Restrictive Cardiomyopathy Research Articles

Exercise limitations in amyloid cardiomyopathy assessed by cardiopulmonary exercise testing-A multicentre study.

Amyloid cardiomyopathy is caused by the deposition of light chain (AL) or transthyretin amyloid (ATTR) fibrils, that leads to a restrictive cardiomyopathy, often resulting in heart failure (HF) with preserved or reduced ejection fraction. This study aimed to determine whether cardiac output reduction or ventilation inefficiency plays a predominant role in limiting exercise in patients with amyloid cardiomyopathy. We conducted a multicentre prospective study in patients with AL or ATTR cardiomyopathy who underwent cardiopulmonary exercise testing across four centres. Patients were compared with a propensity-score matched HF cohort based on age, gender, left ventricular ejection fraction (LVEF), and peak oxygen consumption (VO2). Data from 267 amyloid patients aged 77 (72, 81) years, 86% male, with a median N-terminal pro B-type natriuretic peptide (NT-proBNP) of 2187 (1140, 4383) ng/L, exercise parameters of peak VO2 of 14.1 (11.6;16.9) mL/min/kg, a minute ventilation to carbon dioxide production (VE/VCO2) slope of 37.4 (32.5, 42.6) and a LVEF of 50% (44%, 59%) were analysed. We identified 251 amyloid cardiomyopathy-HF matches. Amyloid patients had a signifnicantly higher VE/VCO2 slope [37.4, inter quartile range (IQR): 32.7, 43.1 vs. 32.1, IQR: 28.7, 37.0, P<0.0001], NT-proBNP (2249, IQR: 1187, 4420 vs. 718, IQR: 405, 2161ng/L, P<0.001), peak heart rate (121±28 vs. 115±27 beats/min, P=0.007) and peak ventilation (51, IQR: 42, 62 vs. 43, IQR: 33, 53L/min, P<0.0001) with earlier anaerobic threshold (VO2 at AT: 8.9, IQR: 6.8, 10.8 vs. 10.8, IQR: 8.9, 12.7mL/min/kg, P<0.0001) compared with HF. Between amyloid patients, AL patients (n=27) were younger (63, IQR: 58, 70 vs. 78, IQR: 72, 81years, P<0.0001), had lower VE/VCO2 slope (35.0, IQR: 30.0, 38.7 vs. 38.0, IQR: 32.8, 43.1, P=0.019), higher end-tidal carbon dioxide partial pressure both at AT (35.1±4.8 vs. 31.4±4.7mmHg, P<0.001) and peak exercise (32, IQR: 28, 35 vs. 30, IQR: 26, 33mmHg, P=0.039) as compared with ATTR (n=233). A higher VE/VCO2 slope and an earlier AT, determining functional capacity impairment, was assessed in patients with amyloid cardiomyopathy compared with the matched HF cohort. Additionally, patients with ATTR might display more severe exercise limitations as compared with AL.

Abstract 4134590: Procedural Related Major Adverse Events of Cardiac Catheterization in Pediatric Patients with Cardiomyopathy: Insights from IMPACT Registry

Background: Despite the role of cardiac catheterization for hemodynamic assessment and endomyocardial biopsy (EMB) in children with cardiomyopathy, data on procedure-related major adverse events (MAE) in this population is lacking. We aim to describe the rate of MAE in children with cardiomyopathy undergoing cardiac catheterization. Our secondary objective is to compare the rate of MAE among patient subsets within this population. Hypothesis: We hypothesize that the rate of MAE will vary among cardiomyopathy types and that EMB will be associated with an increased rate of MAE. Methods: We included patients with cardiomyopathy from the National Cardiovascular Data Registry Improving Pediatric and Adult Congenital Treatment (IMPACT) who were 18 years or younger and had cardiac catheterization from April 2016 to June 2023. We collected demographic, pre-procedural, procedural, and outcome-related variables. We performed univariate and multivariate analyses to identify variables independently associated with MAE. Results: A total of 15,656 procedures were evaluated, with a median age of 11 years; 50.3% were females. Dilated cardiomyopathy (DCM) was the most prevalent cardiomyopathy in 68%, followed by restrictive cardiomyopathy (RCM) in 14% and hypertrophic cardiomyopathy (HCM) in 9%. MAE was present in 1.6%. The most common MAE was arrhythmia, representing 46% of MAE, followed by cardiac arrest and bleeding each 20%. EMB was associated with a lower rate of MAE in univariate analysis p&lt;0.001. The association between a lower rate of MAE and EMB persisted in the multivariate model when those with heart transplant who had EMB were compared to those without heart transplant who did not have EMB p=0.001. The multivariate analysis also revealed that age less than a year, HCM compared to DCM, history of heart failure, pre-procedural inotropic support, and non-elective procedure were associated with increased rate of MAE. The overall mortality rate was 1.66%. The leading cause of mortality was heart failure in 51% of deceased patients. MAE was associated with an increased mortality rate of 11% p&lt;0.001. Conclusion: Cardiac catheterization is a safe procedure in pediatric patients with cardiomyopathy, with an overall MAE rate of 1.6%. Age of less than a year, HCM, history of heart failure, and prior inotropic support are associated with an increased rate of MAE. EMB was not associated with a higher rate of MAE. MAE occurrence is associated with a sevenfold increase in mortality rate.

Abstract 4137103: Myofibril Mechanics and Transcriptomic Profiling Confirm Distinct Phenotype of TNNI3- Cardiomyopathy Mouse Model

Introduction: Cardiac troponin I (cTnI, TNNI3 gene) is a highly conserved subunit of the sarcomere that inhibits contraction by preventing actin-myosin interaction. Pathogenic TNNI3 variants can cause both hypertrophic and restrictive cardiomyopathies but lack targeted therapies. We identified a family with restrictive cardiomyopathy carrying a cTnI variant at amino acid 157 (A157V). Using CRISPR-Cas9, we generated a knock-in mouse model reflecting this mutation (A158V in mouse). Our previous studies showed that homozygous A158V mice had impaired cardiac relaxation on invasive hemodynamics but normal lifespan, no echocardiographic changes, and no fibrosis. Hypothesis: Myofibril mechanics and transcriptomic studies will better discriminate TNNI3 A158V mice from WT than previous phenotyping studies. Methods: Heart tissue was obtained from wild-type (WT) and homozygous A158V mice at 9-10 months. Myofibrils were isolated from heart tissues and mechanical measurements were completed using the fast solution switching method. RNA was extracted for bulk RNA sequencing. Results: Isolated myofibril studies showed significant prolongation of the linear relaxation phase in A158V mice versus controls (p=0.02) but no significant differences in active tension. Unsupervised clustering of bulk RNA samples separated A158V samples from controls, with 44% transcriptional variation derived from genotype. Cardiac changes in the A158V model were confirmed by significant depletion of pathways involved in structural components of the contractile apparatus, including contractile fiber, sarcomere, and I-Band. On an individual gene level, A158V mutated mice displayed higher expression of cardiac remodeling genes such as Timp1 , Postn , and Tnc . Conclusion: The TNNI3 A158V variant consistently produces impaired relaxation with myofibril studies showing prolonged linear relaxation phase. Transcriptomic studies highlight distinct clustering of TNNI3 A158V mice from WT, with prominent depletion in contractile apparatus pathways. Our findings suggest traditional methods to characterize mouse models may fail to capture disease phenotype in cardiomyopathies; however, myofibril studies and transcriptomic profiling may reveal earlier phenotypic changes.

Abstract 4138624: Looking Beyond Respirophasic Ventricular Interdependence: A Case Report of Constrictive Pericarditis Masquerading as Cirrhosis

Case Presentation: A 67-year-old man with recurrent pleural effusions and concern for cirrhosis was referred for liver transplant. Pleural fluid was transudative by Light’s criteria with a high total protein level of 3.5 g/dL, which made hepatic hydrothorax unlikely. Liver biopsy confirmed congestive hepatopathy without advanced fibrosis. Transthoracic echocardiogram showed left ventricular (LV) ejection fraction 55%, right ventricular (RV) systolic pressure 35 mmHg, normal mitral annular tissue doppler velocities, and early diastolic septal bounce. Right and left heart catheterization showed prominent X and Y descent, elevated and equalized diastolic pressures, but no respiratory discordance in the LV-RV pressure gradient. As etiology of these findings were unclear, he underwent aggressive diuresis and hemodialysis, but repeat right heart catheterization showed persistently elevated right and left filling pressures. Cardiac MRI had no evidence of myocardial or pericardial inflammation/edema but showed pericardial thickening (7.9 mm) and septal bounce. There was no inspiratory septal shift, but the large pleural effusion appeared to limit diaphragm excursion. Given lack of respirophasic ventricular interdependence and thickened pericardium on MRI, CT was ordered, showing pericardial calcifications. Diagnosis of constrictive pericarditis was made, and patient underwent complete pericardiectomy. Pathology confirmed calcified and thick pericardium without acute inflammation. Post-operatively, patient developed RV failure, but recovered with inotrope support and was discharged with improvement in congestive symptoms. Discussion: Constrictive pericarditis classically exhibits respirophasic ventricular interdependence, but large pleural effusions may decrease respiratory variation in intrathoracic pressures, blunting this response. Normal mitral annulus tissue doppler velocities and lack of infiltrative process on cardiac MRI made restrictive cardiomyopathy unlikely. In the absence of respirophasic changes on multimodality testing, constriction can be diagnosed with other supportive features such as diastolic septal bounce, rapid Y descent, diastolic pressure equalization, and pericardial thickening and calcifications.

Experimental Modeling of Heart Failure in Mice

The article presents the results of testing a heart failure model in laboratory animals by single administration of amyloidogen. White outbred mice were used as biomodels, which were divided into intact and experimental groups. Animals from the experimental group were once injected with amyloidogen containing mouse myocardial homogenate to reproduce a pronounced cardiopathic effect. Structural and functional changes of the myocardium were monitored using echocardiography. According to the results obtained, animals in the experimental group demonstrated a remodeling of the heart similar to restrictive cardiomyopathy and a myocardial disfunction of both ventricles, indicating the formation of heart failure.

Pediatric restrictive Cardiomyopathy presenting with congestive heart failure: Rare case report and literature review

Restrictive cardiomyopathy (RCM) is an uncommon form of cardiomyopathy and is characterized by impaired diastolic filling of the ventricles due to increased myocardial stiffness and a normal ventricular systolic functions. In India, RCM is frequently observed in the young and endemic endomyocardial diseases are seen in a significant number of cases. RCM is the least common of all the cardiomyopathies among pediatric patients. RCM has a poor prognosis and commonly requires a cardiac transplant. We are reporting here a case of seven-year-old female child presenting with recurrent chest infections and congestive heart failure since early childhood.

Mechanical circulatory support bridge for restrictive cardiomyopathy with biventricular and pulmonary failure to cardiac transplantation

AbstractWe describe a simplified technique for mechanical circulatory support using Berlin EXCOR cannulas in a toddler with restrictive cardiomyopathy and biventricular and respiratory failure as a successful bridge to cardiac transplantation.

The essential role of the miRNA-208a/TARBP2/Sox6 axis in myosin expression in the end stage human heart failure

Abstract Despite diverse aetiologies, failing human hearts (HF) of various origins (coronary artery disease (CAD), dilated cardiomyopathy (DCM), restrictive cardiomyopathy, and hypertrophic cardiomyopathy (HCM)) exhibit impaired contractility and share alterations in MYH6, MYH7, and MYH7B gene expression. Here, we explore the miRNA-208a/TARBP2/Sox6 axis in regulating myosin expression within left ventricles of explanted human hearts. Methods Samples of left ventricles were obtained from explanted hearts of patients with terminal HF (NYHA III-IV) and reduced left ventricle ejection fraction (LVEF &amp;lt;25%) due to CAD (n=10), DCM (n=10), HCM (n=6), and controls (n=5). We analysed the expression of cardiac myosin heavy chains (MYH6, MYH7, MYH7B), cardiac damage markers (ANP, BNP), and heart-related MyoMiRs using quantitative real-time PCR. Results Pre-transplant data for the 31 subjects (25 male, 3 female) included: age 54.4±8.2y, BP 112±18/67±11 mmHg, HR 79±16 min-1, LVEF 27±14%, LVEDD 8.8±15.8mm, RVEDD 32.8±5.1mm, QRS 0.140±0.05s, QT 0.42±0.04s, NT-proBNP 5551±4259 ng/l. In all diseased groups, MYH6 mRNA was downregulated, while MYH7 and MHRT ncRNA were upregulated. We observed strong positive correlations between MYH7, MYH7B, and MHRT transcription, suggesting coordinated expression. The miRNA-208a/miRNA-208b ratio shifted heavily towards miRNA-208b in controls, with a similar effect for miRNA-499 and MYH7B. A strong negative correlation existed between miRNA-499 and MYH7B expression across HF samples. TARBP2 expression decreased slightly in all pathological groups, while Sox6 mRNA increased. Conclusion Elevated Sox6 expression may contribute to MYH6 downregulation and MYH7/MYH7B upregulation. Altered TARBP2 expression could promote cardiomyopathy via Sox6-mediated repression of cardiac slow-twitch myofiber proteins. Changes in miRNA-208a processing leading to Sox6 upregulation may inhibit Sox6-dependent myosin transcript expression.

Effects of the restrictive cardiomyopathy-associated cardiac troponin I K178E mutation on cAMP signalling at the myofilament

Abstract Background Catecholaminergic stimulation of cardiac β-adrenergic receptors (β-ARs) and subsequent cAMP signalling control cardiac inotropy and lusitropy. cAMP signalling is known to be compartmentalised to optimise sympathetic control by producing heterogeneous cAMP signals and protein kinase A (PKA) activation at distinct subcellular sites. This signalling may be disrupted in diseases such as restrictive cardiomyopathy (RCM) characterised by diastolic dysfunction, which is associated with certain mutations including the K178E missense mutation in cardiac troponin I (TPNI). The impaired ventricular relaxation associated with this mutation is thought to arise from myofilament calcium hypersensitivity, which can be modulated by PKA-dependent TPNI phosphorylation. However, a detailed understanding of the pathological effects mediated by the K178E-TPNI mutation is lacking. Purpose This study aims to determine whether the K178E-TPNI mutation alters local cAMP/PKA signalling at TPNI, potentially affecting myofilament calcium sensitivity and cardiac myocyte relaxation. Methods Real-time imaging of cAMP was carried out using the Fluorescence Resonance Energy Transfer (FRET)-based sensor CUTie (cAMP Universal Tag for imaging experiments) [1] fused to wild type (WT)- or K178E-TPNI. The sensors were expressed by transfection in neonatal rat ventricular myocytes (NRVMs) and FRET-changes were recorded at the myofilament on application of the β-AR stimulant isoproterenol (ISO). We further assessed the involvement of cAMP hydrolysing phosphodiesterases (PDEs) in the regulation of cAMP levels selectively at TPNI. Results The peak FRET-change and FRET-change after 5mins on ISO application were significantly higher in NRVMs expressing the mutant compared to the WT sensor, as was the rate of cAMP accumulation. A strong trend showed that the rise in FRET following PDE4 inhibition was larger in NRVMs expressing the WT compared to the mutant sensor, suggesting the involvement of this isoform in degrading cAMP locally at TPNI and reduced PDE4 activity in the presence of the K178E mutation. Co-immunoprecipitation analysis in HEK293 cells demonstrated interaction between WT-TPNI and a PDE4D isoform, and a weaker interaction of this isoform with the K178E-TPNI mutant. Conclusions This study shows that the K178E-TPNI mutation attenuates the TPNI/PDE4D interaction and alters the magnitude and kinetics of the local cAMP response at the myofilament. This mechanistic insight may aid the development of therapeutics targeting the TPNI/PDE4D interaction to treat RCM-associated diastolic dysfunction.The TPNI-CUTie SensorFRET Response Trace

The prevalence and prognostic impact of low voltage zone in patients with cardiomyopathy after catheter ablation for atrial fibrillation

Abstract Background The low voltage zone (LVZ) in left atrium (LA) was observed in 20-30% of patients undergoing catheter ablation of atrial fibrillation (AF). Furthermore, LVZ was associated with not only AF recurrence but also prognosis. However, the prevalence and prognostic impact of LVZ in patients diagnosed with cardiomyopathy remained unclear. Purpose In this study, we focused on the patients with cardiomyopathy after AF ablation and investigated the prevalence and prognostic impact of LVZ after AF ablation. Methods This study is a single-center retrospective observational study. We enrolled 125 patients diagnosed with cardiomyopathy. All patients underwent voltage mapping after pulmonary vein isolation. LVZ was defined as regions where bipolar peak-to-peak voltage was &amp;lt;0.5mV. We set 5 cm² as the cutoff of the presence of LVZ. The etiology of cardiomyopathy was divided into arrhythmia-induced cardiomyopathy (AICM) and non-AICM consisting of idiopathic dilated cardiomyopathy (iDCM), hypertrophic cardiomyopathy (HCM), ischemic cardiomyopathy (ICM), transthyretin amyloidosis wild type (ATTRwt) and others (1 Fabry disease, 1 cardiac sarcoidosis, 1 restrictive cardiomyopathy). AICM was defined as patient whose LVEF was recovered above 50% after maintenance of sinus rhythm. We investigated the proportion of LVZ by etiology, and the association between LVZ and the composite endpoint consisting of all cause death, heart failure hospitalization, ventricular assisting device implantation, ventricular arrhythmia and stroke. Results Out of 125 patients [age 68 (58-73), female 32 (25%), LVEF 34.0 (25-43)], 51 (41%) had LVZ. Sixty-four patients were AICM etiology (LVEF pre to post: 30.7±10.7% to 61.1±6.7% ) and 61 was Non-AICM etiology (LVEF: 40.7 ± 18.1 to 44.7±15.7, P=0.0062). The presence of LVZ was lower in AICM than in non-AICM group (20.3% vs. 62.3%, P&amp;lt;0.0001). The etiology of non-AICM was consisting of 26 iDCM, 18 HCM, 7 ICM, 7 ATRRwt and 3 other etiology. The prevalence of LVZ was lower in AICM than in non-AICM (20.3 vs. 62.3%, P&amp;lt;0.0001). Detail is shown in Figure 1. Next, the incidence of composite endpoint was higher in patients with LVZ than in those without (HR 4.6, 95%CI 2.1-10.0, P=0.0001) (Figure 2A). Among 4 groups stratified by AICM/non-AICM and with/without LVZ, there was significant difference in the incidence of the composite endpoint (Figure 2B, P&amp;lt;0.0001). After adjusted with age, gender, Non-AICM, LVZ, LVZ tended to have association with composite endpoint (2.21, 0.87-5.65, P=0.097) and Non-AICM showed strong association (5.58, 1.55-20.12, P=0.0086). LVZ was associated with HF hospitalization (4.35, 1.21-15.61, P=0.024). Conclusions The prevalence of LVZ was 60% in Non-AICM, while it was 20% in AICM. LVZ tended to be associated with poor prognosis of cardiomyopathy after AF ablation. LVZ was associated with HF hospitalization in patients with cardiomyopathy. LVZ might be the marker for poor prognosis in cardiomyopathy cohort.

Left ventricular longitudinal strain analysis using cardiac computed tomography for the diagnosis of cardiac amyloidosis

Abstract Introduction Cardiac amyloidosis (CA) results in a restrictive cardiomyopathy caused by extracellular deposition of proteins in the myocardium, demanding early identification for effective management. Left ventricular (LV) strain, mainly evaluated by echocardiography or cardiac magnetic resonance, provides sensitive and specific indicators for detecting CA, particularly apical sparing. It represents a pattern where the longitudinal strain (LS) in the basal and middle segments of LV is more impaired compared to the apical segments.¹ Cardiac computed tomography (CT) is useful not only for coronary artery evaluation but also for myocardial assessment, including LV ejection fraction (LVEF). Advanced software made it possible to analyse LS on cardiac CT (Figures A,B). Hypothesis: LS analysis using four-dimensional cardiac CT is helpful for the differential diagnosis of LV hypertrophied myocardial diseases and for detecting CA. Methods We analyzed 60 patients with LV hypertrophied myocardial diseases who underwent cardiac CT using 256-detector row or 320-detector row CT since 2009. Twenty patients of them were diagnosed with CA ( 70 ± 10 years, 14 males), the other 20 patients were diagnosed with hypertrophic cardiomyopathy (HCM) ( 60 ± 14 years, 12 males), and the rest of the 20 patients were diagnosed with severe aortic valve stenosis (AS) ( 86 ± 6 years, nine males). We analyzed LV global LS (GLS) and segmental LS using specific software and four-dimensional CT data. We evaluated relative apical LS as the value dividing the average LS of apical segments by the sum of the average LS of basal segments and mid-ventricular segments (Figure C). If the value was ≥ 1, apical sparing was defined as present. We compared the LS data and the percentage of apical sparing among those three myocardial diseases. Results There was no significant difference in LVEF among the three groups (52 ± 14%, 55 ± 27%, and 50 ± 18%, respectively; P = 0.15). There was no significant difference in GLS among the three groups (-10.6 ± 3.6%, -10.2 ± 5.2%, and -11.6 ± 3.8%, respectively; P = 0.87). Apical sparing was observed in 13 cases (65%) of CA, which was significantly higher than 3 cases (15%) of HCM or 4 cases(20%) of AS (P = 0.0002). Conclusions LV strain analysis using cardiac CT is helpful for detecting apical sparing. Advanced image analysis software has enabled LV strain analysis by cardiac CT, which is useful for the differential diagnosis of CA among LV hypertrophied diseases.Figure A,B,C

Outcomes in patients with light chain cardiac amyloidosis undergoing heart transplantation: a single centre UK study

Abstract Background Light chain cardiac amyloidosis (AL-CA) results in restrictive cardiomyopathy associated with progressive heart failure and poor survival. Traditionally, outcomes following heart transplantation in patients with AL-CA have been worse than in other heart failure cohorts and consequently, many centres do not offer this population transplantation. Purpose and Methods This was a retrospective observational study of 18 patients with AL-CA (age 52.7years +/- 8.3, male 66%) referred to our centre in the UK for assessment for heart transplantation from 2008 to 2023. Seven patients (39%) were listed for transplant, and all received orthotopic heart transplantation (OHT). This study compared pre-transplantation characteristics in those offered cardiac transplantation with those not transplanted. We also examined post-transplantation outcomes in this group (n=7) compared with the overall heart transplantation population (n=95) at our centre. Results Patients with AL-CA who were not offered transplantation (n=11) were older (mean age 54.3 vs 50.3 years), were more likely male (72% vs 57%) but had similar baseline renal function to those transplanted (median eGFR 60.4 vs 54.2ml/min). Reasons against offering OHT included extensive multisystem or renal amyloid deposition (n=4), insufficient haematological response (n=2), heart failure not advanced enough for OHT (n=1) and malignancy (n=1). Pre-transplant right heart catheterisation of patients undergoing OHT demonstrated a mean transpulmonary gradient of 7.8mmHg (+/- 1.9) and cardiac output of 2.94/min (+/- 0.3). Five patients (71%) had a complete and two (29%) a partial haematological response to clonally directed chemotherapy. Three patients were bridged to transplant with biventricular assist devices for 9, 10 and 51 days, respectively. Five patients developed episodes of histologically confirmed rejection of grade 2R that resolved with medical management. One patient experienced first degree atrioventricular block and had a pulseless electrical activity arrest 19 days after transplantation before being fitted with a permanent pacemaker. Two patients went on to receive autologous stem cell transplantation. Patients with AL-CA undergoing OHT had a lower mortality rate compared with non-transplanted patients over a median follow up of 9 months (HR 0.3, 95%CI 0.07-1.3, p = 0.10). Two patients with AL-CA died at 42 days and 7.7 years after OHT. Five patients (71%) are alive under follow up at 4, 7.5, 9, 10 months and 7.7 years post OHT. There was no difference in survival between patients who underwent heart transplantation for AL-CA and patients who underwent heart transplantation for all other indications (HR 1.94, 95%CI 0.3 – 12, p=0.45). Conclusions In selected patients with AL-CA, OHT offers favourable outcomes. After clonally directed therapy to control the underlying plasma cell dyscrasia, heart transplantation should be considered in the absence of widespread systemic disease.

Cardiopulmonary exercise test findings are not the same in distinct types of cardiac amyloidosis

Abstract Background Cardiopulmonary exercise testing (CPET) is a widely used tool for risk stratification and prognosis in patients with chronic heart failure. In amyloid patients, cardiac amyloid deposits are associated with poor prognosis, increased risk for arrhythmias, sudden death, and subsequent exercise limitation due to restrictive cardiomyopathy. The type of amyloidosis and its affectation of the heart are different, and little is known about the CPET parameters according to the type of cardiac amyloidosis. Purpose In this study, we aim to compare CPET data in different types of amyloidosis to determine if CPET variables evaluated could have a significant difference that could impact the follow-up or prognosis of the patients based on the type of amyloidosis. Methods We conducted a retrospective cohort study of 194 patients with a diagnosis of cardiac amyloidosis referred for CPET from February 2010 to February 2024. Patients with at least one CPET data were included in our analysis. The type of amyloidosis, comorbidities, and echocardiogram data were retrieved from medical records. Patients were divided into 3 different groups according to the type of amyloidosis: AL Amyloidosis(AL), Variant TTR Amyloidosis (vTRR), and Wild Type TTR Amyloidosis (wtTTR). Individuals with CPET studies after heart transplant were excluded from the analysis. Fisher’s exact test or chi-square was used to compare categorical variables. ANOVA and Tukey-Kramer (TK) were used to compare continuous variables. Adjustment using General Linear Models (GLM) procedure was used to identify any confounder that could affect the results. A p-value &amp;lt;0.05 was considered significant. Results Out of the 194 patients, 66 had AL Amyloidosis, 40 had vTTR Amyloidosis, and 88 had wtTTR Amyloidosis. Most of the patients were male, and the male predominance was higher in the wtTRR group. There were 41 (62.1%) males in the AL group, 35 (87.5%) in the vTRR group, and 83 (94.3%) in the wtTTR group (p&amp;lt;0.0001). Comorbidities were balanced among the groups. Additional demographic and comorbidities data are shown in Table 1. From the evaluated CPET variables, VE/VCO2 nadir and slope were significantly higher in the wtTTR group when compared to the other groups, as well as Peak VE and Peak TV(Figure A). However, after adjusting for sex, BMI, and age, VE/VCO2 nadir was still significantly higher in the wtTRR group (p=0.003) compared to the other groups, as well as Peak VE, which was higher again in vTTR patients (p=0.001), and Peak TV (Table 2). Conclusion Ventilation variables evaluated in CPET showed alterations in the wtTTR group. These findings suggest that wtTRR amyloid patients could have a severe problem in ventilation that could be of significant relevance in future prognosis.

Gene-echocardiography: refining genotype-phenotype correlations in cardiomyopathy patients with restrictive phenotype

Abstract Background The restrictive phenotype, the least frequent and genetically complex form of cardiomyopathy, is the focus of this investigation. The aim is to clarify the association between restrictive phenotype and genetic variants in cardiomyopathy patient. Methods We utilized whole-exome sequencing in a cohort of 568 cardiomyopathy patients and performed echocardiographic evaluations to identify restrictive phenotypes. Comprehensive analysis of cardiac characteristics and functionality was also undertaken. Results Among the cohort, 33 patients exhibited a restrictive phenotype. These patients were distributed as follows: 7 within the restrictive cardiomyopathy group (RCM), 20 in the hypertrophic cardiomyopathy group (HRCM), and 6 in the dilated cardiomyopathy group (HDRCM). A notable prevalence of gene mutations, mainly in the MYBPC3 gene, was found in these individuals. We observed that mutation carriers, characterized by smaller aortic sinus dimension, demonstrated an association with the mutation and diminished myocardial work. Furthermore, MYBPC3 mutation carriers showed a thicker ventricular wall and a higher predisposition for septal hypertrophy. Both HRCM and HDRCM groups displayed consistent hypertrophic manifestations, with the latter demonstrating a higher frequency of interventricular septal hypertrophy. The 5-year survival rate was calculated at 54.5%, with gene mutations not significantly affecting longevity. Conclusion Genetic factors profoundly influence the restrictive phenotype of cardiomyopathy. There is a strong link between restrictive phenotype and genetic variants in cardiomyopathy, providing a foundation for more accurate genetic testing and personalized management of patients. The emerging "gene-echocardiography" concept may refine the accuracy and productivity of genetic counseling and testing in cardiomyopathy.

Diagnostic and therapeutic challenges in rapidly progressing cardiac amyloidosis: a literature review based on case report

IntroductionCardiac amyloidosis is a rarely reported and potentially fatal variant of the systemic disease. Its early diagnosis could potentially lead to significantly improved clinical outcomes.Case presentationA 56-year-old female presented with dyspnea and palpitations. Her physical exam and non-invasive evaluation with cardiac magnetic resonance imaging (CMRI) revealed restrictive cardiomyopathy, and the bone marrow biopsy results showed systemic amyloidosis.DiscussionThe diagnosis of cardiac amyloidosis is not always straightforward, and delay can cause the progression of the disease and an increased risk of morbidity and mortality. Electrocardiograms, echocardiograms, cardiac magnetic resonance imaging, and histopathologic evaluation are the main methods for diagnosing cardiac amyloidosis. The treatment consists of controlling heart failure symptoms and disease-modifying interventions, including medical and surgical therapeutic methods.Clinical learning point (conclusion)Cardiac involvement is the main cause of death in systemic amyloidosis. Early suspicion, diagnosis, and treatment are crucial in improving patients’ survival. CMRI can play an essential role in the diagnosis of cardiac Amyloidosis. A graphical abstract is provided for visual summary.Graphical

Female Specific Restrictive Cardiomyopathy and Metabolic Dysregulation in transgenic mice expressing a Peptide of the Amino-Terminus of GRK2.

Cardiovascular disease and heart failure are a major health challenge, with sex differences in pathophysiology and treatment responses critically influencing patient outcomes. G protein-coupled receptor (GPCR) kinase 2 (GRK2) is a pivotal regulator of cellular signaling whose elevation is a hallmark of heart failure progression. Its complex network of protein interactions impact a wide range of physiological and pathophysiological processes including cardiac function. In this study, we examined the effects of cardiac-restricted expression of an amino-terminal peptide of GRK2 (βARKnt) in female mice subjected to acute and chronic pressure overload. Our findings reveal that that βARKnt affects hypertrophy development and cardiac function differently in female mice than in males, leading to a transition to heart failure not observed in control females or βARKnt males. Notably, the βARKnt female mice exhibited baseline hypertrophy with distinct left atrial morphology, increased fibrosis, and immune cell infiltration compared to the controls, which progressed under chronic stress, indicating adverse cardiac remodeling. Furthermore, βARKnt female mice, unlike males, exhibit impaired tissue respiration following acute pressure overload and altered glucose sensitivity and insulin tolerance, highlighting significant remodeling of cardiac and systemic metabolism.

Pediatric Extracorporeal Membrane Oxygenation in Restrictive and Hypertrophic Cardiomyopathy: A Single Center Experience

Patients with restrictive cardiomyopathy (RCM) and hypertrophic cardiomyopathy (HCM) were previously considered poor candidates for mechanical circulatory support due to technical limitations related to restrictive ventricular physiology and small ventricular size, limiting the ability to provide adequate flows and decompress the heart. Literature examining use of extracorporeal membrane oxygenation (ECMO) in this population consists of a single case series reporting no survivors. We report our experience providing ECMO in children with RCM or HCM at a large pediatric quaternary cardiac center. Between 2012 and 2022, five patients (four RCM, one HCM) were supported with seven ECMO runs. All patients were cannulated to ECMO with ongoing cardiopulmonary resuscitation. Four patients survived decannulation from ECMO (median support time 209 hr, interquartile range [IQR]: 48–265), of which three (60%) survived to hospital discharge after transitioning to a ventricular assist device (VAD) and undergoing orthotopic heart transplant (OHT). Two remain alive at long-term follow-up with normal or mildly impaired functional status. These findings suggest that while RCM and HCM have traditionally been considered contraindications to ECMO due to adverse outcomes, this population may be successfully supported with ECMO with survival comparable to international registry outcomes in select centers where VAD as a bridge to OHT is available.

Resolution of protein losing enteropathy by left ventricular assist device in a restrictive cardiomyopathy child

Resolution of protein losing enteropathy by left ventricular assist device in a restrictive cardiomyopathy child

Valvular heart disease and cardiomyopathy in China: epidemiology and current treatments.

The Annual Report on Cardiovascular Health and Diseases in China (2022) intricate landscape of cardiovascular health in China. In connection with the previous section, this ninth section of the report offers a comprehensive analysis of valvular heart disease and cardiomyopathy. Although rheumatic valve disease is still the main cause of valvular heart disease in China, with the aging of the population and the improvement of living standards, the prevalence of degenerative valvular heart disease is on the rise. Because many patients with valvular heart disease have only mild to moderate valve stenosis or insufficiency, and no symptoms, the detection rate in the population is low and late, resulting in many patients been in the severe late stage of disease at visit, increasing the difficulty of treatment and affecting effectiveness and prognosis. Therefore, we should strengthen the examination and screening of valvular heart disease in order to find and prevent it as early as possible. In addition, compared with other diseases, the treatment of valvular heart disease needs more and higher technical support (surgery, intervention, etc). However, not all hospitals can provide relevant technologies. At present, the treatment of valvular heart disease is still mainly concentrated in the provincial hospitals. It is necessary to carry out more professional training so that more doctors and hospitals can participate in the treatment of valvular heart disease. Cardiomyopathy is a group of myocardial diseases with abnormal myocardial structure and/or function, but couldn't be explained by hypertension, coronary atherosclerosis, valvular heart disease and congenital heart disease. It includes hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic cardiomyopathy (also known as arrhythmogenic right ventricular cardiomyopathy), restrictive cardiomyopathy (RCM) and undifferentiated cardiomyopathy.

Storytelling of Hypertrophic Cardiomyopathy Discovery.

The discovery of hypertrophic cardiomyopathy (HCM) dates back to 1958, when the pathologist Donald Teare of the St. George's Hospital in London performed autopsies in eight cases with asymmetric hypertrophy of the ventricular septum and bizarre disorganization (disarray) at histology, first interpreted as hamartoma. Seven had died suddenly. The cardiac specimens were cut along the long axis, similar to the 2D echo. In the same year, at the National Institute of Health U.S.A., Eugene Braunwald, a hemodynamist, and Andrew Glenn Morrow, a cardiac surgeon, clinically faced a patient with an apparently similar morbid entity, with a systolic murmur and subaortic valve gradient. "Discrete" subaortic stenosis was postulated. However, at surgery, Dr. Morrow observed only hypertrophy and performed myectomy to relieve the obstruction. This first Braunwald-Morrow patient underwent a successful cardiac transplant later at the disease end stage. The same Dr. Morrow was found to be affected by the familial HCM and died suddenly in 1992. The term "functional subaortic stenosis" was used in 1959 and "idiopathic hypertrophic subaortic stenosis" in 1960. Years before, in 1957, Lord Brock, a cardiac surgeon at the Guy's Hospital in London, during alleged aortic valve surgery in extracorporeal circulation, did not find any valvular or discrete subaortic stenoses. In 1980, John F. Goodwin of the Westminster Hospital in London, the head of an international WHO committee, put forward the first classification of heart muscle diseases, introducing the term cardiomyopathy (dilated, hypertrophic, and endomyocardial restrictive). In 1995, the WHO classification was revisited, with the addition of two new entities, namely arrhythmogenic and purely myocardial restrictive, the latter a paradox of a small heart accounting for severe congestive heart failure by ventricular diastolic impairment. A familial occurrence was noticed earlier in HCM and published by Teare and Goodwin in 1960. In 1989-1990, the same family underwent molecular genetics investigation by the Seidman team in Boston, and a missense mutation of the β-cardiac myosin heavy chain in chromosome 14 was found. Thus, 21 years elapsed from HCM gross discovery to molecular discoveries. The same original family was the source of both the gross and genetic explanations of HCM, which is now named sarcomere disease. Restrictive cardiomyopathy, characterized grossly without hypertrophy and histologically by myocardial disarray, was found to also have a sarcomeric genetic mutation, labeled "HCM without hypertrophy". Sarcomere missense mutations have also been reported in dilated cardiomyopathy (DCM) and non-compaction cardiomyopathy. Moreover, sarcomeric gene defects have been detected in some DNA non-coding regions of HCM patients. The same mutation in the family may express different phenotypes (HCM, DCM, and RCM). Large ischemic scars have been reported by pathologists and are nowadays easily detectable in vivo by cardiac magnetic resonance with gadolinium. The ischemic arrhythmic substrate enhances the risk of sudden death.