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.

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.

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.

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.

Chronic exertional compartment syndrome in a patient with restrictive cardiomyopathy and portal hypertension.

Chronic exertional compartment syndrome (CECS) is a condition that produces exercise-induced pain and swelling due to a transient increase in compartment pressures. It is thought to be due to muscle hypertrophy and is classically associated with young athletes under 30, overtraining, anabolic steroid use, and aberrant running biomechanics. We present a unique case of CECS in a patient without the traditional risk factors but rather diagnosed with cardiac cirrhosis and portal hypertension. This patient's exercise-induced bilateral leg pain met the CECS criteria for leg compartment pressure testing and was attributed to fluid retention secondary to his comorbidities. His symptoms significantly improved after initiating diuretic pharmacotherapy. Based on our literature review, there is a dearth of literature associating CECS with specific chronic cardiac or hepatic conditions as well as describing its incidence in these conditions.

Miocardiopatía restrictiva: la importancia de su diagnóstico precoz / Restrictive cardiomyopathy: Importance of early diagnosis

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Restrictive cardiomyopathy: A rare presentation of gaucher disease.

Restrictive cardiomyopathy is an unusual form of cardiomyopathy accounting only for 2%-5% of all pediatric cardiomyopathies. It is mostly idiopathic. Gaucher disease in association with restrictive cardiomyopathy is extremely rare. We herein report a case of cardiac failure in an 8-year-old male child caused by restrictive cardiomyopathy. Pathogenesis of which was attributed to Gaucher disease. In any case of restrictive cardiomyopathy, Gaucher disease should be included in differential diagnosis and investigated accordingly.

Résumé La cardiomyopathie restrictive est une forme inhabituelle de cardiomyopathie qui ne représente que 2 à 5 % de toutes les cardiomyopathies pédiatriques. C'est surtout idiopathique. La maladie de Gaucher associée à une cardiomyopathie restrictive est extrêmement rare. Nous rapportons ici un cas d'insuffisance cardiaque dans un Enfant de sexe masculin de 8 ans causé par une cardiomyopathie restrictive. dont la pathogenèse a été attribuée à la maladie de Gaucher. En tout cas de restriction cardiomyopathie, la maladie de Gaucher doivent être incluses dans le diagnostic différentiel et étudiées en conséquence.

Reversal of pulmonary hypertension in paediatric patients with restrictive cardiomyopathy.

Left ventricular assist devices can reverse pulmonary hypertension in cardiac transplant candidates with heart failure with a reduced ejection fraction. Whether a similar approach is applicable in restrictive cardiomyopathy is uncertain. We report the successful implantation of a Medtronic HVAD left ventricular assist device in a bridge-to-candidacy concept in 2 paediatric patients with restrictive cardiomyopathy.

Left Ventricular Assist Device Implantation in Hypertrophic and Restrictive Cardiomyopathy: A Systematic Review.

Left ventricular assist device (LVAD) implantation in patients with advanced heart failure due to hypertrophic or restrictive cardiomyopathy (HCM/RCM) presents technical and physiologic challenges. We conducted a systematic review of observational studies to evaluate the utilization and clinical outcomes associated with LVAD implantation in patients with HCM/RCM and compared these to patients with dilated or ischemic cardiomyopathy (DCM/ICM). We searched MEDLINE, EMBASE, and Scopus from inception through May 2019 and included appropriate studies describing the use of an LVAD in patients with HCM/RCM. We identified six studies with a total of 2,766 patients with HCM/RCM and advanced heart failure, among whom 338 patients (12.2%) underwent LVAD implantation. In patients listed for transplant, the rate of LVAD implantation was significantly lower in patients with HCM/RCM compared to that in patients with DCM/ICM (4.4% vs. 18.2%, p < 0.001). Adverse clinical outcomes were significantly higher in HCM/RCM than in DCM/ICM, including operative/short-term mortality (14.0% vs. 9.0%), right ventricular failure (50.0% vs. 21.0%), infection (15.5% vs. 11.2%), bleeding (40.2% vs. 12.5%), renal failure (15.0% vs. 5.1%), stroke (5.0% vs. 2.4%), and arrhythmias (18.0% vs. 7.7%) (all p values <0.001).

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.

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.

[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.

Characteristics and Outcomes of Patients Undergoing Combined Organ Transplantation (from the United Network for Organ Sharing).

Studies have shown that highly selected patients who underwent combined heart-kidney (HK) and heart-liver transplants (HLv) have short- and long-term outcomes comparable to those observed in primary heart transplantation (HT). Adults patients with stage D heart failure that underwent combined HK, HLv, and heart-lung (HL) were identified in the United Network for Organ Sharing registry from 1991 to 2016, with follow-up through March 2018. We conducted inverse probability of treatment weighting survival analysis of long-term survival stratified by type of combined organ transplant, accounting for donor, recipient, and operative characteristics. We identified 2,300 patients who underwent combined organ transplant (HK 1,257, HLv 212, HL 831). HL recipients were more likely white (77%), women (58%), with congenital heart disease (44.5%), and longer waiting list time (median 195 days). HK transplant increased significantly during the study period where as HL decreased significantly. Median survival was 12.2 years for HK (95% confidence intervals [CI] 10.8 to 12.8), 12 for HLv (95% CI 8.6 to 17.6) but significantly lower at 4.5 years for HL (95% CI 3.6 to 5.8). Combined HK and HLv transplantation rates are increasing and long-term survival is comparable to primary HT, unlike HL which is associated with decreasing trends and significantly lower survival.

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.

Amiloidosis cardíaca en un paciente con mieloma múltiple / Cardiac amyloidosis in a patient with multiple myeloma

Resumen La amiloidosis sistémica constituye una enfermedad poco frecuente, donde la infiltración cardíaca es la principal causa de morbimortalidad, sin importar la causa subyacente del depósito amiloide. Se reporta el caso de una paciente femenina de 48 años con síndrome nefrótico, insuficiencia cardíaca e inmunocompromiso, estableciéndose el diagnóstico de amiloidosis primaria con infiltración cardíaca secundaria a mieloma múltiple. Se discute brevemente la enfermedad, la importancia del juicio clínico apoyado en medios diagnósticos y los retos terapéuticos actuales.

Abstract Systemic amyloidosis constitutes a non common disease in which cardiac involvement is the leading cause of morbidity and mortality, regardless of the underlying pathogenesis of amyloid production. We present the case of a 48 years old female with nephrotic syndrome, heart failure and immunocompromise in which Primary Amyloidosis with cardiac involvement secondary to Multiple Myeloma is established as diagnosis. The disease is briefly discussed, as well as the value of clinical judgment supported on diagnostic means and the therapeutic challenges now days.

Endovascular treatment of stroke in children under 2 years with heart failure and ventricular assist device.

INTRODUCTION: Strokes in children are characterised by a high mortality rate while, at the same time, the low number of cases makes it difficult to gain practical experience. As heart disease is the most common risk factor, and as more and more cardiological interventions are being carried out, an increase in the incidence of paediatric stroke is expected. In some cases a transplant is required. While waiting for a donor, the use of ventricular assist devices may be necessary. These present with a high rate of neurological complications. We present two cases of children under 2 years of age awaiting heart transplantation supported by ventricular assist devices who had a stroke which was treated by endovascular techniques. Case 1: A 16-month-old boy with restrictive cardiomyopathy who was listed for a cardiac transplant. At 20 months he required an implantation of an external biventricular support device (Berlin Heart) and had a left hemisphere stroke at 23 months. An intra-arterial approach was used and produced good clinical results. One month later, a heart transplant was performed successfully. Case 2: An 18-month-old girl with non-compacted dilated cardiomyopathy included in the cardiac transplant programme and in need of a Levitronix Centrimag ventricular assist device presented with an acute left hemisphere stroke at 23 months. An intra-arterial procedure was carried out leading to positive clinical results except for residual right hypertonia. Seven months later she received her transplant. CONCLUSION: As a result of the difficulty in performing arterial puncture, the small vessel calibre and the limitation in the use of iodated contrast, there are certain limitations to endovascular treatment of strokes in children that can lead to complications. A multidisciplinary approach to managing such cases would be helpful.