable LVOTO and provide symptomatic benefit [ 49 , 50 ]. Archard, N. Bowles, L. Cunningham, C. Freeke, P. Morgan-Capner, E. Olsen et al. Anderson, J. Carlquist, M. Murray, J. Maisch, E. Bauer, M. Herzum, G. Hufnagel, T.

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Genetics of hypertrophic cardiomyopathy: advances and pitfalls in molecular diagnosis and therapy

Izumi, S. Nunoda et al. Biomolecular Changes in Dilated Cardiomyopathy. Schultheiss, U.


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  • Schulze, P. Schwimmbeck, B. De Maria, R. Accinni, G. Baroldi, A. Repossini, G. Garino-Canina, A. Caroli et al. Ultrastructural Changes in Myocarditis and Dilated Cardiomyopathy. Arbustini, A. Pucci, R. Pozzi, M. Grasso, G. Graziano, C. Campana et al. Hammond, J. Anderson, R. Sekiguchi, M. Hiroe, S. Nunoda, M. Hongo, T. Salvi, L. Dreas, A. Di Lenarda, F. Silvestri, E. Della Grazia, B. Pinamonti et al.

    Advances in the Genetic Basis and Pathogenesis of Sarcomere Cardiomyopathies.

    Immunosuppressive Therapy in Active Myocarditis. Immunosuppressive Therapy in Myocarditis —Month Follow-up. Myocardial Perfusion and Metabolism in Dilated Cardiomyopathy.

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