Different Forms Of Cardiomyopathies Research Articles

Abstract 4118425: Prevalence and Spectrum of Pathogenic Genetic Variants in Korean Cardiomyopathy Patients: Insights from Next-Generation Sequencing

Background and Aim: Next-generation sequencing (NGS) is increasingly used to identify genetic variants associated with cardiomyopathies, which can aid in precise diagnosis and management. This study aimed to elucidate the prevalence and spectrum of pathogenic and likely pathogenic genetic variants in a cohort of Korean population diagnosed with different forms of cardiomyopathy. Methods: This retrospective study analyzed 122 patients diagnosed with cardiomyopathy at three tertiary hospitals in Korea, all of whom underwent NGS to identify genetic variants between December 2017 and October 2023. Detailed patient records, including clinical diagnoses, imaging results, and family histories, were reviewed to correlate genetic findings with phenotypic data. Results: Of the patients, 35 (28.7%) were found to have pathogenic or likely pathogenic variants, and 43 (35.2%) were found to have only variants of uncertain significance. Of the patients with pathogenic or likely pathogenic variants, 16 had hypertrophic cardiomyopathy (HCM) and 16 had dilated cardiomyopathy (DCM), while 3 remained with an uncertain clinical phenotype. In the HCM group, 16 patients exhibited variants predominantly in MYBPC3 (62.5%), followed by MYH7 (12.5%), and others such as TPM1, TNNI3, PRKAG2, and SCN5A (each 6.3%). Additionally, 43.8% of the HCM group had a familial history of sudden cardiac death or cardiomyopathy, with a mean left ventricular mass index (LVMi) of 148.3 ± 70.4 g/m2 and a mean maximal wall thickness of 17.7 ± 3.9 mm. The DCM group showed a different pattern, with TTN variants in 43.8%, LMNA in 18.8%, and others including MYBPC3, RBM20, TTN2, and KCNQ1 (each 6.3%). This group had a mean left ventricular ejection fraction (LVEF) of 27% and a LVMi of 119.7 g/m2. Conclusion: Our findings highlight significant genetic diversity in cardiomyopathies among Korean patients, with distinct genetic backgrounds observed in HCM and DCM. The high prevalence of specific mutations such as MYBPC3 in HCM and TTN in DCM could guide targeted genetic testing and personalized treatment strategies in these populations.

Generation of a patient-specific induced pluripotent stem cell line carrying the DES p.R406W mutation, an isogenic control and a DES p.R406W knock-in line

Mutations in the DES gene, which encodes the intermediate filament desmin, lead to desminopathy, a rare disease characterized by skeletal muscle weakness and different forms of cardiomyopathies associated with cardiac conduction defects and arrhythmias. We generated human induced pluripotent stem cells (hiPSC) from a patient carrying the DES p.R406W mutation, and employed CRISPR/Cas9 to rectify the mutation in the patient's hiPSC line and introduced the mutation in an hiPSC line from a control individual unrelated to the patient. These hiPSC lines represent useful models for delving into the mechanisms of desminopathy and developing new therapeutic approaches.

Regulatory Potential of Non-Coding RNAs Colocalized with Cardiomyopathy-Related Genes

Non-coding RNAs (ncRNAs) play an important role in the regulation of the activity of genes essential for the development and function of the cardiovascular system. Intragenic ncRNAs have been shown to be coordinately regulated and/or expressed with their host genes, including ncRNAs resided within cardiomyopathy (CMP)-related genes. This review summarizes the results of CMP-related intragenic ncRNA studies in the function of the healthy heart and in the development of different forms of CMPs. CMP-related intragenic ncRNAs such as miRNAs (miR-1, miR-133a, miR-208a, miR-208b, miR-324, miR-490, miR-499a) and long ncRNAs (MHRT, TTN-AS1 and KCNQ1OT1) are actively involved in research. It has been established that the level of these of ncRNAs in myocardium is characterized by developmental-stage-specific dynamics, gender-specific and chamber-specific patterns. These ncRNAs exhibit differential expression in myocardium/serum of humans and model animals under the influence of exogenous and endogenous factors. The expression levels of these ncRNAs in the myocardium/serum is associated with clinical features during the development and progression of CMPs. The change in the level of ncRNAs preceding clinical manifestation of CMPs have been reported. The possibility to arrest the development of CMPs and even the restoration of the normal phenotype by controlling the levels of these regulatory molecules indicate their involvement in the pathogenesis of the disease. miRNAs and long ncRNAs, whose genes resided within CMP-related genes, are involved in various metabolic processes that are important for the heart function, including their involvement in epigenetic processes.

Ventricular non-compaction review.

Left ventricular non-compaction cardiomyopathy (LVNC) is a rare and unclassified cardiomyopathy that carries the potential to cause heart failure, arrhythmias, and embolic events within adults. The diagnosis of this cardiomyopathy can be based off a variety of echocardiographic, cardiac magnetic resonance (CMR), and computed tomography (CT) imaging criteria; none of which have been standardized to establish a firm diagnosis. This is further complicated by the observation from prior studies that LVNC may present as different forms of cardiomyopathy, each with its own subset of nuances that may change treatment strategies. Management of such cardiomyopathy has been debated in terms of anticoagulation, electrophysiologic studies to prevent arrhythmia, as well as heart failure prevention. Not enough data exists in regard to establishing firm guidelines for management. The following article aims to provide a comprehensive review in regard to the etiologies, pathogenesis, diagnostic criteria, management, and treatment of LVNC.

Las enfermedades que produce el Coronavirus

We are living and suffering a unique medical experience right now. A small virus, of no more than 100 nanometers, from the coronavirus family, known as SARS-COV 2 or COVID-19 (Coronavirus Disease, 2019) began its expansion around the world, starting from the city of Wuham in China in the last months of 2019. In December of that year it was already recognized by the WHO authorities as a possible serious disease. Its extension has been gradual, but explosive, by more than 200 countries on all continents. Most of the infected (up to 80%) will pass their process asymptomatic. But the sick who develop the disease will do so to varying degrees. 40% mildly, paucisymptomatic, while the other 60% will present respiratory symptoms that in 15% will be severe and in 5% will place the patient in a critical situation. The most common clinical presentation is in the form of progressive bilateral bronchopneumonia, with hypoxemia and severe acute respiratory distress, which compromises the patient’s life. These are patients who will need hospital admission for treatment with respiratory assistance, and in critical situations, admission to intensive care units, to connect to assisted breathing, and if it is complicated by cardiac pathology, which can accompany a significant percentage of these severe patients, for circulatory support. These are the patients that reach a high mortality. The virus has a characteristic structure in which the single-stranded chain of RNA is enveloped by a series of proteins, among which the surface spicules that give it the characteristic shape, or S proteins, stand out. They serve as binding to specific receptors cells of the Angiotensin 2 Converting Enzyme, ECA2, with which it interacts. Through them it is introduced into the respiratory epithelial cells or the cardiovascular system and other organs. It uses the genetic structure of invaded cells to replicate and spread throughout the affected organ and throughout the body. The immune response system, both humoral and cellular, tries to stop the replicative stimulus of the virus. The resistance of the virus to limit its replication causes the uncontrolled response of anti-inflammatory mediators to continue, which is summarized in what is called a cytokine storm. This is the most important damage mechanism produced by the body’s response. Homeostatic balances are decompensated, both in maintaining blood pressure with critical hypotension and shock situations, and in the balance of pro and anticoagulant systems, with a general production of thrombi that produces the most serious complications, as well as the destruction of own anti-infective barriers. Pulmonary pathology progresses progressively from pneumonia to fibrosis, complicating many of the critically ill patients with pulmonary thromboembolism. Myocardial damage occurs in the circulatory system, with criteria for thrombosis and inflammation in the form of ischemic damage and different forms of cardiomyopathy. One of the most unique occurs specifically in the young population, in the form of a multisystemic hyperinflammatory response. But they can also damage the liver, kidney, central nervous system and other non-vital organs and systems.

Cardiac magnetic resonance in hypertrophic and dilated cardiomyopathies.

Cardiomyopathies are a heterogeneous entity. The progress in the field of genetics has allowed over the years to determine its origin more and more often. The classification of these pathologies has changed over the years; it has been updated with new knowledge. Imaging allows to define the phenotypic characteristics of the different forms of cardiomyopathy. Cardiac magnetic resonance (CMR) allows a morphological evaluation of the associated (and sometimes pathognomonic) cardiac findings of any form of cardiomyopathy. The tissue characterization sequences also make magnetic resonance imaging unique in its ability to detect changes in myocardial tissue. This review aims to define the features that can be highlighted by CMR in hypertrophic and dilated forms and the possible differential diagnoses. In hypertrophic forms, CMR provides: precise evaluation of wall thickness in all segments, ventricular function and size and evaluation of possible presence of areas of fibrosis as well as changes in myocardial tissue (measurement of T1 mapping and extracellular volume values). In dilated forms, cardiac resonance is the gold standard in the assessment of ventricular volumes. CMR highlights also the potential alterations of the myocardial tissue.

Proteomic Analysis of Myocardia Containing the Obscurin R4344Q Mutation Linked to Hypertrophic Cardiomyopathy.

Obscurin is a giant cytoskeletal protein with structural and regulatory roles encoded by the OBSCN gene. Recently, mutations in OBSCN were associated with the development of different forms of cardiomyopathies, including hypertrophic cardiomyopathy (HCM). We previously reported that homozygous mice carrying the HCM-linked R4344Q obscurin mutation develop arrhythmia by 1-year of age under sedentary conditions characterized by increased heart rate, frequent incidents of premature ventricular contractions, and episodes of spontaneous ventricular tachycardia. In an effort to delineate the molecular mechanisms that contribute to the observed arrhythmic phenotype, we subjected protein lysates prepared from left ventricles of 1-year old R4344Q and wild-type mice to comparative proteomics analysis using tandem mass spectrometry; raw data are available via ProteomeXchange with identifier PXD017314. We found that the expression levels of proteins involved in cardiac function and disease, cytoskeletal organization, electropotential regulation, molecular transport and metabolism were significantly altered. Moreover, phospho-proteomic evaluation revealed changes in the phosphorylation profile of Ca2+ cycling proteins, including sAnk1.5, a major binding partner of obscurin localized in the sarcoplasmic reticulum; notably, this is the first report indicating that sAnk1 undergoes phosphorylation. Taken together, our findings implicate obscurin in diverse cellular processes within the myocardium, which is consistent with its multiple binding partners, localization in different subcellular compartments, and disease association.

Physico-chemical properties of two point mutants of small heat shock protein HspB6 (Hsp20) with abrogated cardioprotection

Physico-chemical properties of HspB6 S10F and P20L mutants with abrogated cardioprotective activity and associated with different forms of cardiomyopathy were analyzed. Under normal conditions both the wild-type HspB6 and its mutants formed small size oligomers (dimers) with apparent molecular weight of 50–60 kDa. Under crowding conditions (0.5 M trimethylamine N-oxide, TMAO) the wild-type HspB6 remained predominantly dimeric or formed small molecular weight complexes, whereas both mutants tended to form high molecular weight complexes. Catalytic subunit of cAMP-dependent protein kinase phosphorylated the wild-type HspB6 and its S10F mutant with comparable rate. The rate of P20L mutant phosphorylation was higher than that of the wild-type HspB6. S10F and P20L mutations did not affect interaction of phosphorylated HspB6 with universal adapter proteins 14-3-3. The wild-type HspB6 was resistant to heat-induced denaturation and aggregation, whereas both its mutants were denatured and started to aggregate at temperature much lower than its wild-type counterpart. Titration with fluorescent probe bis-ANS was accompanied by larger increase of fluorescence in the case of both mutants than in the case of the wild-type HspB6. Both mutants possessed higher chaperone-like activity than the wild-type protein. It is concluded that both S10F and P20L mutations are accompanied by increase of hydrophobicity of the very N-terminal region of HspB6 leading to increased aggregation at elevated temperature, formation of large complexes under crowding conditions and increased chaperone-like activity measured in vitro. Increased hydrophobicity and self-association can affect substrate specificity and interaction with certain target proteins thus leading to decrease or complete abrogation of cardioprotective activity.

P6450Plasminogen activator inhibitor type-1 (PAI-1) expression relates to the presence of myocardial inflammation in patients with nonischemic cardiomyopathy

Abstract Background Plasminogen activator inhibitor type-1 (PAI-1) is an important inhibitor of the fibrinolytic pathway and an acute phase reactant in response to inflammatory cytokines, resulting in thrombosis, arteriosclerosis, and tissue fibrosis. It has been identified as a potential biomarker for coronary artery disease and metabolic syndrom. However, so far, nothing is known about its importance in nonischemic cardiomyopathy. Aims To analyzed PAI-1 expression in patients with different forms of cardiomyopathies and evaluate possible influence of PAI-1-dependent pathomechanisms in patients with intramyocardial inflammation. Methods and results In this study, endomyocardial biopsies (EMBs) from 309 patients (mean age 48.0±13.9 years) with different forms of cardiomyopathies were enrolled, including 123 patients with dilated cardiomyopathy (DCM) (mean LVEF 28.01±9.06%) and 186 patients with EMB-proven virus-negative inflammatory cardiomyopathy (DCMi) (mean LVEF 31.76±14.14%). 10 patients (mean LVEF 60.50±4.76%) without viral or inflammation in EMB served as controls. Hemodynamic parameters were measured by catheterization and echocardiography. EMBs were performed at first admission after exclusion of ischemic of valvular heart disease. In EMBs PAI-1 was assessed by immunohistology including digital imaging analysis. PAI-1 expression was significantly higher in patients with DCMi in contrast to DCM patients and controls (0.517±2.20 vs. 0.187±0.598 vs. 0.023±0.032% Area Fraction; p=0.0002). PAI-expression correlates significantly with lymphocytic infiltrates (for CD3 r=0.56, p<0.0001, and LFA-1 r=0.59, p<0.0001). This was found to be independent of hemodynamic parameters, and age. Conclusion Myocardial inflammation is associated with a significant increase in PAI-1 expression in DCMi independently of the hemodynamic conditions. This new pathophysiological axis could be a potiential therapeutic target in future treatment stategies in DCMi.

Non-familial cardiomyopathies in Lebanon: exome sequencing results for five idiopathic cases

BackgroundCardiomyopathies affect more than 0.5% of the general population. They are associated with high risk of sudden cardiac death, which can result from either heart failure or electrical abnormalities. Although different mechanisms underlie the various types of cardiomyopathies, a principal pathology is common to all and is usually at the level of the cardiac muscle. With a relatively high incidence rate in most countries, and a subsequent major health burden on both the families and governments, cardiomyopathies are gaining more attention by researchers and pharmaceutical companies as well as health government bodies. In Lebanon, there is no official data about the spectrum of the diseases in terms of their respective prevalence, clinical, or genetic profiles.MethodsWe used exome sequencing to unravel the genetic basis of idiopathic cases of cardiomyopathies in Lebanon, a relatively small country with high rates of consanguineous marriages.ResultsFive cases were diagnosed with different forms of cardiomyopathies, and exome sequencing revealed the presence of already documented or novel mutations in known genes in three cases: LMNA for an Emery Dreifuss Muscular Dystrophy case, PKP2 for an arrhythmogenic right ventricle dysplasia case, and MYPN for a dilated cardiomyopathy case. Interestingly two brothers with hypertrophic cardiomyopathy have a novel missense variation in NPR1, the gene encoding the natriuretic peptides receptor type I, not reported previously to be causing cardiomyopathies.ConclusionOur results unravel novel mutations in known genes implicated in cardiomyopathies in Lebanon. Changes in clinical management however, require genetic profiling of a larger cohort of patients.

The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC.

Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies.

Diagnostic clues for the diagnosis of nonsarcomeric hypertrophic cardiomyopathy (Phenocopies): Amyloidosis, fabry disease, and mitochondrial disease

Hypertrophic cardiomyopathy (HCM) is the most common known inherited heart disorder, with a prevalence of 1:500 of the adult population. Etiology of HCM can be heterogeneous, with sarcomeric gene disease as the leading cause in up to 60% of the patients, and with a number of possible different diseases (phenocopies) in about 10%–15% of the patients. Early diagnosis of storage and infiltrative disorders, particularly those with specific treatments (i.e., Fabry disease and/or amyloidosis), means early management and treatment, with a significant impact on patients prognosis. Here, we report on four different cases of HCM, highlighting difficulties to make differential diagnosis of different forms of cardiomyopathies, and their potential impact on the management.

Advanced Ngs Platforms in Molecular Diagnostics of Hypertrophic and Dilated Cardiomyopathies

In the wide scenery of heart pathologies the field of cardiomyopathies is one of those showing a great unreliability. After years of generic classifications the American Heart Association (AHA 2006) first, the European Society of Cardiology (ESC 2008) and just recently the MOGE’S Classification (2013), signed a decided step forward to depict more accurately the different forms of cardiomyopathies. During the last decades, technology improvement realized an important growing of knowledge, about clinical and diagnostics instrumental assessment of the cardiomyopathies. At the same time, the large diffusion of genetic and molecular diagnostic procedures, represent the powerful tool to create a more accurate correlation, between clinical evidences and genetic and molecular damage. Although the important advancements realized, we are still far away to understand why to determinate DNA aberration may correspond a wide range of cardiomyopathies, especially for hypertrophic (HCM) and dilated (DCM) forms, characterized by a different quality and quantity of myocardial damage. The poor alignment between genotypes and phenotypes of these cardiomyopathies is the main reason that makes this topic still obscure and scarcely understood. The newest and most advanced high throughput next generation sequencing (NGS) technologies, could represent, at the moment, the powerful tool able to realize a complete and rapid sequencing of the whole genome (WGS), exome (WES) or transcriptome. This goal is certainly a starting point for each patient affected of cardiomyopathy, making possible to individuate all the genetic mutations, genomic variations and epigenetic keys implicated in the myocardial structural damage. The aim of this work is to review and update the state of the art of the knowledge on Hypertrophic CM (HCM) and Dilatative CM (DCM).

Fast assessment of long axis strain with standard cardiovascular magnetic resonance: a validation study of a novel parameter with reference values.

BackgroundAssessment of longitudinal function with cardiovascular magnetic resonance (CMR) is limited to measurement of systolic excursion of the mitral annulus (MAPSE) or elaborate strain imaging modalities. The aim of this study was to develop a fast assessable parameter for the measurement of long axis strain (LAS) with CMR.Methods40 healthy volunteers and 125 patients with different forms of cardiomyopathy were retrospectively analyzed. Four different approaches for the assessment of LAS with CMR measuring the distance between the LV apex and a line connecting the origins of the mitral valve leaflets in enddiastole and endsystole were evaluated. Values for LAS were calculated according to the strain formula.ResultsLAS derived from the distance of the epicardial apical border to the midpoint of the line connecting the mitral valve insertion points (LAS-epi/mid) proved to be the most reliable parameter for the assessment of LAS among the different approaches.LAS-epi/mid displayed the highest sensitivity (81.6 %) and specificity (97.5 %), furthermore showing the best correlation with feature tracking (FTI) derived transmural longitudinal strain (r = 0.85). Moreover, LAS-epi/mid was non-inferior to FTI in discriminating controls from patients (Area under the curve (AUC) = 0.95 vs. 0.94, p = NS). The time required for analysis of LAS-epi/mid was significantly shorter than for FTI (67 ± 8 s vs. 180 ± 14 s, p < 0.0001). Additionally, LAS-epi/mid performed significantly better than MAPSE (Delta AUC = 0.09; p < 0.005) and the ejection fraction (Delta AUC = 0.11; p = 0.0002).Reference values were derived from 234 selected healthy volunteers. Mean value for LAS-epi/mid was −17.1 ± 2.3 %. Mean values for men were significantly lower compared to women (−16.5 ± 2.2 vs. -17.9 ± 2.1 %; p < 0.0001), while LAS decreased with age.ConclusionsLAS-epi/mid is a novel and fast assessable parameter for the analysis of global longitudinal function with non-inferiority compared to transmural longitudinal strain.

Keep your heart in shape: molecular chaperone networks for treating heart disease

Despite major advances in the treatment of cardiac diseases, there is still a great need for drugs capable of counteracting the deterioration of cardiac muscle function in congestive heart failure. The role of misfolded protein accumulation as a causal event in the physiopathology of common cardiac diseases is an important emerging concept. Indeed, diverse stress conditions, including mechanical stretching and oxidative stress, can induce misfolded protein accumulation, causing cardiomyocyte death. Cells react to these stress conditions by activating molecular chaperones, a class of proteins that represents an endogenous salvage machinery, essential for rescuing physiological cell functions and sustaining cell survival. Chaperones, also known as heat shock proteins (Hsps), prevent accumulation of damaged proteins by promoting either their refolding or degradation via the proteasome or the autophagosome systems. In addition, molecular chaperones play a key role in intracellular signalling by controlling conformational changes required for activation/deactivation of signalling proteins, and their assembly in specific signalosome complexes. The key role of molecular chaperones in heart function is highlighted by the fact that a number of genetic mutations in chaperone proteins result in different forms of cardiomyopathies. Moreover, a considerable amount of experimental evidence indicates that increasing expression of chaperone proteins leads to an important cardio-protective role in ischaemia/reperfusion injury, heart failure, and arrhythmia, implicating these molecules as potential innovative therapeutic agents.

Abstract P212: Haploinsufficiency of Target of Rapamycin Attenuates Different Forms of Cardiomyopathies in Adult Zebrafish

In contrast to the wide application of zebrafish embryos in developmental genetic studies, the value of an adult zebrafish to dissect signaling pathways in human diseases such as cardiomyopathy remains largely elusive. Previously, we have established anemic tr265/tr265 fish as the first adult zebrafish model of cardiomyopathy. Here, we generate the second adult zebrafish cardiomyopathy model induced by injection of a single bolus of doxorubicin (DOX). Despite their different pathogenesis, cardiac enlargement induced by either anemia or DOX can be effectively attenuated by inhibition of target of rapamycin (TOR) signaling via rapamycin treatment. However, along the progression of both models, we have also detected dynamic TOR activity and distinct effects of TOR signaling inhibition at different stages of pathogenesis. To assess the long term effects of TOR haploinsufficiency, we utilized a zebrafish target of rapamycin (ztor) mutant that was identified from a mutagenesis screen. We show that sustained TOR inhibition in ztor/+ improved cardiac function, prevented pathological remodeling events, and ultimately reduced mortality in both adult fish models of cardiomyopathy. Mechanistically, these cardioprotective effects are conveyed by the anti-hypertrophy, anti-apoptosis, and pro-autophagy function of TOR signaling inhibition. Together, our results prove adult zebrafish as a novel vertebrate model for human cardiomyopathies and provide genetic evidences for a cardioprotective function of TOR signaling inhibition in different forms of cardiomyopathies.

Speckle tracking: distinction of physiologic from pathologic LVH?

Speckle tracking: distinction of physiologic from pathologic LVH?

Expanded Spectrum of Gene Causing Both Hypertrophic Cardiomyopathy and Dilated Cardiomyopathy

See related articles, pages 375–382 Cardiomyopathy can be classified into at least four main forms, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), restrictive cardiomyopathy, and left ventricular noncompaction. HCM produces ventricular wall thickening, especially in the interventricular septum, with decrease in ventricular chamber volumes. DCM produces a prominent increase in chamber volumes without ventricular wall thickening. In HCM, systolic function is increased or at least preserved, whereas diastolic function is impaired in part because of the hypertrophy itself, interstitial fibrosis, and/or myocyte disarrays. Diastolic dysfunction is thought to be responsible for symptoms of heart failure and premature sudden cardiac death of HCM patients. In contrast, DCM is characterized by systolic dysfunction, which leads to congestive heart failure requiring cardiac transplantation. Restrictive cardiomyopathy is characterized by restrictive diastolic dysfunction (restrictive filling and reduced diastolic volume of either or both ventricles) with normal or near normal systolic function and wall thickness. Left ventricular noncompaction is characterized by deep trabeculation in the ventricular wall with systolic and diastolic dysfunction, arrhythmias, and thromboembolic events. More than 400 mutations that cause HCM, DCM, restrictive cardiomyopathy, and left ventricular noncompaction have been found in the genes for proteins constituting the sarcomere of cardiac muscle in human, including α- and β-myosin heavy chains, α-cardiac actin, cardiac troponin (cTn)T, cTnI, cTnC, α-tropomyosin (αTM), cardiac myosin-binding protein-C, cardiac myosin essential light chain, cardiac myosin regulatory light chain, and cardiac titin/connectin. Most mutations cause cardiomyopathies in an autosomal dominant manner. Interestingly, the same sarcomeric gene was found to be simultaneously responsible for different forms of cardiomyopathy.1,2 For example, many mutations in cTnT, cTnC, α-tropomyosin, α-cardiac actin, β-myosin heavy chain, and titin have been found in both HCM and primary DCM that is clearly distinguished from an end-stage …

Association between cardiac energy metabolism and gain of left ventricular mass in Fabry disease

Left ventricular (LV) hypertrophy is the hallmark of cardiac involvement in Fabry disease (FD). However, its pathogenesis is not clearly understood as pathologic substrate accumulation represents only 1-2% of the total cardiac mass. Abnormal myocardial energy metabolism has been previously demonstrated in different forms of cardiomyopathies. We hypothesized that myocardial energy status at the time of diagnosis could have a relationship to gain of LV mass in FD. In the group of 16 affected subjects, the indicators of energetic state of cardiac muscle determined by magnetic resonance spectroscopy showed significant negative correlation with annual increase in LV mass, evaluated during long-term follow-up (8 ± 3 years). Myocardial energy metabolism may therefore represent one of the mechanisms contributing to development of FD-related cardiomyopathy.

Duchenne muscular dystrophy; a cardiomyopathy that can be prevented?

Cardiac magnetic resonance imaging (CMR) has long been recognized as an accurate and reliable means of evaluating cardiac anatomy and ventricular function. Considerable progress has been made in the field of CMR, providing accurate evaluation of myocardial ischemia and infarction [1–3]. Contrast-enhanced CMR can be used to visualize the transmural extent of myocardial infarction with high spatial resolution [4–6]. Infarcted myocardium appears hyperenhanced compared with normal myocardium when imaged by a late enhancement MRI technique with the use of T1-weighted sequence after injection of gadolinium chelates. Late gadolinium-enhanced CMR can clearly delineate subendocardial infarction and the transmural extent of delayed enhancement potentially predicts functional outcome after revascularization in acute myocardial infarction and chronic ischemic heart disease [7]. Stress first-pass contrast-enhanced myocardial perfusion CMR can be used to detect subendocardial ischemia and recent studies have demonstrated the high diagnostic accuracy of stress myocardial perfusion CMR for detecting significant coronary artery disease [8–10]. Magnetic resonance angiography (MRA) was recently introduced as a method that can provide visualization of all three major coronary arteries, coronary bypasses, and the aorta within a single three-dimensional acquisition [11, 12]. CMR has become the first choice imaging modality in complex congenital heart disease [13–16] and imaging great vessels [17, 18]. In recent years, late gadolinium enhancement CMR has also been used to visualize myocardial interstitial abnormalities. Previous studies have clearly shown late enhancement patterns in patients with different forms of cardiomyopathies, amyloidosis, myocarditis, and storage diseases [19–22]. Silva et al. [20] showed that late gadolinium enhancement can be demonstrated in cardiomyopathy patients, with a mean signal intensity of 390 ± 220% compared with normal regions. The affected areas included papillary muscles (sarcoid), the mid-myocardium (Anderson-Fabry disease, glycogen storage disease, myocarditis, Becker, and Duchenne muscular dystrophy) and the global subendocardium (systemic sclerosis, Loeffler’s endocarditis, amyloid, and ChurgStrauss). Focal myocardial late gadolinium enhancement is found in the specific cardiomyopathies, and the pattern is distinct from that seen in myocardial infarction, recent studies have demonstrated right ventricular late gadolinium enhancement in patients with congenital heart disease and right ventricular loading conditions [14, 23]. Myocardial preservation is likely a multifactorial process that may affect the right and left ventricles differently [24–28]. B. J. M. Mulder Cardiology Department, B2-240, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands