The clinical profile, genetic basis and survival of childhood cardiomyopathy: a single-center retrospective study.

Cardiomyopathy (CM) is a heterogeneous group of myocardial diseases in children. This study aimed to identify demographic features, clinical presentation and prognosis of children with CM. Clinical characteristics and prognostic factors associated with mortality were evaluated by Cox proportional hazards regression analyses. Genetic testing was also conducted on a portion of patients. Among the 317 patients, 40.1%, 25.2%, 24.6% and 10.1% were diagnosed with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), left ventricular noncompaction cardiomyopathy (LVNC) and restrictive cardiomyopathy (RCM), respectively. The most common symptom observed was dyspnea (84.2%). Except for HCM, the majority of patients were classified as NYHA/Ross class III or IV. The five-year survival rates were 75.5%, 67.3%, 74.1% and 51.1% in DCM, HCM, LVNC and RCM, respectively. The ten-year survival rates were 60.1%, 56.1%, 57.2% and 41.3% in DCM, HCM, LVNC and RCM, respectively. Survival was inversely related to NYHA/Ross class III or IV in patients with DCM, HCM and RCM. Out of 42 patients, 32 were reported to carry gene mutations. CONCLUSIONS: This study demonstrates that CM, especially RCM, is related to a high incidence of death. NYHA/Ross class III or IV is a predictor of mortality in the patients and gene mutations may be a common cause. TRIAL REGISTRATION: MR-50-23-011798. WHAT IS KNOWN: • Cardiomyopathy (CM) is a heterogeneous group of myocardial diseases and one of the leading causes of heart failure in children due to the lack of effective treatments. • There remains scarce data on Asian pediatric populations though emerging studies have assessed the clinical characteristics and outcomes of CM. WHAT IS NEW: • A retrospective study was conducted and the follow-up records were established to investigate the clinical characteristics, the profile of gene mutations and prognostic outcomes of children with CM in Western China. • CM, especially RCM, is related to a high incidence of death. NYHA/Ross class III or IV is a predictor of mortality in the patients and gene mutations may be a common cause.

Role of the Alpha-B-Crystallin Protein in Cardiomyopathic Disease.

Alpha-B-crystallin, a member of the small heat shock family of proteins, has been implicated in a variety of cardiomyopathies and in normal cardiac homeostasis. It is known to function as a molecular chaperone, particularly for desmin, but also interacts with a wide variety of additional proteins. The molecular chaperone function is also enhanced by signal-dependent phosphorylation at specific residues under stress conditions. Naturally occurring mutations in CRYAB, the gene that encodes alpha-B-crystallin, have been suggested to alter ionic intermolecular interactions that affect dimerization and chaperone function. These mutations have been associated with myofibrillar myopathy, restrictive cardiomyopathy, and hypertrophic cardiomyopathy and promote pathological hypertrophy through different mechanisms such as desmin aggregation, increased reductive stress, or activation of calcineurin-NFAT signaling. This review will discuss the known mechanisms by which alpha-B-crystallin functions in cardiac homeostasis and the pathogenesis of cardiomyopathies and provide insight into potential future areas of exploration.

Effects of diabetes mellitus on left ventricular function and deformation in patients with restrictive cardiomyopathies: a 3.0T CMR feature tracking study.

BACKGROUND: Diabetes mellitus (DM) is the most common metabolic disease worldwide and a major risk factor for adverse cardiovascular events, while the additive effects of DM on left ventricular (LV) deformation in the restrictive cardiomyopathy (RCM) cohort remain unclear. Accordingly, we aimed to investigate the additive effects of DM on LV deformation in patients with RCM. MATERIALS AND METHODS: One hundred thirty-six RCM patients without DM [RCM(DM-)], 46 with DM [RCM (DM+)], and 66 age- and sex-matched control subjects who underwent cardiac magnetic resonance (CMR) scanning were included. LV function, late gadolinium enhancement (LGE) type, and LV global peak strains (including radial, circumferential, and longitudinal directions) were measured. The determinant of reduced LV global myocardial strain for all RCM patients was assessed using multivariable linear regression analyses. The receiver operating characteristic curve (ROC) was performed to illustrate the relationship between DM and decreased LV deformation. RESULTS: Compared with the control group, RCM (DM-) and RCM(DM+) patients presented increased LV end-diastolic index and end-systolic volume index and decreased LV ejection fraction. LV GPS in all three directions and longitudinal PDSR progressively declined from the control group to the RCM(DM-) group to the RCM(DM+) group (all p < 0.05). DM was an independent determinant of impaired LV GPS in the radial, circumferential, and longitudinal directions and longitudinal PDSR (ß = - 0.217, 0.176, 0.253, and - 0.263, all p < 0.05) in RCM patients. The multiparameter combination, including DM, showed an AUC of 0.81(95% CI 0.75-0.87) to predict decreased LV GLPS and an AUC of 0.69 (95% CI 0.62-0.76) to predict decreased LV longitudinal PDSR. CONCLUSIONS: DM may have an additive deleterious effect on LV dysfunction in patients with RCM, especially diastolic dysfunction in RCM patients, indicating the importance of early identification and initiation of treatment of DM in patients with RCM.

Successful heart transplant in a child with congenital core myopathy and delayed-onset restrictive cardiomyopathy due to recessive mutations in the titin (TTN) gene.

BACKGROUND: Mutations in the TTN gene, encoding the muscle filament titin, are a major cause of inherited dilated cardiomyopathy. Early-onset skeletal muscle disorders due to recessive TTN mutations have recently been described, sometimes associated with cardiomyopathies. CASE DESCRIPTION: We report the case of a boy with congenital core myopathy due to compound heterozygosity for TTN variants. He presented in infancy with rapidly evolving restrictive cardiomyopathy, requiring heart transplantation at the age of 5 years with favorable long-term cardiac and neuromuscular outcome. CONCLUSION: Heart transplantation may have a role in selected patients with TTN-related congenital myopathy with disproportionally severe cardiac presentation compared to skeletal and respiratory muscle involvement.

Pediatric patient with restrictive cardiomyopathy on staged biventricular assist device support with Berlin Heart EXCOR® underwent heart transplantation successfully: the first case in Japan.

Pure restrictive cardiomyopathy is a strong risk factor for poor outcomes in children with cardiomyopathy on ventricular assist devices. Owing to concomitant right heart failure, children with end-staged restrictive cardiomyopathy who are supported with a ventricular assist device often require a biventricular assist device, which is another risk factor for waitlist mortality in heart transplantation candidates. Herein, we report the case of a 3-year-old boy with pure restrictive cardiomyopathy who successfully underwent heart transplantation after 12 months of support with staged biventricular assist devices. Owing to the progression of diastolic dysfunction, the left ventricular assist device could not provide adequate circulation support. Despite the provision of biventricular assist device support, the patient required a complex management strategy that involved balancing the left and right ventricular assist device supports. We were able to stabilize the patient by careful synchronization of the supports and proceeded to heart transplantation. TRIAL REGISTRATION: Clinical Registration No.: Institutional Review Board of Osaka University Hospital, approval no. 16105.

Genetic Restrictive Cardiomyopathy: Causes and Consequences-An Integrative Approach.

The sarcomere as the smallest contractile unit is prone to alterations in its functional, structural and associated proteins. Sarcomeric dysfunction leads to heart failure or cardiomyopathies like hypertrophic (HCM) or restrictive cardiomyopathy (RCM) etc. Genetic based RCM, a very rare but severe disease with a high mortality rate, might be induced by mutations in genes of non-sarcomeric, sarcomeric and sarcomere associated proteins. In this review, we discuss the functional effects in correlation to the phenotype and present an integrated model for the development of genetic RCM.

Restrictive cardiomyopathy in a patient with systemic sclerosis and Fabry disease: a case-based review.

Systemic sclerosis (SSc) is a rare immune-mediated vasculopathy characterized by fibrosis of the skin and internal organs. Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene producing α-galactosidase-A enzyme (α-Gal A) deficiency. Being a systemic disease, cardiac involvement in FD has a high mortality rate due to heart failure and arrhythmia. The coexistence of these two entities has not been reported previously. We describe the case of a female patient with limited SSc (lcSSc), a diagnosis based on the presence of sclerodactyly, Raynaud phenomenon, microvascular involvement, and positive anti-centromere antibodies. On follow-up, she developed chest pain, a second-degree A-V block, and restrictive cardiomyopathy (without cardiovascular risk factors). Although heart involvement is common in these two entities, the abnormal thickening of lateral and inferior wall, the infiltration pattern and the conduction system disorders presented herein are more characteristic in a heterozygous female with a cardiac variant of FD. The diagnosis of FD was confirmed with high globotriaosylsphingosine (Lyso-Gb3) levels and identification of GLA gene mutation. The patient was treated with enzymatic replacement (agalsidase alpha) following mild improvement in ventricular mass at 6th month, without clinical deterioration. The related literature on SSc associated with FD is also reviewed.

Contemporary Outcomes of Pediatric Restrictive Cardiomyopathy: A Single-Center Experience.

BACKGROUND: Pediatric restrictive cardiomyopathy (RCM) has high mortality in historical cohorts, and traditional management often involves early referral for heart transplantation (HTx). This study sought to determine outcomes of pediatric RCM at a center that has favored medical management over early listing for HTx. METHODS: All patients (N = 43) with pure RCM phenotype (RCM, N = 26) and hypertrophic cardiomyopathy with restrictive physiology (RCM/HCM, N = 17) managed at our center over a 15-year period were investigated. Outcomes of those listed for HTx (N = 18) were compared to a benchmark of contemporaneous pediatric RCM patients in the UNOS database (N = 377). Proportional hazards models were used to determine predictors of adverse outcomes. RESULTS: The mean age was 11 ± 9 years and 49% were male. 14 of 18 patients listed received HTx. Overall mortality (12%) was identical between the phenotypes; however, RCM patients were more likely to be listed (P = 0.001) and receive HTx (P = 0.02) compared to RCM/HCM. Prior to HTx, 60% had documented arrhythmia, 16% had cardiac arrest, and 7% required mechanical circulatory support. 4 of 17 patients with an ICD/PM received device therapies (four of five shocks appropriate for VT/VF, and two effective anti-tachycardia pacing interventions). Outcomes of those listed for HTx at our center were similar to the UNOS benchmark. In multivariate analysis, markers of congestive heart failure were associated with adverse outcomes. CONCLUSION: Heart failure and arrhythmia treatments can delay or possibly prevent the need for HTx in some cases of pediatric RCM. Survival post-HTx is not compromised using this approach.

Assessment of cerebral microbleeds by susceptibility-weighted imaging at 3T in patients with end-stage organ failure.

PURPOSE: Cerebral microbleeds (CMBs) are small rounded lesions representing cerebral hemosiderin deposits surrounded by macrophages that results from previous microhemorrhages. The aim of this study was to review the distribution of cerebral microbleeds in patients with end-stage organ failure and their association with specific end-stage organ failure risk factors. MATERIALS AND METHODS: Between August 2015 and June 2017, we evaluated 15 patients, 9 males, and 6 females, (mean age 65.5 years). Patients population was subdivided into three groups according to the organ failure: (a) chronic kidney failure (n = 8), (b) restrictive cardiomyopathy undergoing heart transplantation (n = 1), and (c) end-stage liver failure undergoing liver transplantation (n = 6). The MR exams were performed on a 3T MR unit and the SWI sequence was used for the detection of CMBs. CMBs were subdivided in supratentorial lobar distributed, supratentorial non-lobar distributed, and infratentorial distributed. RESULTS: A total of 91 microbleeds were observed in 15 patients. Fifty-nine CMBs lesions (64.8%) had supratentorial lobar distribution, 17 CMBs lesions (18.8%) had supratentorial non-lobar distribution and the remaining 15 CMBs lesions (16.4%) were infratentorial distributed. An overall predominance of supratentorial multiple lobar localizations was found in all types of end-stage organ failure. The presence of CMBs was significantly correlated with age, hypertension, and specific end-stage organ failure risk factors (p < 0.001). CONCLUSIONS: CMBs are mostly founded in supratentorial lobar localization in end-stage organ failure. The improved detection of CMBs with SWI sequences may contribute to a more accurate identification of patients with cerebral risk factors to prevent complications during or after the organ transplantation.

Outcomes of Berlin Heart EXCOR® pediatric ventricular assist device support in patients with restrictive and hypertrophic cardiomyopathy.

The outcomes of pediatric ventricular assist device support in patients with diastolic heart failure have not been well described. This study reviews the North American experience with Berlin Heart EXCOR® ventricular assist device implants in children with such physiology. The Berlin Heart clinical database was reviewed. Patients with primary diastolic dysfunction are included in this study. Twenty pediatric patients with restrictive cardiomyopathy (n = 13), hypertrophic cardiomyopathy (n = 3), or congenital heart disease with restrictive physiology (n = 4) who were supported with EXCOR® were identified. Of these, nine (45%) were successfully bridged to transplant, one (5%) weaned from support, and 10 (50%) died after support was withdrawn. Of patients under age 3 years (n = 13), 38.5% survived, whereas those aged 3 or older (n = 7) had 71.4% survival (P = .35). Biventricular assist device (BiVAD) patients experienced a 27.3% survival, vs 77.8% for patients with left ventricular assist device only (P = .07). Primary causes of death included stroke, infection, acidosis, multisystem organ failure, and bleeding. Pediatric patients with diastolic heart failure comprise a high-risk population for mechanical circulatory support. However, half of patients with this physiology have been successfully supported to explant with EXCOR® . The trends toward higher mortality for younger patients and those receiving BiVAD support warrant consideration.

The use of a Berlin Heart EXCOR LVAD in a child receiving chemotherapy for Castleman's disease.

We present the unique case of a pediatric patient who received chemotherapy for a diagnosis of CD, while mechanically supported with a Berlin EXCOR LVAD secondary to restrictive cardiomyopathy. A four-yr-old previously healthy male with restrictive cardiomyopathy required MCS after cardiac arrest but was diagnosed with multicentric CD, a non-malignant lymphoproliferative disorder fueled by excessive IL-6 production. Treatment with IL-6 blockade (tocilizumab) every two wk and methylprednisolone had no effect on his lymph nodes or cardiac function while on temporary RotaFlow. A Berlin LVAD was placed for treatment with rituximab, COP, vincristine, and methylprednisolone. After three courses of chemotherapy, his inflammatory markers normalized and his lymphadenopathy decreased but cardiac function remained severely depressed. He tolerated chemotherapy on the Berlin but required frequent titrations of his anti-coagulation regimen and he did suffer a hemorrhagic stroke. His clinical status improved significantly with rehabilitation, and he tolerated heart transplantation without further complications. MCS is a feasible option as a bridge to recovery or heart transplant eligibility for patients with hemodynamic collapse requiring chemotherapy but it does necessitate close titration of the anti-coagulation regimen to coincide with changes in the inflammatory state.

Restrictive cardiomyopathy in a patient presented with fever, vomiting, and consciousness disorder.

Restrictive cardiomyopathy (RCM) is an uncommon form of myocardial disorder characterized by diastolic dysfunction and increased myocardial stiffness. Endomyocardial fibrosis is one type of RCM hallmarked by formation of fibrous tissue on the endocardium. This report describes a case of RCM confirmed by autopsy in a young man who presented atypically with fever, vomiting, and delirium.

Effect of the oral vasopressin receptor antagonist tolvaptan on congestive cardiac failure in a child with restrictive cardiomyopathy.

Tolvaptan, an oral vasopressin receptor antagonist, was administered to a 6-year-old boy with advanced congestive cardiac failure due to restrictive cardiomyopathy. Slow up-titration of the tolvaptan improved the loop diuretic-resistant congestive cardiac failure without hypernatraemia, deterioration of vital signs, and significant complications. Tolvaptan could be useful and safe for children with severe congestive cardiac failure. It is necessary to accumulate clinical data on tolvaptan administration in children in order to determine the optimal method of administration.

Use of oral budesonide in the management of protein-losing enteropathy due to restrictive cardiomyopathy.

A 7-year-old male patient who had abdominal swelling and eyelid oedema was diagnosed with restrictive cardiomyopathy. His serum albumin level was 2.3 g/dl. Protein-losing enteropathy due to restrictive cardiomyopathy was diagnosed and oral budesonide was started. His serum albumin level began to rise and ascites and peripheric oedema disappeared. The patient underwent a successful cardiac transplantation and budesonide was stopped. After the heart transplantation, the albumin level decreased to 2.3 g/dl, and therefore it was restarted. When the serum albumin level increased, the budesonide dose was tapered and stopped in 1 month. Budesonide may be an effective drug in patients with protein-losing enteropathy due to heart failure.

Waitlist Outcomes in Candidates With Rare Causes of Heart Failure After Implementation of the 2018 French Heart Allocation Scheme.

BACKGROUND: In 2018, an algorithm-based allocation system for heart transplantation (HT) was implemented in France. Its effect on access to HT of patients with rare causes of heart failure (HF) has not been assessed. METHODS: In this national study, including adults listed for HT between 2018 and 2020, we analyzed waitlist and posttransplant outcomes of candidates with rare causes of HF (restrictive cardiomyopathy [RCM], hypertrophic cardiomyopathy, and congenital heart disease). The primary end point was death on the waitlist or delisting for clinical deterioration. Secondary end points included access to HT and posttransplant mortality. The cumulative incidence of waitlist mortality estimated with competing risk analysis and incidence of transplantation were compared between diagnosis groups. The association of HF cause with outcomes was determined by Fine-Gray or Cox models. RESULTS: Overall, 1604 candidates were listed for HT. At 1 year postlisting, 175 patients met the primary end point and 1040 underwent HT. Candidates listed for rare causes of HF significantly differed in baseline characteristics and had more frequent score exceptions compared with other cardiomyopathies (31.3%, 32.0%, 36.4%, and 16.7% for patients with hypertrophic cardiomyopathy, RCM, congenital heart disease, and other cardiomyopathies). The cumulative incidence of death on the waitlist and probability of HT were similar between diagnosis groups (P=0.17 and 0.40, respectively). The adjusted risk of death or delisting for clinical deterioration did not significantly differ between candidates with rare and common causes of HF (subdistribution hazard ratio (HR): hypertrophic cardiomyopathy, 0.51 [95% CI, 0.19-1.38]; P=0.18; RCM, 1.04 [95% CI, 0.42-2.58]; P=0.94; congenital heart disease, 1.82 [95% CI, 0.78-4.26]; P=0.17). Similarly, the access to HT did not significantly differ between causes of HF (hypertrophic cardiomyopathy: HR, 1.18 [95% CI, 0.92-1.51]; P=0.19; RCM: HR, 1.19 [95% CI, 0.90-1.58]; P=0.23; congenital heart disease: HR, 0.76 [95% CI, 0.53-1.09]; P=0.14). RCM was an independent risk factor for 1-year posttransplant mortality (HR, 2.12 [95% CI, 1.06-4.24]; P=0.03). CONCLUSIONS: Our study shows equitable waitlist outcomes among HT candidates whatever the indication for transplantation with the new French allocation scheme.

Sudden death possibly related to lenalidomide given for cardiac and muscle AL amyloidosis secondary to light chain deposition disease.

OBJECTIVES: Restrictive cardiomyopathy due to AL amyloidosis has not been reported as the cause of sudden death. The risk of sudden death in AL amyloidosis may be further increased by potentially cardiotoxic medication, as in the following case. CASE REPORT: In a 69-year-old female, AL amyloidosis from light-chain deposition disease manifested as gastrointestinal pseudo-obstruction, restrictive cardiomyopathy, and secondary myopathy. AL amyloidosis was histologically confirmed by endomyocardial biopsy and muscle biopsy. One month after initiation of steroids and lenalidomide the patient suddenly died during sleep. It is speculated that sudden death was due to restrictive cardiomyopathy, cardiotoxicity of lenalidomide, pulmonary embolism, sudden unexplained death in epilepsy syndrome or stroke. The possible causes of sudden death are discussed. CONCLUSIONS: This case shows that AL amyloidosis from light-chain deposition disease may predominantly affect the intestines, myocardium and the skeletal muscle and that lenalidomide may have a beneficial effect on the amyloidosis but should be given with caution for its potential arrhythmogenic and thrombogenic side-effects.

Paediatric cardiomyopathy and anaesthesia.

'Cardiomyopathy' (CM) is defined by the World Health Organization as 'a disease of the myocardium associated with cardiac dysfunction'. In a child, it is associated with a significant risk for anaesthesia. In addition, cardiac arrest under anaesthesia has been attributed to an undiagnosed CM. Care of these patients is complicated by the fact that there are several different forms of CM that have differing anaesthesia management goals, aimed at maintaining the patient's baseline haemodynamic variables of preload, heart rate, contractility, and afterload. With the emergence of new diagnostic tools, together with advances in cardiac imaging and improved treatment modalities (such as ventricular assist devices), the anaesthetic management of a child with a CM is evolving. This review describes the different forms of the disease in terms of pathology, aetiology, and clinical presentation. Dilated, hypertrophic, and restrictive CM are the most common forms. We examine recent advances in therapy, including the management of severe end-stage disease, while highlighting the specific anaesthetic considerations for children with each type of CM.

Mixed constrictive pericarditis and restrictive cardiomyopathy in a 36-year-old female.

Mixed lesion of Restrictive Cardiomyopathy and Constrictive Pericarditis is a rarely reported clinical entity which poses a diagnostic and therapeutic enigma to physicians. The management of both conditions differs markedly. Restrictive Cardiomyopathy is managed either conservatively or cardiac transplant may be offered. On the other hand, Constrictive Pericarditis can be surgically treated by pericardiectomy. We report a rare case of decompensated heart failure presenting with mixed features of both constrictive and restrictive cardiomyopathy.

[A woman with a chronic cough and dyspnoea]. / En kvinne med kronisk hoste og dyspné.

A previously healthy woman in her forties with a six-month history of persistent coughing, breathlessness and fatigue was referred to our hospital for further evaluation. She was initially treated with antibiotics for a possible respiratory tract infection but with only minor effect. A chest x-ray and computer tomography (CT) of the thorax demonstrated a solid tumour in the right lung hilus. Bronchoscopy revealed slight oedema of the bronchial mucous membrane in the area in question. Cytological examination of bronchoalveolar lavage fluid (BAL) showed normal respiratory epithelial cells. Histological examination of a needle biopsy from the tumour showed lymphoproliferative changes of uncertain cause. Magnetic resonance imaging (MRI) of the thorax provided no further information. An electrocardiogram (ECG) revealed signs of left ventricular hypertrophy and sinus bradycardia. Her complaints were palpitations, mild exertional dyspnoea and attenuated heart rate response to exercise. Echocardiography showed increased wall thickness with heterogeneous echogenicity in both ventricles, a slightly enlarged left atrium and mild mitral regurgitation. Tissue Doppler measurements showed impaired relaxation. These findings were suggestive of restrictive cardiomyopathy with diastolic dysfunction. Cardiac MRI confirmed the echocardiographic findings. The tumour was removed by thoracotomy and was shown to be made up of lymphatic tissue with granulomas, consistent with sarcoidosis. The restrictive cardiomyopathy was regarded as a cardiac manifestation of sarcoidosis. The patient was treated with corticosteroids. Clinical follow up with cardiac MRI and echocardiography did not reveal any progression of the cardiac involvement. Cardiac sarcoidosis must be considered in all sarcoid patients because of its significance for prognosis and treatment.