Gene correction and overexpression of TNNI3 improve impaired relaxation in engineered heart tissue model of pediatric restrictive cardiomyopathy.

Research on cardiomyopathy models using engineered heart tissue (EHT) created from disease-specific induced pluripotent stem cells (iPSCs) is advancing rapidly. However, the study of restrictive cardiomyopathy (RCM), a rare and intractable cardiomyopathy, remains at the experimental stage because there is currently no established method to replicate the hallmark phenotype of RCM, particularly diastolic dysfunction, in vitro. In this study, we generated iPSCs from a patient with early childhood-onset RCM harboring the TNNI3 R170W mutation (R170W-iPSCs). The properties of R170W-iPSC-derived cardiomyocytes (CMs) and EHTs were evaluated and compared with an isogenic iPSC line in which the mutation was corrected. Our results indicated altered calcium kinetics in R170W-iPSC-CMs, including prolonged tau, and an increased ratio of relaxation force to contractile force in R170W-EHTs. These properties were reversed in the isogenic line, suggesting that our model recapitulates impaired relaxation of RCM, i.e., diastolic dysfunction in clinical practice. Furthermore, overexpression of wild-type TNNI3 in R170W-iPSC-CMs and -EHTs effectively rescued impaired relaxation. These results highlight the potential efficacy of EHT, a modality that can accurately recapitulate diastolic dysfunction in vitro, to elucidate the pathophysiology of RCM, as well as the possible benefits of gene therapies for patients with RCM.

Overview of Restrictive Cardiomyopathies.

Restrictive cardiomyopathy (RCM) includes a heterogeneous group of diseases that cause increased myocardial stiffness, leading to impaired ventricular relaxation and severe diastolic dysfunction. Given that it is the least common type of cardiomyopathy, it can be a diagnostic challenge due to its varied pathogenesis, clinical presentation, and diagnostic evaluation. In this review, we provide an overview of different etiologies of RCM and examine the diagnostic and treatment approaches for various types.

Restrictive cardiomyopathy: from genetics and clinical overview to animal modeling.

Restrictive cardiomyopathy (RCM), a potentially devastating heart muscle disorder, is characterized by diastolic dysfunction due to abnormal muscle relaxation and myocardial stiffness resulting in restrictive filling of the ventricles. Diastolic dysfunction is often accompanied by left atrial or bi-atrial enlargement and normal ventricular size and systolic function. RCM is the rarest form of cardiomyopathy, accounting for 2-5% of pediatric cardiomyopathy cases, however, survival rates have been reported to be 82%, 80%, and 68% at 1-, 2-, and 5-years after diagnosis, respectively. RCM can be idiopathic, familial, or secondary to a systemic disorder, such as amyloidosis, sarcoidosis, and hereditary hemochromatosis. Approximately 30% of cases are familial RCM, and the genes that have been linked to RCM are cTnT, cTnI, MyBP-C, MYH7, MYL2, MYL3, DES, MYPN, TTN, BAG3, DCBLD2, LNMA, and FLNC. Increased Ca2+ sensitivity, sarcomere disruption, and protein aggregates are some of the few mechanisms of pathogenesis that have been revealed by studies utilizing cell lines and animal models. Additional exploration into the pathogenesis of RCM is necessary to create novel therapeutic strategies to reverse restrictive cardiomyopathic phenotypes.

Outcomes of Restrictive Cardiomyopathy in Japanese Children　- A Retrospective Cohort Study.

BACKGROUND: There has been no nationwide survey on the prognosis of pediatric restrictive cardiomyopathy (RCM) in Japan; therefore, this retrospective multicentered study was designed to investigate the long-term survival rate of pediatric patients with RCM in Japan.Methods and Results: A multicentered, retrospective observational study was performed between 1990 and 2014 and included patients diagnosed with RCM who were aged <18 years from 18 Japanese institutions. A total of 54 patients were diagnosed with RCM. The median age at diagnosis was 4.4 years, and the median duration of observation was 2.2 years at the time of this study. Of these patients, 54% had symptoms, including heart failure. Twelve patients died without heart transplantation, mostly due to heart failure. The median time to death from diagnosis was 2.5 years. Freedom from death at 1, 5, and 10 years was 91%, 68%, and 62%, respectively. Death occurred within 5 years of diagnosis in most patients. Twenty-two patients underwent heart transplantation. Freedom from heart transplantation at 1, 5, and 10 years was 77%, 58%, and 53%, respectively. Freedom from death or heart transplantation at 1, 5, and 10 years was 72%, 40%, and 34%, respectively. The presence of symptoms was a risk factor for death or transplantation. CONCLUSIONS: The prognosis of pediatric RCM is poor, and the heart transplantation rate is low in Japan.

Overexpression of human BAG3P209L in mice causes restrictive cardiomyopathy.

An amino acid exchange (P209L) in the HSPB8 binding site of the human co-chaperone BAG3 gives rise to severe childhood cardiomyopathy. To phenocopy the disease in mice and gain insight into its mechanisms, we generated humanized transgenic mouse models. Expression of human BAG3P209L-eGFP in mice caused Z-disc disintegration and formation of protein aggregates. This was accompanied by massive fibrosis resulting in early-onset restrictive cardiomyopathy with increased mortality as observed in patients. RNA-Seq and proteomics revealed changes in the protein quality control system and increased autophagy in hearts from hBAG3P209L-eGFP mice. The mutation renders hBAG3P209L less soluble in vivo and induces protein aggregation, but does not abrogate hBAG3 binding properties. In conclusion, we report a mouse model mimicking the human disease. Our data suggest that the disease mechanism is due to accumulation of hBAG3P209L and mouse Bag3, causing sequestering of components of the protein quality control system and autophagy machinery leading to sarcomere disruption.

[Non-compaction and restrictive cardiomyopathy in pediatrics: Two types of myocardial diseases that are important to recognize]. / Miocardiopatía no compactada y restrictiva en pediatría: Dos tipos de enfermedades del miocardio que son importantes saber reconocer.

Left ventricular non-compaction (LVNC) and restrictive cardiomyopathies (RCM) are rare diseases with high morbidity and mortality in the pediatric age group, particularly the restrictive. They can be diagnosed at any age even in fetal life, in isolation or association with other cardiomyopathies or congenital heart disease. The causes may be genetic, neuromuscular, metabolic, storage, or idiopathic disorders. The main morphological characteristic of LVNC is the presence of a non-compact myocar dium with numerous prominent trabeculations and deep recesses, which may results in myocardial dysfunction, malignant arrhythmias and thromboembolism. On the other hand, in RCM there is an abnormal myocardial stiffness, which generates a restrictive ventricular filling and atrial dilatation secondary. Clinically it manifested by severe diastolic dysfunction, pulmonary hypertension, arrhyth mias and sudden death. For both cardiomyopathies, the Doppler color echocardiography, electro cardiography and Holter monitoring of arrhythmias are the gold standard for diagnosis and follow up. Cardiac resonance adds information on functional assessment and quantification of myocardial fibrosis. The therapy is oriented to improve symptoms and quality of life. Patients with severe forms of LVNC and RCM may require extracorporeal ventricular support and cardiac transplantation, even in early stages of the disease. The pediatrician plays an important role in the early recognition of these pathologies for timing to referral as well as in the follow-up and screening for complications. The objective of this review is to update the clinical, genetic, diagnostic, therapeutic issues and prognostic of the LVNC and RCM.

Alpha-Loop for Permanent Pacemaker Implantation in Restrictive Cardiomyopathy.

High-grade and complete heart block commonly occurs in adult patients with restrictive cardiomyopathy, and requires aggressive monitoring and prophylactic pacemaker/defibrillator. There are limited data on the procedural details of pacemaker implantation in this group of patients, and as reported, special maneuvers may be required for ventricular lead placement.

[A practical approach to the diagnosis of cardiomyopathy: a roadmap from the phenotype]. / Un approccio pratico alla diagnosi di cardiomiopatia: una roadmap a partire dal fenotipo.

Cardiomyopathies are a heterogeneous group of cardiac diseases for which diagnosis and treatment are not always simple. The diagnosis of cardiomyopathy, in particular the etiology, comes from an integration between symptoms and results collected by several instrumental exams. The brain storming for the diagnosis includes also the identification of the "red flags", i.e. the pathognomonic features for each etiology that can drive the choice of appropriate diagnostic tests and therapy. In this review, we provide a step by step approach in order to help cardiologists, not specifically dedicated to cardiomyopathies, to draw the diagnosis, therapy and follow-up. This approach will be accompanied by the consultation of other specialists to discuss together the results of the exams performed and to deepen extracardiac signs and symptoms.

Hemodynamics of constrictive pericarditis and restrictive cardiomyopathy.

Constrictive pericarditis (CP) and restrictive cardiomyopathy (RCM) are indolent disabling diseases of diastolic function. The two conditions share common pathophysiologic features, resulting in similar and overlapping clinical presentations, echocardiographic findings, and hemodynamic characteristics. However, their clinical course differs, as CP is surgically curable whereas RCM is a chronic condition managed medically. Separating these two entities is based on delineation of anatomic and physiologic derangements employing multimodality hemodynamic interrogation by advanced imaging techniques (Echo-Doppler, CT, and especially MRI) combined with sophisticated invasive hemodynamics.

Endomyocardial Fibrosis: an Update After 70 Years.

PURPOSE OF REVIEW: This review aims at highlighting the need to better understand the pathogenesis and natural history of endomyocardial fibrosis when set against its changing endemicity and disease burden, improvements in diagnosis, and new options for clinical management. RECENT FINDINGS: Progress in imaging diagnostic techniques and availability of new targets for drug and surgical treatment of heart failure are contributing to earlier diagnosis and may lead to improvement in patient survival. Endomyocardial fibrosis was first described in Uganda by Davies more than 70 years ago (1948). Despite its poor prognosis, the etiology of this neglected tropical restrictive cardiomyopathy still remains enigmatic nowadays. Our review reflects on the journey of scientific discovery and construction of the current guiding concepts on this mysterious and fascinating condition, bringing to light the contemporary knowledge acquired over these years. Here we describe novel tools for diagnosis, give an overview of the improvement in clinical management, and finally, suggest research themes that can help improve patient outcomes focusing (whenever possible) on novel players coming into action.

Heart failure in cardiomyopathies: a position paper from the Heart Failure Association of the European Society of Cardiology.

Cardiomyopathies are a heterogeneous group of heart muscle diseases and an important cause of heart failure (HF). Current knowledge on incidence, pathophysiology and natural history of HF in cardiomyopathies is limited, and distinct features of their therapeutic responses have not been systematically addressed. Therefore, this position paper focuses on epidemiology, pathophysiology, natural history and latest developments in treatment of HF in patients with dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathies. In DCM, HF with reduced ejection fraction (HFrEF) has high incidence and prevalence and represents the most frequent cause of death, despite improvements in treatment. In addition, advanced HF in DCM is one of the leading indications for heart transplantation. In HCM, HF with preserved ejection (HFpEF) affects most patients with obstructive, and ∼10% of patients with non-obstructive HCM. A timely treatment is important, since development of advanced HF, although rare in HCM, portends a poor prognosis. In RCM, HFpEF is common, while HFrEF occurs later and more frequently in amyloidosis or iron overload/haemochromatosis. Irrespective of RCM aetiology, HF is a harbinger of a poor outcome. Recent advances in our understanding of the mechanisms underlying the development of HF in cardiomyopathies have significant implications for therapeutic decision-making. In addition, new aetiology-specific treatment options (e.g. enzyme replacement therapy, transthyretin stabilizers, immunoadsorption, immunotherapy, etc.) have shown a potential to improve outcomes. Still, causative therapies of many cardiomyopathies are lacking, highlighting the need for the development of effective strategies to prevent and treat HF in cardiomyopathies.

Short-term Use of Ventricular Assist Device in a Patient With Restrictive Cardiomyopathy: A Case Report.

The CentriMag (Levitronix LLC, Waltham, MA, USA) ventricular assist device is a centrifugal pump designed for short-term support in patients with cardiogenic shock. In patients with restrictive physiology, there is some concern about the use of these devices due a very small ventricular cavity. We review the evolution of a 32-year-old woman with restrictive cardiomyopathy, moderate pulmonary hypertension, and severe biventricular systo-diastolic dysfunction in whom a biventricular Centrimag device was implanted due to a progressive clinical worsening.

Idiopathic Restrictive Cardiomyopathy in Children and Young Adults.

Idiopathic restrictive cardiomyopathy (IRC) is a rare condition characterized by reduced ventricular compliance. Children with IRC have poor outcomes with most patients proceeding to cardiac transplantation. We sought to analyze our institutional experience and assess contemporary outcomes for children with IRC. We reviewed the medical record for patients (<21 years old) evaluated for a primary diagnosis of IRC between 1975 and 2013 at our institution. Demographic, clinical, echocardiographic, and catheterization data were abstracted. The patients were divided into 2 groups comprising a historical cohort (HC) (diagnosis: 1975 to 1993, n = 8) and a contemporary cohort (CC) (diagnosis: 1994 to 2013, n = 12). Twenty children were identified with IRC (mean age at presentation 9.7 ± 6.5 years, 55% female). Mean length of follow-up was 6.5 ± 8.4 years (range 0.1 to 35.6 years). In the CC, 7 of 12 patients (58%) progressed to cardiac transplantation (mean age of 9 ± 4 years at transplant, mean interval from diagnosis of IRC: 1.5 ± 0.9 years). Overall survival was improved significantly in the CC compared with the HC (80% vs. 38%, p = 0.02), but transplantation free survival was no different between the CC and HC over 5 years (38% vs 38%, p = 0.65). In the CC, elevation of mitral valve Doppler E/e' ratio on echocardiography was associated with increased mortality (p = 0.01). In conclusion, IRC continues has a poor prognosis. Early referral for transplantation was associated with improved overall survival in the modern era. Patients with markedly elevated E/e' ratio may have increased risk of death.

The Cardiomyopathy Registry of the EURObservational Research Programme of the European Society of Cardiology: baseline data and contemporary management of adult patients with cardiomyopathies.

Aims: The Cardiomyopathy Registry of the EURObservational Research Programme is a prospective, observational, and multinational registry of consecutive patients with four cardiomyopathy subtypes: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM). We report the baseline characteristics and management of adults enrolled in the registry. Methods and results: A total of 3208 patients were enrolled by 69 centres in 18 countries [HCM (n = 1739); DCM (n = 1260); ARVC (n = 143); and RCM (n = 66)]. Differences between cardiomyopathy subtypes (P < 0.001) were observed for age at diagnosis, history of familial disease, history of sustained ventricular arrhythmia, use of magnetic resonance imaging or genetic testing, and implantation of defibrillators. When compared with probands, relatives had a lower age at diagnosis (P < 0.001), but a similar rate of symptoms and defibrillators. When compared with the Long-Term phase, patients of the Pilot phase (enrolled in more expert centres) had a more frequent rate of familial disease (P < 0.001), were more frequently diagnosed with a rare underlying disease (P < 0.001), and more frequently implanted with a defibrillator (P = 0.023). Comparing four geographical areas, patients from Southern Europe had a familial disease more frequently (P < 0.001), were more frequently diagnosed in the context of a family screening (P < 0.001), and more frequently diagnosed with a rare underlying disease (P < 0.001). Conclusion: By providing contemporary observational data on characteristics and management of patients with cardiomyopathies, the registry provides a platform for the evaluation of guideline implementation. Potential gaps with existing recommendations are discussed as well as some suggestions for improvement of health care provision in Europe.

Cardiac amyloidosis: An update on pathophysiology, diagnosis, and treatment.

The amyloidoses are a group of systemic diseases characterized by organ deposition of misfolded protein fragments of diverse origins. The natural history of the disease, involvement of other organs, and treatment options vary significantly based on the protein of origin. In AL amyloidosis, amyloid protein is derived from immunoglobulin light chains, and most often involves the kidneys and the heart. ATTR amyloidosis is categorized as mutant or wild-type depending on the genetic sequence of the transthyretin (TTR) protein produced by the liver. Wild-type ATTR amyloidosis mainly involves the heart, although the reported occurrence of bilateral carpal tunnel syndrome, spinal stenosis and biceps tendon rupture in these patients speaks to more generalized protein deposition. Mutant TTR is marked by cardiac and/or peripheral nervous system involvement. Cardiac involvement is associated with symptoms of heart failure, and dictates the clinical course of the disease. Cardiac amyloidosis can be diagnosed noninvasively by echocardiography, cardiac MRI, or nuclear scintigraphy. Endomyocardial biopsy may be needed in the case of equivocal imaging findings or discordant data. Treatment is aimed at relieving congestive symptoms and targeting the underlying amyloidogenic process. This includes anti-plasma cell therapy in AL amyloidosis, and stabilization of the TTR tetramer or inhibition of TTR protein production in ATTR amyloidosis. Cardiac transplantation can be considered in highly selected patients in tandem with therapy aimed at suppressing the amyloidogenic process, and appears associated with durable long-term survival.

Antimalarial-induced cardiomyopathy: a systematic review of the literature.

Background Antimalarials (AMs) are widely used in the treatment of connective tissue diseases. Their main side effect is retinal damage, while heart disease has been described in isolated cases. The aim of this study is to systematically review the existing literature on AM-induced cardiomyopathy (AMIC). Methods The PubMed database was searched for heart biopsy-confirmed AMIC cases. Information on demographics, clinical presentation, concomitant AM-related toxicity, cardiological investigations, treatment and outcome were collected. Descriptive statistics were used. Results Forty-seven cases (42 females) were identified with a mean age at diagnosis 56.4 ± 12.6 and mean AM treatment duration 12.7 ± 8.2 years. Systemic lupus erythematosus ( n = 19) and rheumatoid arthritis ( n = 18) were the most common primary diseases. Clinical presentation was that of congestive heart failure in 77%, while eight patients presented with syncope (17%). Complete atrioventricular block was reported in 17 patients; 24 received a permanent pacemaker (51%). Impaired systolic function was detected in 52.8%, bi-ventricular hypertrophy in 51.4% and restrictive filling pattern of the left ventricle in 18 patients. Cardiac magnetic resonance showed late gadolinium enhancement in seven cases, with a non-vascular pattern in the interventricular septum. Cardiomyocyte vacuolation was reported in all cases; intravacuolar lamellar and curvilinear bodies were observed in 46 (98%) and 42 (89.4%) respectively. Mortality rate was 45% (18/40). Conclusion AMIC is a rare, probably under-recognized, complication of prolonged AM treatment. It presents as a hypertrophic, restrictive cardiomyopathy with or without conduction abnormalities. Early recognition and drug withdrawal are critical with a survival rate of almost 55%.

Restrictive Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy.

Restrictive cardiomyopathy (RCM) is characterized by nondilated left or right ventricle with diastolic dysfunction. The restrictive cardiomyopathies are a heterogenous group of myocardial diseases that vary according to pathogenesis, clinical presentation, diagnostic evaluation and criteria, treatment, and prognosis. In this review, an overview of RCMs will be presented followed by a detailed discussion on 3 major causes of RCM, for which tailored interventions are available: cardiac amyloidosis, cardiac sarcoidosis, and cardiac hemochromatosis. Each of these 3 RCMs is challenging to diagnose, and recognition of each disease entity is frequently delayed. Clinical clues to promote recognition of cardiac amyloidosis, cardiac sarcoidosis, and cardiac hemochromatosis and imaging techniques used to facilitate diagnosis are discussed. Disease-specific therapies are reviewed. Early recognition remains a key barrier to improving survival in all RCMs.

Clinical features of idiopathic restrictive cardiomyopathy: A retrospective multicenter cohort study over 2 decades.

Idiopathic restrictive cardiomyopathy (RCMP) has not been fully understood because this disease is difficult to diagnose. The present study aimed to assess the clinical profile and outcome of idiopathic RCMP from a multicenter cohort.This investigation is a retrospective study of consecutive patients with idiopathic RCMP at 10 centers in Korea between 1990 and 2010. We evaluated the clinical characteristics of the patients and prognostic factors associated with mortality using multivariate Cox proportional hazards regression analyses.The study included 53 patients (26 men, 49.1%). During a median follow-up of 1.7 years, 17 patients (32.1%) died and 5 patients (9.4%) received a heart transplant. The 5-year survival rate of the overall patients was 64.4% ±â€Š7.8%. In multivariable analyses, the predictors of mortality were tricuspid regurgitation (TR) ≥ moderate (hazard ratio [HR] 32.55, P < .001) and left ventricular end-diastolic diameter (LVEDD) (HR 0.85, P < .001).Idiopathic RCMP showed unfavorable prognosis. Advanced TR and lower LVEDD are independent adverse predictors of mortality in patients with idiopathic RCMP.