bluuebunny/crossref_metadata_2025 huggingface dataset:
High intensity plaque in carotid artery on magnetic resonance imaging predict long term major adverse cardiac and cerebrovascular events
Authors: Fujtia A , Miura H , Asaumi Y , Morita Y , Oota Y , Fukuda T , Noguchi T , Iihara K
Published: November 2023

Background

Cardiocerebrovascular diseases remain the major cause of death in the world. The presence of carotid plaque is a surrogate marker for systemic atherosclerosis. High intensity plaque (HIP) in carotid artery on magnetic resonance imaging (MRI) was reported to be associated with the ipsilateral ischemic stroke as well as coronary artery disease. However, few studies have examined the impact of carotid HIP on long-term prognosis of cardiocerebrovascular disease.

Purpose

We investigated whether HIP in carotid artery associated with long term major adverse cardiac and cerebrovascular events (MACCE).

Method

We retrospectively analyzed 241 patients suspected carotid artery stenosis and underwent MRI at our hospital between January 2002 and December 2004. Plaque imaging was performed with non-contrast T1 imaging, and we defined as HIP if plaque-to-myocardium signal-intensity ratio (PMR) ≥2.0. Patients were divided into the HIP group (n=134) or non-HIP group (n=107). The outcome of this study was first incidence of ischemic cardiac or cerebrovascular events. Cardiovascular events were defined as cardiac death (sudden death, fetal myocardial infarction) and non-fetal myocardial infarction. Cerebrovascular events were defined as cerebral infarction. We compared the cumulative incidents of MACCE between with or without HIP groups using Kaplan-Meier method and log-rank test. Multivariate Cox regression analysis was carried out to assess whether HIP could be independent predicter of MACCE.

Results

Median age of study patients was 70 (inter quartile range; 65-75) and 215 (88.1%) patients were male, 185 patients (76.6%) had established vascular diseases. The median follow-up periods were 8.6 years (inter quartile range; 4.0-14.2 years). The presence of HIP was associated with MACCE (p<0.001). Multivariate analysis shows that the presence of HIP was an independent predicting factor for MACCE. When we analyzed incidence of each cardiovascular and cerebrovascular event, the presence of HIP was significantly associated with cerebrovascular events (p=0.004) and cardiovascular events(p=0.03), respectively.

Conclusion

The presence of carotid HIP was associated with long term prognosis for MACCE. Our findings indicate that carotid HIP is a surrogate marker for vulnerable patients with cardiocerebrovascular disease.
Lamin A/C cardiomyopathy in children
Authors: Smedsrud M , Chivulescu M , Hasselberg N E , Albinski M , Barnes A , Field E , Fruh A , Kaski J P , Haugaa K H
Published: November 2023

Background

Lamin A/C gene (LMNA) variants cause familial dilated cardiomyopathy (DCM) with a malignant cardiac phenotype characterized by atrioventricular (AV) block and supraventricular and ventricular arrhythmias, often preceding cardiac dilatation and dysfunction. Current guidelines recommend genetic and clinical screening of family members, starting at 10-12 years of age. However, children with LMNA variants are underrepresented in research publications and data are lacking on both the onset of a cardiac phenotype and the prevalence of cardiac events in this population.

Purpose

The study aimed to investigate the prevalence of cardiac events in LMNA genotype positive children and penetrance of LMNA cardiac phenotype in genotype positive paediatric relatives.

Methods

We conducted a longitudinal cohort study including consecutive genotype-positive LMNA patients and genotype positive relatives, all ≤18 years of age, followed between 2009 and 2022. The patients were examined by electrocardiography, Holter monitoring, and echocardiography. A cardiac phenotype was defined as the presence of either atrioventricular (AV) block, prolonged sinus arrest, atrial fibrillation/ flutter (AF), ventricular tachycardia (VT), or echocardiographic DCM. Cardiac events were defined as AF, VT, cardiac syncope, sudden cardiac arrest (SCA) or heart transplantation (Htx). Childhood-onset disease was defined as the presence of a cardiac phenotype ≤12 years of age.

Results

Among 44 LMNA genotype-positive children (age 10.4 [IQR 6.5-12.9] years, 34 relatives), 12 (27 %) became phenotype-positive at a median age of 12.8 [IQR 7.9-14.1] years, of which 7 (58 %) had childhood-onset disease (Figure 1). Nine (18 %) of the children experienced a cardiac event and 44 % of these were ≤12 years of age (Figure 2). Three children had AF, 5 had VT, and one had cardiac syncope. Htx was performed in two unrelated children, at 6 and 8 years of age, respectively.

Among the 34 genotype-positive paediatric relatives, 21 % (n=7) became phenotype-positive at a median age of 10.9 [IQR 7.5-15.1] years, of which 57 % (n=4) had childhood-onset disease.

Conclusions

In a cohort of LMNA genotype children, there was a high prevalence of cardiac events and 44 % of these occurred in children ≤12 years of age. The penetrance of LMNA cardiac phenotype in genotype positive paediatric relatives was 21 %, highlighting the importance of early family screening and cardiological follow-up.
Contribution of copy number variants to the genetic etiology of dilated cardiomyopathy
Authors: Cardenas Reyes I , Gomez Diaz I , De La Higuera Romero L , Amor Salamanca A , Garcia Hernandez S , Valverde Gomez M , Cabrera Argana D , Fernandez Fernandez X , Ortiz Genga M , Cazon Varela L , Perez Barbeito M , Peteiro Deben R , Sanchez Flores M , Ochoa J P
Published: November 2023

Background/Introduction

Dilated cardiomyopathy (DCM) is one of the most common cardiomyopathies, with a prevalence of 1 in 250. Single nucleotide variants (missense, nonsense, or frameshift) in definitive DCM genes are the most frequently identified in positive genetic studies. Despite major advances in genetic diagnostic technologies in recent decades, and more than 100 genes potentially associated with DCM identified to date, the diagnostic yield is still lower than 40%. Copy number variants (CNVs) have been identified as cause of the disease in several studies, especially in genes intolerant to haploinsufficiency. However, the contribution of CNVs to the etiology of DCM has not been evaluated in large cohorts of DCM patients and remains unknown.

Purpose

To determine the percentage of cases in which CNVs have been identified as the cause of disease in a large cohort of DCM patients evaluated genetically.

Methods

Retrospective study in which the presence of CNVs was evaluated in a cohort of patients diagnosed with DCM and studied by next-generation-sequencing (NGS). CNVs were detected using a read depth approach and confirmed by an orthogonal molecular technique (Sanger sequencing, MLPA, or dPCR).

Results

6,512 DCM patients referred for genetic testing were sequenced in our center by NGS, and the median age at the time of genetic study was 51.1 years (range 0-93). A pathogenic (P) or likely-pathogenic (LP) disease-causing variant was identified in 1,495 of the patients (diagnostic yield of 22.9%). In 67 (1.02%) of the cases, a CNV classified as P/LP was identified. DMD was the gene with the highest number of CNVs identified (n=40), followed by TTN (n=7) and LMNA (n=5). Of the 67 cases, 45 (67%) corresponded to deletions, with a lesser extent to duplications (n=9; 13%), complex alterations (n=7; 11%), and deletion/insertion (n=6; 9%). Only two of the patients harboring disease-causing CNVs had other variants potentially associated with DCM: a likely-pathogenic variant in MYH7 and a homozygous pathogenic variant in the ALMS1 gene.

Conclusion

In our cohort of DCM patients, 1.02% harbored CNVs considered P/LP, being DMD the most frequently identified gene. These results show that systematic CNVs analysis in NGS studies improves the yield of genetic testing in DCM and highlights the importance of a complete genetic study that includes structural variant detection in the diagnosis of the disease.
Disease penetrance in genotype-positive relatives from families with dilated cardiomyopathy
Authors: Cannie D , Syrris P , Protonotarios A , Bakalakos A , Lorenzini M , Guttmann O , Lopes L , O'mahony C , Sekhri N , Savvatis K , Mohiddin S , Elliott P
Published: November 2023

Background

Genetic testing of patients with dilated cardiomyopathy (DCM) results in identification of a causative gene variant in around 19-37% of individuals [1]. Serial clinical assessment of relatives found to carry genetic variants is recommended, but there are no data to guide screening intervals or to better understand the influence of age, sex and genotype on disease expression.

Purpose

To evaluate the trajectory of disease development in clinically unaffected relatives with a positive genetic test.

Methods

Families with a likely pathogenic or pathogenic variant in DCM related genes were identified from the database at a cardiomyopathy unit. Families were included only where phenotypes were consistent with DCM or hypokinetic non-dilated cardiomyopathy [2]. Consecutive relatives from these families were retrospectively recruited where they had tested positive for the familial genetic variant and were clinically unaffected at baseline evaluation. Incidence rates of disease penetrance during follow-up were stratified by sex and genotype.

Results

131 relatives (59 male (45%) with median age 28.6 [21.5 – 42.0] years at first evaluation) representing 75 families were included. The most prevalent genotypes were DSP (46/131, 35.1%), TTN (32/131, 24.4%) , LMNA (22/131, 16.8%), RBM20 (14/131, 10.7%) and BAG3 (8/131, 6.1%). The overall incident rate of phenotype development during follow-up was 11.6 [8.9 – 14.2] per 100 person years and rates were significantly different between males and females (16.1 versus 8.8 per 100 person-years, log-rank p value = 0.006; Figure 1). LMNA variant-carriers had the highest incidence rate of disease penetrance at 17.7 [9.8 – 25.7] per 100 person-years and disease penetrance occurred at a younger age than DSP and TTN variant-carriers (Figure 2).

Conclusions

Disease development during follow-up is common in genotype-positive relatives, particularly in males and in LMNA variant-carriers. Genotype-positive relatives should be rescreened at least once each year.Figure 1Figure 2
Skeletal muscle involvement in patients with truncations of titin and familial dilated cardiomyopathy
Authors: Vissing C R , Skriver S V , Krett B , Poulsen N S , Krag T , Walas H R , Christensen A H , Bundgaard H , Vissing J
Published: November 2023

Background

Variants in TTN are associated with dilated cardiomyopathy (DCM) and skeletal myopathy with or without cardiac affection. However, the skeletal muscle phenotype has not been systematically evaluated in patients with predisposition to or manifest cardiac involvement due to heterozygous truncating TTN variants (TTNtv), the most common cause of DCM.

Purpose

Assess the skeletal muscle phenotype associated with TTNtv.

Methods

This cross-sectional study examined skeletal muscle involvement in individuals with TTNtv by quantifying and comparing fat fraction from muscle magnetic resonance imaging to controls (matched on body-size, sex, and age), and evaluating muscle strength by dynamometry and features from muscle biopsies.

Results

Twenty-five participants (11 women, age 51±15 years, left ventricular ejection fraction 45±10%) with TTNtv were included (19 had DCM). Compared to controls, participants with TTNtv had higher fat fraction in calf- (12.5% vs 9.9%, p=0.013), thigh- (12.2% vs 9.3%, p=0.004) and paraspinal muscles (18.8% vs 13.9%, p=0.008), see figure. Muscle strength was relatively intact (within 1 SD of normal values). Muscle biopsies in 21 participants showed that 13 (62%) displayed myopathic features, most notably an increased proportion of central nuclei. Electron microscopy showed well-ordered Z-lines and T-tubuli but uneven and discontinuous M-lines and excessive glycogen depositions flanked by large autophagosomes, lysosomes, and abnormal mitochondria with mitophagy.

Conclusion

Skeletal muscle involvement is prevalent in patients with cardiac involvement or predisposition to DCM due to TTNtv and is characterized by an increased muscle fat fraction, and excessive accumulation of glycogen, possibly due to reduced autophagic flux. This emphasizes the need for specialized diagnostic work-up in patients with TTNtv, especially if reporting symptoms or objective signs of muscle involvement.
Prognostic implications of family screening in Dilated and Arrhythmogenic Cardiomyopathies
Authors: Del Mestre E , Paldino A , Pio Loco C , Dal Ferro M , Gandin I , Setti M , Folgheraiter A , Rizzi J , Korkova R , Merlo M , Sinagra G
Published: November 2023

Introduction

Dilated cardiomyopathy (DCM) and arrhythmogenic left dominant cardiomyopathy (ALVC) are overlapping phenotypes of inherited cardiomyopathies characterized by left ventricular systolic dysfunction (LVSD), sharing the same genetic background. The risk of disease development in relatives is relevant and influenced by multiple factors. The purpose of familial screening (FS) is to early detect cardiac manifestations by ECG and echocardiogram every 2-5 years. Recent studies suggested a possible role of Holter-ECG and Global Longitudinal Strain (GLS) for disease prediction. However, these are not strongly recommended in the current FS guidelines. Moreover, it is unclear if FS represents a useful tool to prevent cardiac events in family members.

Purpose

Our study aims to 1) elucidate the role of genetic and environmental factors for cardiac disease development in relatives of probands affected by DCM/ALVC, 2) quantify the predictive role of FS for LVSD, and 3) assess the prognostic impact of FS on relatives.

Methods

Reasons for first medical contact, genetic data, baseline and follow-up (FU) clinical, ECG, echocardiogram, GLS, Holter-ECG data and outcomes were compiled. LVSD was defined as ejection fraction < 50%. Moreover, a primary outcome including all-cause death (D) and heart transplantation (HT) and an arrhythmic secondary outcome including sudden cardiac death (SCD) and major ventricular arrhythmias (MVA) were evaluated in affected relatives.

Results

A total of 385 relatives (85% with a proband affected by DCM) were enrolled. Among these, 223 (58%) were unaffected at baseline. During a median follow-up of 60 (IQR 30-110) months, 81 (36%) developed LVSD. Being carrier of pathogenic variants and having a family history of SCD were the main clinical factors significantly associated with LVSD development in the multivariable model, whereas environmental factors were not. Moreover, the GLS value at baseline was significantly lower in relatives developing LVSD compared to persistent unaffected relatives (-14.9 ±3.2 vs -19.8 ±3.2, p<0.001), and its value was an independent predictor of LVSD. Furthermore, in comparison to previously published predictive models which included age, ECG and echocardiographic abnormalities (C-index 0.64), adding Holter-ECG offers a better fit and increases the concordance by 20% (C-index 0.77). In conclusion, in the total population of 243 relatives (63%) with LVSD (at the baseline or at FU), cardiac events were less frequent among relatives detected by FS.

Conclusions

Genetic background plays a major role in the development of LVSD in relatives of DCM/ALVC probands. GLS and Holter-ECG could be useful tools to improve the efficiency of FS to predict LVSD, suggesting early FU visits. FS shows a significant prognostic protective impact in this study population.
Multimodality imaging in cardiac masses
Authors: Bodega F , Angeli F , Bergamaschi L , Paolisso P , Armillotta M , Fedele D , Bertolini D , Cavallo D , Ryabenko K , Casuso Alvarez M , Lovato L , Rinaldi A , Foa' A , Galie' N , Pizzi C
Published: November 2023

Background

Cardiac masses (CM) are an extremely heterogeneous clinical scenario, including benign and malignant neoformations. After a first echocardiographic assessment, Cardiac Computed Tomography (CCT) together with Cardiac Magnetic Resonance (CMR) and 18-Fluorodeoxyglucose Positron Emission Tomography (18- FDG-PET) represent second line and third-line imaging techniques to determine the nature of the mass. However, data regarding their diagnostic performance and a standardized imaging algorithm are lacking.

Purpose

To evaluate the different roles of CCT, CMR, and PET in defining the nature of CMs and to propose an evidence-based, stepwise, diagnostic approach.

Materials and methods

Out of 312 patients with suspected mass from January 2000 and August 2022, we enrolled 87 patients who underwent CCT, CMR and 18-FDG-PET within a month from the initial evaluation. A definitive diagnosis was achieved by histological examination or, in case of cardiac thrombi, with radiological evidence of thrombus resolution after an appropriate anticoagulant treatment. For each imaging technique, we identified a model with the strongest predictors of malignancy at multivariate analysis and evaluated their ability to discriminate between benign and malignant neoformations. A multiple model with forwarding selection was performed to identify the strongest predictors of malignancy at CCT, CMR and 18-FDG-PET.

Results

CCT model included 4 variables (irregular margins, mass dimension, invasiveness, and not-hypodense lesion) with an Area Under the Curve (AUC) of 0.972, 95% Confidence Interval (CI) 0.94-1.0; CMR model included 3 parameters (invasiveness, pericardial effusion and irregular margins, AUC 0.976 with 95% CI 0.95-1.0); PET model included only cardiac maximum Standardized Uptake Value (SUVmax), with an AUC 0.87 (95% CI 0.74-0.971). When implemented with SUVmax, CCT and CMR models showed only a slight improvement in their discrimination ability (AUC 0.975 and 0.986, respectively). No statistical difference was observed between CCT and CMR models regarding their discrimination ability (AUC 0.972 vs 0.976, p=0.26). However, on a multiple model with forwarding selection evaluating CCT, CMR and PET variables, only the 3 MR parameters remained significant predictors of malignancy.

Conclusion

After a first echocardiographic assessment, the application of the CMR model may be the most accurate second-level investigation to discriminate between benign and malignant lesions. When CMR is not available, or the patient has contraindications to CMR, the CCT model performs similarly, and 18-FDG-PET provides a negligible advantage.
Prevalence of cardiac amyloidosis in patients undergoing carpal tunnel release with amyloid deposition in removed tenosynovium
Authors: Takashio S , Kato T , Tashima H , Irie H , Komohara Y , Morikawa K , Oguni T , Kuyama N , Ueda M , Tsujita K
Published: November 2023

Background

Carpal tunnel syndrome (CTS) is an early symptom and important clinical indicator for the diagnosis of cardiac amyloidosis. Amyloid deposition in removed tenosynovium during carpal tunnel release (CTR) is often confirmed; however, the prevalence of concomitant cardiac amyloidosis is not yet understood.

Purpose

This study aimed to evaluate the prevalence of amyloid deposition in removed tenosynovium in patients who underwent CTR and to clarify the prevalence of concomitant cardiac amyloidosis in patients who had amyloid deposition in removed tenosynovium.

Methods

Overall, 669 patients who underwent CTR were prospectively examined and evaluated for amyloid deposition after tenosynovium removal. Invitation and proposal letters for cardiac screening were sent to patients with amyloid deposition. Electrocardiography, echocardiography, and biomarkers were evaluated to assess the likelihood of cardiac amyloidosis.

Results

Amyloid deposition was observed in 261 (39%) patients, who were significantly older and predominantly male (p<0.05). Among them, 111 patients (mean age; 70.8 ± 7.3 years old; men: 55%) agreed to cardiac screening. 99mTc-labeled pyrophosphate (99mTc-PYP) scintigraphy was performed in 12 patients who met the following criteria: 1) interventricular septum diameter (IVSd) ≥14 mm or 2) 12 mm ≤ IVSd <14 mm with above-normal limits in high-sensitivity cardiac troponin T (hs-cTnT; >0.014 ng/mL). Six patients (50%) had positive findings on 99mTc-PYP scintigraphy and were diagnosed with wild-type transthyretin cardiac amyloidosis with Mayo prognostic stage I. The prevalence of concomitant cardiac amyloidosis was observed in 6/111 (5.4%) CTR patients with amyloid deposition and 50% (6/12) in patients with left ventricular hypertrophy (≥12 mm) with increased hs-cTnT levels.

Conclusion

Amyloid deposition in removed tenosynovium was frequently observed in elderly men with CTS. Cardiac screening may be useful for the early diagnosis of cardiac amyloidosis in patients undergoing CTR with amyloid deposition. This knowledge should be shared with orthopedic surgeons and cardiologists for the early diagnosis of cardiac amyloidosis.Flowchart of participant selectionGraphical Abstract
Transtyretin cardiac amyloidosis in the elderly patient: always a wild type?
Authors: Costantino J , Ballatore F , Ajmone F M , Manguso G , Ciaramella P , Maggio E , Alfarano M , Vizza C D , Chimenti C
Published: November 2023

Background

Transthyretin amyloidosis (ATTR) exists in two forms: a genetic form transmitted by autosomal dominant inheritance (ATTRv) and a wild type form (ATTRwt). Clinically, the hereditary form tends to have an early onset in adulthood and it is characterized by a particular tropism for nervous as well as cardiac tissue. In contrast, the "wild type" form has a later onset with major cardiac involvement and neurological manifestations usually limited to carpal tunnel syndrome (1).

Methods and results

in our centre, from January to October 2022, 20 patients older than 75 years received a diagnosis of cardiac ATTR (73% male, 27% female, mean age 83±5). In all patients, blood tests showed a significant and stable increase in the values of troponin Ths (0.070± 0.074 ng/mL) and NT-proBNP (1533±1204 pg/ml), with the absence of a monoclonal component in the blood and urine, and miocardial bisphosphonate scintigraphy positive grade 2/3. All patients showed absence of peripheral neuropathy with the presence of carpal tunnel syndrome in 9 cases. Before starting therapy with Tafamidis all patients underwent genetic testing by amplification of exons 2,3 and 4 of the TTR gene with subsequent sequencing. Unexpectedly, in 3 elderly male patients (15%) the genetic test resulted positive with 3 different mutations of pathogenetic significance (Val50Met; Ile88Leu; Val142Ile). First-degree relatives (10 consanguineous, average age 49±12 years) agreed to be subjected to genetic screening; of these 4 (1 male and 3 females, age 47±8 years) were positive for the corresponding mutation and underwent echocardiogram, MRI and myocardial scintigraphy. All of these tests were normal and they were included in an annual follow-up protocol at the to identify an early manifestation of the disease.

Conclusions

our experience shows that 15% of patients older than 75 years and diagnosed with cardiac ATTR may be affected by a genetic form. Making genetic diagnosis in this context is particularly important for screening family members: current therapies are in fact much more effective if started early before organ damage can occur (2).
Diagnostic agreement between echocardiography and second-level imaging techniques in patients with cardiac masses
Authors: Suma N , Amicone S , Bodega F , Sansonetti A , Cavallo D , Di Iuorio O , Tattilo F P , Angeli F , Bergamaschi L , Foa' A , Paolisso P , Rinaldi A , Lovato L , Galie' N , Pizzi C
Published: November 2023

Background

Cardiac masses (CMs) are a diagnostic dilemma in clinical practice and require multimodality imaging to assess malignancy, which is essential to guide the proper treatment.

Aim

To define diagnostic accuracy and agreement between echocardiographic features and second-level imaging techniques (cardiac computed tomography – CCT or cardiac magnetic resonance – CMR) in patients with CMs.

Methods

All consecutive patients with histologically confirmed cardiac masses from January 2004 to December 2020, undergoing CCT and/or CMR after echocardiographic assessment were enrolled. Six echocardiographic variables, namely infiltration, polylobate mass, moderate-severe pericardial effusion, inhomogeneity, sessile and non-left localization, were used to predict malignancy. Patients with more than 3 of these features were considered at higher risk of malignancy. For the patients before 2017, the choice of which second-level imaging to perform was up to the clinical cardiologist. Since 2017, the has been the result of a multidisciplinary discussion by the Heart Team. A definitive diagnosis was achieved by histological examination or, in the case of cardiac thrombi, with radiological evidence of thrombus resolution after an appropriate anticoagulant treatment. The echo-vs-CCT agreement and echo-vs-CMR agreement were evaluated. Accuracy indicators (sensitivity, specificity, PPV, NPV, Cohen’s Kappa coefficient) were calculated by standard formulas.

Results

Out of 249 patients with histologically confirmed CM, 138 underwent a CCT and 112 a CMR, after the standard echocardiographic assessment. A complete agreement between the echocardiographic assignment (using the cut-off of 3 parameters as a marker for malignancy) and CCT was reached in 104 out of 138 cases (75.4%), ranging from 85.1 to 70.3% for benign and malignant cardiac masses, respectively. On the other side, the agreement between the echocardiographic assignment and CMR report was in 93 out of 112 cases (83%), ranging from 88.7 to 82% for benign and malignant cardiac masses. The agreement between these imaging techniques expressed as Cohen’s κ was higher for echocardiography versus CMR (k=0.73), compared to echocardiography versus CCT (k=0.61). These results were also confirmed by the higher diagnostic accuracy of echocardiography versus CMR compared to echocardiography versus CCT (87% vs 80%), with best values of sensitivity, and specificity, denoting good reliability between the first 2 techniques.

Conclusions

A multimodal imaging approach is mandatory in the diagnostic work-up of CMs. The CMR, after a standard echocardiographic assessment, turned out to be the most accurate second-level investigation to discriminate between benign and malignant masses. However, when CMR is not available or the patient has a contraindication, the CCT could still be reliable.
Temporal trends and outcomes of heart failure patients between light-chain cardiac amyloidosis and transthyretin cardiac amyloidosis: insights from the national inpatient sample database
Authors: Gandhi K , Moras E , Correa A , Mahmood K
Published: November 2023

Background

Systemic amyloidosis comprises a family of diseases caused by deposition of misfolded fibrillar proteins in the extracellular space. Cardiac involvement is the leading cause of morbidity and mortality in systemic amyloidosis and a major determinant of survival, regardless of the underlying pathogenesis of amyloid production. Data regarding the clinical outcomes in immunoglobulin light-chain (AL) va amyloid transthyretin (ATTR) cardiac amyloidosis (CA) is scarce.

Purpose

We aimed to investigate the trends, baseline clinical characteristics, and clinical outcomes of AL CA vs ATTR CA in heart failure (HF) patients.

Methods

Data from United States National Inpatient Sample database from 2017-2020 was used to identify hospitalizations for CA with concurrent cardiomyopathy in HF patients and were further subclassified into AL vs ATTR CA. Outcomes were compared using univariate and multivariate logistic regression analysis.

Results

During 2017-2020, there were 12430 hospitalizations of CA of which 96.3% were ATTR CA and 3.7% were AL CA. Patients with ATTR-CA when compared to AL-CA were older, predominantly male, more blacks, and had a higher prevalence of co-morbidities including atrial arrythmias, sick sinus syndrome, and aortic stenosis. Patients with AL CA had significantly increased in-hospital mortality, length of stay, total charges, acute heart failure exacerbations, and cardiopulmonary resuscitation. After adjustment for baseline characteristics, AL CA patients had significantly increased odds of in-hospital mortality and HF hospitalizations when compared to ATTR CA cohort. There is an increasing trend in hospitalizations in AL CA from 2017-2019.

Conclusion

AL cardiac amyloidosis had significantly higher odds of in-hospital mortality and HF hospitalizations in comparison to ATTR cardiac amyloidosis cohort. AL CA had lower incidence of stroke, thromboembolism and major bleeding with similar need for cardiac device implantation.Figure 1Figure 2
Human in vitro disease modeling of ATTR cardiac amyloidosis
Authors: Qin J , Dokter I , Qiang Y , Lei Z , Sluijter J P G , Oerlemans M I F , Van Mil A
Published: November 2023

Background

Amyloidosis is a systemic protein-folding disorder characterized by extracellular misfolded fibrillar protein aggregates that are insoluble and resistant to proteolysis, leading to progressive and vital organ damage [1]. Transthyretin amyloidosis (ATTR) is one of the primary amyloidosis types that affect the heart. Based on the TTR gene sequence, ATTR is further classified into wild-type ATTR (ATTRwt) and hereditary ATTR (ATTRv). Advanced stage TTR amyloid infiltration of the myocardium results in progressive thickening and stiffening of the ventricle wall, and symptoms of restrictive cardiomyopathy and congestive heart failure. Due to the lack of specificity of cardiac amyloidosis symptoms, misdiagnosis and delays in diagnosis are common, resulting in worsening symptoms, organ damage, and increased mortality [2]. Despite the development of several disease-modifying agents [3], current experimental cell and animal models do not adequately represent the human situation, thereby limiting disease understanding and therapeutic discovery.

Purpose

This project aims to develop an in vitro ATTR disease model, which is critical to define early disease stages and disease progression, map human disease-specific pathways, and screen for novel drugs or validating cutting-edge therapeutic strategies.

Methods

Recombinant WT-TTR and V122I mutated TTR (V122I) were prepared using E.coli protein production system. TTR purification and acid-mediated TTR-fibril were characterized by SDS-PAGE, Thioflavin T fluorescence measurement, and transmission electron microscope (EM). iPSC-derived cardiomyocytes (iPS-CMs) were differentiated using GiWi protocol as described [4,5]. iPS-CMs or HUVECs were seeded on TTR or TTR-fibril, and we measured beating rate, cell viability (AlamarBlue and LiveDead), and cell/fibril morphology using immunofluorescence.

Results

Purified recombinant WT and V122I TTR was successfully generated (Figure 1A). Fluorescence increase (Thioflavin T) and EM revealed the presence of TTR-fibril (Figure 1B). iPS-CMs seeded on TTR-fibril resulted in a dose- and time-dependent increase in cell death. Confocal microscopy revealed the attachment of TTR-fibril on iPS-CMs, leading to sarcomere disarray, loss of cell-to-cell coupling, resulting in irregular beating (Figure 2A). Additionally, we found drastically affected viability of HUVECs upon TTR-fibril exposure (Figure 2B).

Conclusion

Here, we demonstrate an established method to generate purified TTR and TTR-fibril. TTR-fibril attached to the surface of iPS-CMs decreased cell viability and functionality. Similar reduction in HUVEC viability were observed as well. These findings reflect the cytotoxicity of TTR-fibril in a human in vitro model.TTR and TTR-fibril characterizationCell viability up TTR-fibril exposure
Sex-related disparities in cardiac masses: clinical features and outcomes
Authors: Pizzi C , Di Iuorio O , Angeli F , Bergamaschi L , Cavallo D , Impellizzeri A , Canton L , Amicone S , Bertolini D , Casuso M , Foa A , Rinaldi A , Paolisso P , Galie N , Sansonetti A
Published: November 2023

Background

Cardiac masses (CM) represent a heterogeneous clinical scenario. Sex-related differences of these patients remain to be established. Purpose: To evaluate sex-related disparities in CMs regarding clinical presentation and outcomes.

Material and Methods

Thestudy cohort included 321 consecutive patients with cardiac mass enrolled in our Centre between 2004 and 2022. A definitive diagnosis was achieved by histological examination or, in case of cardiac thrombi, with radiological evidence of thrombus resolution after anticoagulant treatment. All-cause death at follow-up was evaluated. Multivariable regression analysis was performed to assess potential prognostic disparities between men and women.

Results

Out of 321 patients with CM, 172 (54%) were female. Women were more frequently younger (p=0.02) than men. Regarding CM histotypes, females were more frequently affected by benign masses (with cardiac myxoma above all), while metastases were more common in men (p<0.001). At presentation, peripheral embolism occurred predominantly in women (p=0.03). Echocardiographic features such as greater dimension, irregular margin, infiltration, sessile mass and immobility were far more common in men. Despite a better overall survival in women, no sex-related differences were observed in the prognosis of benign or malignant masses. In fact, at multivariate analyses, sex was not independently associated with all-cause death. Conversely, age, smoking habit, malignancy and peripheral embolism resulted independent predictors of mortality.

Conclusion

In a large cohort of heart masses, a significant sex-related difference in histotype prevalence was found: benign CMs affected female patients more frequently, while malignant tumours affected predominantly men. Despite better overall survival in women, sex does not influence prognosis in benign and malignant masses.
Need an endomyocardial biopsy? Call your electrophysiology team
Authors: Fitzpatrick N , Tovmassian L , Calvert P , Ness N , Mc Connon N , Luther V , Rao A , Mahida S , Dobson R , Fairbairn T , Cooper R , Ntouskou M , Ali N , Gosney J , Modi S
Published: November 2023

Introduction

With significant advances in targeted chemotherapeutic options for soft tissue tumours, obtaining a tissue diagnosis is more important than ever. Primary and secondary cardiac tumours are rare [1] and endomyocardial biopsy of these tumours has been sparsely reported [2-9]. Advanced tools in cardiac electrophysiology happen to lend themselves well to cardiac tumour biopsy. Our electrophysiology (EP) guided endomyocardial biopsy (EMB) service includes electrophysiologists, cardio-oncology specialists, cardiac imaging specialists, oncologists, and pathologists. For the last 9 years all targeted endomyocardial biopsies in our tertiary institution have been undertaken by our EP guided EMB service with extensive experience in electroanatomical mapping (EAM), visualisable sheaths and integrated intracardiac echography (ICE). We report the findings.

Methods

We performed a retrospective review of all cases referred to the EP guided endomyocardial biopsy service at our centre and identified those with attempts to biopsy a cardiac mass. We describe the incorporation of advanced electrophysiology techniques utilised by the service. Specifically, the use of intracardiac echocardiography integrated into an electro-anatomical mapping system and bioptome delivery via a visualisable, deflectable sheath. This allows for the real time 3D visualisation of the target mass, surrounding anatomy and position of the bioptome during biopsy.

Results

Of 38 patients who underwent targeted biopsy at our centre, a total of 8 patients (5 female; mean ± SD age 54 ± 21 years) were referred for cardiac tumour biopsy, undergoing a total of 9 procedures (mean ± SD duration 116 ± 21 mins). Table 1 details the patient’s pertinent history and underlying pathology, the tumour site, possible alternative biopsy sites, a summary of techniques and technologies utilised and the eventual diagnosis. In 100% of cases, tissue was sampled from the desired location, though in two patients the histological result was inconclusive due the retrieval of necrotic tissue or fibrotic tissue only. This translated into a definitive histopathological diagnosis in 75% of patients. One patient experienced a transient right bundle branch block during the procedure, in all others the procedures were uncomplicated. Image 1 exemplifies some of the cases with pre-procedure imaging results and intra-procedural views from both ICE and the EAM.

Conclusion

In this study, our approach to utilising the combination of intracardiac echocardiography integrated into an electro-anatomical mapping system and bioptome delivery via a visualisable, deflectable sheath appears safe, and provides unparalleled accuracy in endomyocardial sampling of cardiac tumours.Table 1Image 1
Atrial septal defect patients have an elevated risk for infective endocarditis
Authors: Muroke V , Jalanko M , Haukka J , Patila T , Hartikainen J , Tahvaneinen A , Ukkonen H , Ylitalo K , Anttila V , Pihkala J , Sinisalo J
Published: November 2023

Background

It has been unclear whether simple atrial septal defect (ASD) is an independent risk factor for infective endocarditis (IE). This study aimed to untangle the risk of endocarditis in a large nationwide cohort.

Methods

We acquired data from the Finnish hospital discharge register on all individuals with ASD diagnosis from 1969 to 2019. Patients with complex congenital cardiac abnormalities were ruled out. Five individualized controls from the general population were matched to the ASD patient's birth year, sex, and residence at the index date. All the patients with ICD-8, -9, or -10 diagnosis codes for IE were gathered from the hospital discharge registry.

Results

After exclusion, 8322 ASD patients and 39 237 individualized controls were enrolled in the study. Median follow-up was 21.6 years (IQR 11.8-36.9) from the first hospital contact.

In total, 24 (16 male) cases of infective endocarditis among ASD patients and 10 (8 male) cases among controls were diagnosed during the follow-up. The incidence of endocarditis was 0.11 per 1000 person-years in the ASD patients and 0.011 per 1000 person-years in the controls. The adjusted risk ratio for endocarditis was 13.51 (95% CI: 6.20–29.46) in ASD patients compared to the control cohort. Patients with ASD and endocarditis had higher long-term mortality than individualized control patients (MRR 2.25, 95% CI: 1.23-4.11).

Conclusions

The incidence of endocarditis in atrial septal defect patients is higher than in the general population, and ASD seems to carry an increased risk of developing endocarditis.Cumulative incidence of endocarditisSurvival after endocarditis diagnosis
Long-term outcomes and risk factors for reoperation after subaortic stenosis resection in children and adults
Authors: Esposito A , D'anna C , Chinali M , Franceschini A , Brancaccio G , Santilli A , Guccione P , Galletti L
Published: November 2023

Background

Sub-valvular aortic stenosis (SAS) is an extremely heterogeneous form of left ventricular outflow tract (LVOT) obstruction, which can lead to aortic valve damage. Although corrective surgery is considered the most effective treatment, rates of recurrence and reoperation are still high. Previous studies have focused on predictors of reoperation in several subgroups of patients with SAS, but rarely in the whole population of patients with SAS.

Purpose

We sought to describe long-term outcomes after SAS resection and to determine the predictors of reoperation after successful primary resection.

Methods

We retrospectively reviewed the records of patients who underwent SAS resection between 1994 and 2021 at our institution with at least 12 months’ follow-up. Patients with a single-ventricle physiology and idiopathic hypertrophic cardiomyopathy were excluded. Demographic, surgical and echocardiographic data were analyzed. Outcomes were reoperation after successful primary resection, death and morbidities, including postoperative complete heart block and aortic regurgitation (AR) grade at latest follow-up.

Results

Seventy-six patients (paediatric, n = 72 and adult, n = 4) who underwent SAS resection were included in the analysis. Median length of postoperative follow-up was 11.1 years (IQR range: 7.3 – 15.7 years), with two late deaths. Reoperation due to recurrent obstruction or severe AR occurred in 24 patients (31.6%). Median time to reoperation was 7.5 years (IQR range: 3.6 – 11 years). Overall freedom from reoperation at 5 years and 10 years was 84.6% and 69.1% respectively. Gender and association with other cardiac defects did not differ significantly between those with reoperation and those without. In multivariate analysis, independent predictors of reoperation were age at first surgery younger than 5 years (HR 3.54, 95% CI 1.06 – 11.83; P = 0.040) and tunnel-type lesions (HR 4.42, 95% CI 1.70 – 11.51; P = 0.002). Three patients (3.9%) had complete heart block and required placement of an implantable pacemaker. Following SAS resection, progression of AR was common (39/68, 57.3%) but only 5 patients (7.3%) developed sufficient regurgitation to require surgical repair or replacement.

Conclusions

Reoperation is not infrequent after surgical relief of SAS and reaches a plateau after 10 years. Younger age at first surgery and tunnel-type SAS independently predict reoperation. Progression of AR after corrective surgery of SAS is common, but fortunately only a minority of patients develop hemodynamically significant AR requiring reintervention.
Associations of maternal exposure to multiple plasma metals with the risk of fetal congenital heart defects: a prospective nested case-control study
Authors: Nie Z , Ou Y A N Q I U
Published: November 2023

Background

Congenital heart defects (CHDs) are the most common congenital anomalies with complex etiologies. There is knowledge gap with respect to the association between single and combined exposures to multiple heavy metals during pregnancy and the risk of CHDs in the fetus. Thus, we aimed to examine the association between maternal plasma heavy metal concentrations in mid-pregnancy and the risk of CHDs in the fetus.

Methods

A prospective nested case-control study was conducted in a cohort of 11,578 newborns. Exposure odds ratios (ORs) were compared between 164 CHD cases and 164 non-malformed controls delivered at the same hospital, individually matched by maternal age (±5 years) and parity. Concentrations of 21 metals were determined in maternal peripheral blood plasma via an ultra-performance liquid chromatography inductively coupled to mass spectrometry (ICP-MS). Single- and multiple-metal logistic regressions, the adaptive least absolute shrinkage and selection operator (LASSO) penalized regression analysis and restricted cubic spline (RCS) analysis were applied to explore the associations and dose-response relationships of plasma metals with CHD. We also applied Bayesian Kernel Machine Regression (BKMR) model to evaluate the cumulative effect of the exposure metals.

Results

Median (interquartile range, IQR) Vanadium (V) [0.3 (0.3-0.4) vs. 0.3 (0.3-0.4) μg/L, P = 0.027] and cadmium (Cd) [0.1 (0.0-0.1) vs. 0.1 (0.0-0.1) μg/L, P = 0.036] levels were different between the CHDs and control groups. Compared with the first quartile, the Directed acyclic graph(DAG) model-adjusted ORs (95% CI) were 3.12 (1.72-5.64) for kalium (K), 2.21 (1.23-3.94) for manganese (Mn), 0.55 (0.33-0.94) for cerium (Ce), 1.96 (1.06-3.64) for lead (Pb) in the second quartile, and ORs (95%CIs) were 1.88 (1.08-3.26) for V, 0.53 (0.30-0.93) for Cr, 1.92 (1.10-3.35) for copper (Cu), 2.09 (1.18-3.70) for Cd, 2.14 (1.24-3.70) for stannum (Sn) and 3.05 (1.69-5.49) for Pb in the third quartile. In the multi-metal model, compared to the lowest quartile, the ORs for Sn and Pb in the second quartile were 1.32 (95% CI: 0.69-2.55) and 1.94 (95% CI: 0.98-3.84), respectively, and the ORs for both metals in the third quartiles were 2.15 (95% CI: 1.16-3.98) and 3.32 (OR=0.66, 95% CI: 1.68-6.55), suggesting that Sn and Pb had relatively stable positive results with a linear dose progression. BKMR models with 2 cluster for 9 metals showed that the overall effect of metal mixture was not statistically significant at or below 35th percentile and at or above the 70th percentile, compared to their median levels. Pb was the major contributor to the combined effect.

Conclusions

Elevated level of plasma plumbum was associated with increased risk of CHDs. Further investigations in larger perspective cohorts are needed to confirm our findings.fig 1fig 2
Risk stratification of non-cardiac surgeries in adult congenital heart disease
Authors: Fischer A J , Koeppe J , Gerss J , Freisinger E , Reinecke H , Baumgartner H , Diller G
Published: November 2023

Background

Adults with congenital heart disease (ACHD) face multiple surgeries throughout their lifetime. Data on the specific risk of undergoing non-cardiac surgery and impact of severity of ACHD on outcome are limited. We aimed to assess frequency and outcome of non-cardiac surgery and to identify ACHD patients specifically at risk.

Methods

Based on data including all hospital admissions in Germany from 2011 to 2018, we identified all ACHD cases that were admitted for non-cardiac surgery. Non-cardiac surgery was categorized in low-, medium and high-risk based on a clinically implemented risk score validated for non-congenital cardiac patients. The analyzed data contained information on patient demographics, diagnoses, in-hospital complications, and mortality. The primary endpoints of the study were major adverse cardiovascular events (MACE), major infection, major bleeding, thromboembolism and in-hospital death. Outcomes of ACHD were compared to a propensity score matched cohort of non-ACHD.

Results

Overall, 13,041 ACHD inpatient cases were included in the analysis (simple n=9,333 (72%), moderate n=2,741 (21%), and complex heart defects n=966 (7%)). 23.0% simple ACHD underwent low-risk surgery, whilst 31.1% were intermediate and 45.0% high-risk procedures. In the medium complexity ACHD cohort, 35.8% received low-risk, 42.3% intermediate risk and 21.8% high-risk surgery. In complex ACHD, 42.4% underwent low-risk, 41.2% intermediate risk and 16.4% high-risk surgery. Simple ACHD more frequently presented with typical cardiovascular risk factors such as dyslipidemia, arterial hypertension and diabetes mellitus compared to moderately and severely complex ACHD at time of non-cardiac surgery (p<0.001 for all). Compared to a propensity score matched cohort of non-ACHD, congenital cardiac patients more often met the endpoints with an increasing frequency depending on complexity of disease and pre-defined risk of surgery. After adjustment on multivariable logistic regression analysis, moderate and severe complexity of the congenital cardiac defect was associated with an adverse outcome. Risk for death was increased in moderately complex (OR 1.44, 95% CI 1.15 - 1.81, p=0.001) and severely complex ACHD (OR 2.28, 95% CI 1.63 - 3.20, p<0.001) compared to non-ACHD. Compared to low-risk surgeries, patients were at increased risk for death when undergoing mid- (OR 7.66, 95% CI 5.18 - 11.34, p<0.001) or high-risk surgeries (OR 8.03, 95% CI 5.42 - 11.90, p<0.001).

Conclusions

ACHD patients are at increased risk of adverse complications when undergoing non-cardiac surgery. Risk for adverse outcomes increased with complexity of disease and was generally higher than in non-ACHD individuals. The presented data show that surgical risk classifications implemented for non-congenital cardiac patients were also associated with a much higher adverse outcome in cases undergoing high- versus low-risk procedures.