bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of coronary and carotid atheroma volume in patients with severe and familial hypercholesterolemia (VOCCA-3D HF)
Authors: Fawaz S , Boulestreau R , Pucheu Y , Liegey J S , Gaufroy A , Broitman J , Ducos C , Bazin C , Sridi-Cheniti S , Coste P , Cochet H , Montaudon M , Couffinhal T
Published: October 2024

Background

Stratifying the risk of CV event of familial hypercholesterolemia (FH) patients is not always simple, as they usually are excluded from CV disease risk estimation scores. It has become increasingly clear over the last several years that the heterogeneity in risk among patients with FH is far greater than previously appreciated. To that end, not all patients with FH will require the use of PCSK9 inhibitors.

Aim

We described the type of coronary artery disease (CAD) in patients with severe and familial hypercholesterolemia and without known atherosclerotic cardiovascular disease and searched for the best determinants of CAD. We searched for correlation between epicardial adipose tissue and CAD.

Methods

We evaluated the atherosclerosis burden with a combination of calcium score (CAC), computed tomography angiography, and the quantification of coronary atheroma volume and the analysis of the composition of the plaques, alongside with the use of ultrasonography of supra-aortic trunks with 3D quantification of atheroma volume. We also evaluated epicardial adipose tissue volume with CT.

Results

We analyzed 89 individuals with LDL-c > 190 mg/dL, with a mean age of 56,7 years. LDL-c burden was high (maximal LDL-c level across life of 2.77 g/L in mean, duration of hypercholesterolemia of 21.5 years in mean). Forty percent of the individuals had a CAC score of zero, and only one patient had non-calcified atheroma despite a CAC score of zero. Among patients with CAD, 50% had a CAC > 100 AU, 9% had a stenosis > 50%. Coronary atheroma volume amounted to a median of 50.9 mm3 in patients with CAD, representing 4% of the analyzed coronary lumen volume, and was mainly made of calcified and non-calcified fibrous plaques. At-risk plaques were not frequent (9% of low-attenuation plaques, 15.2% of positive remodeling and 2% of napkin-ring sign) in patients with CAD. Fifty percent of the individuals had no carotid plaque. Among various clinical and biological risk factors (LDL-year-score, age, blood pressure, smoking, familial history, diabetes), the carotid atheroma volume was the only variable to be independently correlated with both CAC (t=3.1, p=0.006) and coronary atheroma volume (t=4.9, p<0.001). Epicardial adipose tissue was not associated with CAD.

Conclusion

A significant part of the patients with severe and familial hypercholesterolemia has no CAD, however half of the patients with CAD have an important atherosclerosis burden, which can be well predicted by the carotid atheroma volume. Such a screening could help identify the individuals who would benefit the most from intensive cholesterol-lowering drugs.CAC categoriesType of coronary plaques
New clinical staging proposal applied to a Fabry cardiomyopathy cohort
Authors: Oliveira C , Marques C , Santos J , Fortuna I , Santos L , Pinho A , Cabrita A , Oliveira J P , Martins E
Published: October 2024

Background

Fabry disease (FD) is a rare cause of hypertrophic cardiomyopathy (HCM), and early diagnosis is important considering the response to enzyme replacement or chaperone therapies. Recently, a practical clinical staging for Fabry cardiomyopathy was proposed by Olivotto et al 2023, considering several features, being potentially useful for standardizing the criteria for initiation and response assessment to therapy. Imaging characterization of hypertrophy and fibrosis are critical key items to determine stages. This new proposal suggested 4 main stages (0, I, II, III) according to these parameters. Stages 0 and I are further divided in 2 sub-stages according to minor findings and hypertrophy severity, respectively. Unfortunately, not all patients with Fabry cardiomyopathy are identified early in the disease, limiting the response to treatment.

Aim

Our study aimed to evaluate retrospectively the staging of Fabry cardiomyopathy at first imaging cardiac evaluation according to the recent proposal (1), in a cohort of 35 patients with FD at a reference centre of Fabry disease.

Results

At the first cardiac evaluation, the group of patients had a median age of 46 years (28-68 years), 69% were female and 5% were already under enzymatic therapy. The majority of Fabry patients (66%) were in non-hypertrophic stage 0: 4 patients in 0A with no detected cardiac involvement and 19 patients in 0B with subclinical cardiac findings (17% presenting diastolic dysfunction, 14% impaired global longitudinal strain, 6% hypertrabeculation, 6% reduced native T1, 3% short PR duration, 3% cardiac symptoms). In hypertrophic stage I, 14% of patients were classified according to the presence and severity of LVH: 3 in IA (12-15 mm) and 2 in IB (>15mm). All patients (n=3, 9%) in hypertrophic fibrotic stage II presented non-extensive late enhancement (< 3 LV segments) in the first CMR. Patients with overt dysfunction or stage III (n=4; 11%), presented diffuse myocardial fibrosis (> 3 LV segments) or impaired systolic function (LVEF < 50%).

Conclusion

In our cohort patients, the new staging scheme allows us to identify and classify the different stages of FD cardiomyopathy. The majority of patients were unexpectedly identified in early disease stages, but that could be related to diagnosis in the context of familial screening.

This proposal seems useful for clinical staging standardization to facilitate the evaluation of responses to treatments and to predict outcomes, however, needs to be validated in larger and prospective studies.
A comprehensive evaluation of available evidence of mavacamten in obstructive HCM: a meta-analysis of randomised controlled trials
Authors: Ramadan S , Abdelaziz A , Husain M A , Mesbah S M , Elnady M I , Mohamed A E , Hafez A H , Ghaly R , Mostafa M , Abdelazeem B , Banour S , Lavie C J , Slipczuk L
Published: October 2024

Introduction

Obstructive hypertrophic cardiomyopathy (HCM) poses a significant clinical challenge, characterized by left ventricular hypertrophy and impaired cardiac function. mavacamten, a novel medication targeting the sarcomere protein myosin, has emerged as a promising therapeutic option for patients with symptomatic obstructive HCM. Despite its potential efficacy, the comparative effectiveness and safety of Mavacamten remain uncertain, necessitating a comprehensive evaluation of available evidence.

Purpose

We aimed to give a comprehensive appraisal on mavacamten as a treatment option for patients with obstructive HCM informing clinical decision-making.

Methods

We systematically searched PubMed, Web of Science, Scopus, and Cochrane Central, and EMBASE from inception until February 2024. We included randomised controlled trials (RCTs) comparing mavacamten versus placebo in patients with obstructive HCM. The primary outcomes were improvement in NYHA class, Change from baseline in KCCQ-CSS, and the incidence of atrial fibrillation. All data were pooled as either Mean difference in the random effect model with the corresponding SD or pooled as RR and 95% CI for dichotomous data.

Results

Four randomised controlled trials involving 503 patients were included in the final analysis. the overall odds ratio demonstrated a substantial preference for Mavacamten in achieving more than a one-level improvement in NYHA functional class from baseline (OR: 3.83 (95% CI [2.54 to 5.77], P=0.0001). However, there was no significant difference in terms of KCCQ-CSS (MD= 1.06, 95% CI [ -0.03 to 2.15], P=0.06) or the incidence of atrial fibrillation (OR=1.27, 95% CI [0.51 to 3.14], P=0.60).

Conclusion

Mavacamten showed a significant improvement on NYHA functional class, with no observed significance in terms of reducing the incidence of AF, or improving the KCCQ-CSS score.KCCQ-CSSNYHA
Coronary CT angiography using photon counting CT for the detection of coronary artery stenoses and coronary atherosclerotic plaque: comparison of reconstructions with 0.2 mm and 0.4 mm slice thickness
Authors: Zuhair Kassem T , Achenbach S , Moshage M , Weidinger F , Jung S , Smolka S , Marwan M
Published: October 2024

Photon Counting CT allows the acquisition of high-resolution data sets with 0.2 mm reconstructed slice thickness. It is unknown whether the detection of coronary artery stenoses, of coronary plaque or of vulnerable plaque characteristics is improved in data sets that employ maximum resolution. We therefore compared the identification of above characteristics in data sets reconstructed with 0.2 mm and 0.4 mm slice thickness

In 30 patients with suspected coronary artery disease, sinus rhythm, a heart rate ≤65 beats/min, and body weight ≤ 100 kg, high-resolution data sets were acquired by photon counting CT (60 ml contrast i.v. at 6 ml/s) after s.c. application of nitrates in inspiratory breathhold. Data were reconstructed with 0.2 mm slice thickness at 0.1 mm increment and 0.4 mm slice thickness at 0.2 mm increment. Next to quantitative analysis of image quality parameters, all data sets were evaluated by two independent expert reviewers concerning subjective image quality as well as the ability to determine the presence of coronary artery stenoses, calcified and non- calcified plaque, as well as parameters of plaque vulnerability (positive remodeling, necrotic core, density < 30 HU and napkin-ring sign) using a 5-point Likert scale (-2 to +2) and a dedicated 11-segment coronary model.

Of the 30 patients, 47% were male (mean age 58±12 years, mean heart rate 53±6 bpm, mean body weight 80±15 kg). The median dose length product was 508 mGy*cm. Mean image noise was 42±7 HU vs. 34±7 HU for 0.2 mm vs. 0.4 mm reconstructions (p < 0.001). The median image quality score was significantly higher for 0.2 mm reconstructions (3.8±0.8 vs 3.6±0.7). Of 335 coronary segments, none were classified as "unevaluable" while 87% vs. 76% were classified as "perfect" in 0.2 mm vs. 0.4 mm reconstructions (p < 0.001). Full confidence to rule-in or rule out significant coronary stenoses was achieved in 93% of segments in both reconstructions. The number of non-calcified plaques identified in 0.2 mm reconstructions was numerically higher than in 0.4 mm reconstructions (77 vs. 71, p = n.s.). On the Likert scale, the confidence to identify parameters of plaque vulnerability was significantly higher for 0.2 mm reconstructions (1.93 vs. 1.85, p < 0.001). In a selected patient group, photon counting CT coronary angiography demonstrated excellent image quality and an extremely low rate of unevaluable coronary segments. High-resolution reconstructions improve subjective image quality as was as the assessment of vulnerable plaque characteristics.
Left ventricular apical aneurysms and outcomes in hypertrophic cardiomyopathy
Authors: Malcolmson J , Amarin M , Davies W , Husselbury T , Mezzanotte G , Learoyd A , Petersen S E , O'mahony C , Mohiddin S A
Published: October 2024

Background/Introduction

The presence of left ventricular apical aneurysm (LVAA) has been shown to be associated with increased risk of adverse events in patients with hypertrophic cardiomyopathy (HCM). However, the between LVAA size and outcomes is uncertain.

Purpose

To explore associations between baseline LVAA diameter and progressive changes in LVAA size over time and poor outcomes in HCM patients.

Methods

Our HCM multimodality imaging database (transthoracic echocardiography (TTE) or cardiac magnetic resonance (CMR)) was retrospectively assessed for studies reporting LVAA, defined as one or more akinetic or dyskinetic apical segments. LVAA size (widest systolic diameter in millimetres in the transverse plane) was recorded at two time points: earliest identification and most recent imaging, with LVAA size progression (mm/year) calculated. Patients’ electronic records were reviewed for composite outcome including stroke, apical thrombus, death, and appropriate therapy from implantable cardioverter defibrillator (ICD). Continuous variables are presented as mean ± standard deviation (SD), categorical data numerically or as percentages. Comparisons between groups were made using Wilcoxon ranks sum and Fischer exact test for continuous and binary variables, respectively. Cox regression was used to assess independent associations with composite outcomes. A p value of <0.05 was considered statistically significant.

Results

A total of 106 patients were identified with LVAA and clinical follow-up (mean age 64.7±11.4 years, 70% male). Mean follow-up duration was 6.5±3.0 years. Baseline LVAA was confirmed by CMR and TTE in 70 and 30% of cases respectively. Mean LVAA size at baseline was 16.2±7.6 mm (range 6-56 mm). During multivariate Cox analysis, baseline LVAA size in mm was independently associated with the composite outcome (HR 1.04, 95% CIs 1.0 to 1.08, p=0.04). Mean duration between baseline and maximal LVAA size scan was 5.4±3.0 years. Median progression in LVAA size was 1.0 (IQR 0.6 to 1.8) mm per annum (range 0.0 to 8.1 mm). During multivariate analysis, LVAA progression rate in mm per year was independently associated with the composite outcome (HR 1.4 95% CIs 1.11 to 1.7, p=0.002).

Conclusion(s)

These data support the association between LVAA size and poor outcomes in HCM patients. We also demonstrate the progressive nature of LVAAs and indicate those more rapidly increasing in size are at highest risk of adverse events, with potential implications for management strategies.
Phenotypic and clinical evaluation of hypertrophic cardiomyopathy caused by the deep intronic variant MYBPC3:c.2308+227G>A
Authors: Gallego Delgado M , Rodriguez Diego S , Lorenzo Hernandez S M , Diez Pelaez E , Rincon Diaz L M , Heredero Jung D , Merino A M , Roldan A , Mayorga A , Garcia Salgado M J , Ruiz Olgado M J , Perdiguero Martin P D , Garcia Berrocal B , Sanchez P L , Villacorta E
Published: October 2024

Introduction

Deep intronic variants can be the cause of hypertrophic cardiomyopathy (HCM), although these regions of the genome are not always sequenced in genetic studies. It is unknown if there are differences in phenotypic expressivity and prognosis compared to other forms of HCM.

Objective

to describe the phenotypic and clinical characteristics of a cohort of probands with HCM due to the variant MYBPC3:c.2308+227G>A and compare whether there are differences with other HCM groups.

Methods

Retrospective observational study of the clinical and imaging data of patients with HCM evaluated in a reference center for Inherited Cardiovascular Disease. Probands carrying the MYBPC3:c.2308+227G>A variant, other pathogenic or likely pathogenic variants in MYBPC3 and those with a negative genotype (NGS sequencing) were included.

Results

151 probands with HCM (70% males; age of diagnosis 56±14) were included, 26 carrying MYBPC3:c.2308+227G>A (figure). No significant differences were found between the three groups in terms of baseline characteristics, phenotypic features or risk profile. In the survival curves, the subgroup with the variant had a earlier tendency to events, particularly for heart failure (figure).

Conclusions

HCM associated with MYBPC3:c.2308+227G>A variant does not have differential characteristics in its phenotypic and clinical expression, having a similar prognosis to other HCM in our cohort.
Improving the yield of genetic testing in dilated cardiomyopathy using late gadolinium enhancement
Authors: Ferreira A , Antunes M M , Cardoso I , Viegas J , Bras P , Almeida I , Ferreira V , Antunes D , Ferreira R C , Rosa S A
Published: October 2024

Background

Genetic testing has become an important tool in the work-up of dilated cardiomyopathy (DCM), aiding in family screening and providing information about prognosis and arrhythmic risk. Nonetheless, a significant proportion of patients with DCM present negative genetic test results. The "Madrid Score" was created to evaluate the likelihood of positive genetic tests and increase their yield in DCM patients.

Purpose

To determine if late gadolinium enhancement (LGE) assessment can improve the Madrid Score accuracy and increase the yield of genetic tests for DCM.

Methods

A single-centre retrospective study of patients diagnosed with DCM who underwent cardiac magnetic resonance (CMR) and genetic test between January 2017 and October 2023. The CMR imaging included the assessment of LGE. Multivariate logistic regression was performed and the model’s change in performance was evaluated when adding LGE.

Results

A total of 90 patients with the diagnosis of DCM underwent CMR and genetic test during the study period. Patient’s mean age was 51.0±14.6 years, and 57.1% were male. The genetic test was positive (G+) in 42 (46.7%), and negative (G-) in 48 (53.3%) patients. A variant of uncertain significance was present in 31 (34.4%), and these were included in the G- group. Most of the known independent predictors of a G+ given by the Madrid Score were significant in our cohort: Family history of DCM (OR: 4.82; CI: 1.73-11.60; p < 0.001), absence of hypertension (OR: 0.19; CI: 0.06-0.58; p < 0.001), absence of left bundle branch block (OR: 0.22; CI: 0.05-0.98; p = 0.047), and low electrocardiogram voltage in peripheral leads (OR: 3.13; CI: 0.87-11.26; p = 0.081). When analyzing the effect of LGE in the regression model (R2 = 0.622, p < 0.001), we found that the number of LGE segments (OR: 2.54; CI: 1.10-5.90; p = 0.031), and the presence of LGE in the anterior wall (OR: 3.01; CI: 1.42-12.04; p = 0.041), were associated with a higher rate of positive genetic tests. When comparing both regression models, the incorporation of LGE increased the prediction power of the standard Madrid Score, correctly predicting 82.0% of the tests in our sample, with a probability of a G+ result ranging from 2% when all predictors were absent to 84% when ≥6 predictors, including LGE, were present.

Conclusion

Our study suggests that LGE assessment may enhance the Madrid Score performance and consequently improve genetic testing decisions in DCM, potentially leading to better use of the limited resources in our health care system.
AI-enabled cardiac chambers volumetry in non-contrast coronary artery calcium CT scans vs. contrast-enhanced coronary CT angiography scans in the same patients
Authors: Naghavi M , Atlas K , Zhang C , Mao S S , Reeves A P , Budoff M J , Henschke C , Yankelevitz D
Published: October 2024

Introduction

We have developed an AI-enabled automated volumetry of cardiac chambers (AutoChamber) that works both on non-contrast ECG-gated cardiac CT scans used for coronary artery calcium (CAC) score, and non-contrast non-gated lung cancer screening CT scans. We have recently reported the agreement between AutoChamber measurements vs cardiac MRI measurements. Here we report AutoChamber results on non-contrast CAC scans and contrast enhanced coronary CT angiography (CTA).

Methods

We have obtained CT images from a previously published study in which 131 cases underwent non-contrast CAC and contrast enhanced CCTA at research institute. The cases consisted of 52.4% women with ages 55.0 ± 10.1 years. The cardiac chambers volume in 131 cases of contrast enhanced CCTA were measured using automated chamber volumetry by Philips Brilliance Volume v 4.5; Philips Healthcare.

Results

The correlations between Philips’ automated chamber volumetry in contrast enhanced CCTA scans versus AutoChamber automated volumetry in non-contrast CAC scans for left atrium (LA), left ventricle (LV), right atrium (RA), right ventricle (RV), and left ventricular wall (LVW) volume were 0.73, 0.65, 0.85, 0.93, 0.90, respectively (P for all <0.01).

Conclusion

AI-enabled AutoChamber volumetry based on non-contrast cardiac scans is feasible, and correlates reasonably well with contrast-enhanced cardiac CT scans. Further studies are warranted to reproduce these results and explore the add-on value of AutoChamber to CAC scans.
Subclinical myocardial phenotype in genotype-positive relatives attending clinical and genetic screening for familial dilated cardiomyopathy
Authors: Tellefsen S , Vissing C R , Dybro A M , Bundgaard H , Poulsen S H , Jensen M S K , Christensen A H , Rasmussen T B
Published: October 2024

Aim

To investigate if asymptomatic relatives carrying genetic variants associated with familial dilated cardiomyopathy (DCM) show early signs of myocardial disease assessed by echocardiography.

Methods and Results

Asymptomatic relatives without a DCM-phenotype (n=176, 46% males, mean age 39 years ± 16) of 111 DCM index patients carrying likely pathogenic or pathogenetic variants in TTN, RBM20, and FLNC genes were recruited from two tertiary referral centers for inherited cardiac diseases. All participants underwent echocardiographic examinations focusing on left ventricular (LV) ejection fraction (LVEF), LV global longitudinal strain (LVGLS), and LV end-diastolic diameter (LVEDD), with operators blinded to genetic results. The participants were grouped into genotype positive ([G+], n=82) or genotype negative relatives ([G-], n=94) carrying or not carrying the disease-causing variant.

The G+ group had significantly lower systolic LV parameters compared to G- individuals with a mean LVGLS of -18.7% ± 2.4 versus -20.1% ± 2.8, p: 0.0029; and a mean ejection fraction of 57.8% ± 3.7 versus 59.7% ± 2.4, p: <0.0001. The proportion of G+ individuals with an abnormal LVGLS (defined as less than -18%) was 46% compared to 18% in the G- group. 26 % of G+ individuals had an LVEF in the interval between 50 - 55% compared to of 5% G- individuals[MOU1] . Mean LVEDD did not differ significantly between G+ and G-groups (49.7 mm ± 4.9 versus 48.8 mm ± 4.7). However, LVEDD indexed to BSA were significantly increased in G+ individuals (26.7 mm/m2 ± 2.8 versus 25.4 mm/m2 ± 2.5, p-value 0.001).

Conclusion

Overall, the absolute mean values of LVGLS, LVEF, and LVEDD were within normal ranges in both G+ and G- groups of individuals. However, compared to non-carrier relatives, almost half of the asymptomatic G+ DCM relatives had signs of subclinical myocardial dysfunction with significantly lower values of LVGLS, LVEF, and larger left ventricular dimensions.
Protein redistribution in buccal cells as a prognostic marker for arrhythmogenic cardiomyopathy in paediatric patients
Authors: Moscatelli S , Jager J , Field E , Barnes A , Heenan I , Kaski J P , Asimaki A
Published: October 2024

Background

Mutations in genes encoding desmosomal proteins [plakoglobin (JUP), desmoplakin (DSP), plakophilin-2 (PKP2), desmoglein-2 (DSG2) and desmocollin-2 (DSC2)] cause complex genetic heart muscle disorders collectively described as arrhythmogenic cardiomyopathies (ACM). Diagnosis and risk stratification, particularly in the paediatric population, remain challenging owing to heterogeneous phenotypic manifestations and reduced genetic penetrance. Immunohistochemical analysis of heart muscle samples has shown that several junctional and signalling molecules are redistributed in patients with ACM, offering diagnostic information. However, the use of this approach in living patients was limited by need for heart samples. Recent studies in adults with ACM showed that the same set of proteins re-localised in the ACM heart also do so in the buccal epithelium.

Purpose

Given the ease of analysing serial cheek smears, we sought to establish how protein redistribution in buccal cells relates to disease onset and progression in children bearing desmosomal gene mutations.

Methods

Serial cheek smears from children with desmosomal variants were subjected to immunocytochemistry and confocal microscopy to study the distribution of JUP, DSP and PKP-1 as well as the major gap junction protein connexin43 (Cx43; GJA1) and the major subunit of the NFκB inflammatory pathway; RelA.

Results

37 patients

Conclusion

These data indicate that shifts in junctional/signalling proteins precede the onset of clinical disease. Indeed, in the majority of pre-clinical children, Cx43 and RelA seem to be redistributed first, suggesting that onset of abnormalities in electrical conductivity and inflammatory pathways occur first in the natural disease progression, in agreement with previous clinical observations. Moreover, the data suggest that additional proteins are shifted as the disease progresses. Although further verification is required, this study suggests that analysis of buccal smears may be used as a prognostic/risk stratification test in children with desmosomal variants.
Amplicon-based long-read sequencing is useful for confirming zygosity of DSG2 variants associated with Japanese ARVC
Authors: Sonoda K , Horie M , Ohno S
Published: October 2024

Background

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy mainly caused by desmosomal gene variants. Previously, we reported that DSG2 variants were the most common in 153 Japanese ARVC probands (DSG2 multiple, n=62 and single, n=4; PKP2, n=28; others, n=7). Among the multiple DSG2 variant carriers, 22 probands were compound heterozygous carriers, and 25 were homozygous, which were confirmed by genetic testing for family members (Figure A). On the other hand, 88% of their family members with single DSG2 variant carriers were not diagnosed with ARVC, which meant that recessive DSG2 variants were the major cause of ARVC in Japan. However, zygosities in remaining 15 probands with multiple DSG2 variants were unknown due to the lack of genome data from their parents.

Purpose

This study aimed to clarify the zygosities of multiple DSG2 variants using amplicon-based long-read sequencing.

Methods

Genomic DNA was extracted from whole blood using standard protocols. The range containing multiple variants was amplified by long-range PCR. Sequencing libraries were prepared using ONT Ligation Sequencing Kit. Each library was loaded onto a flow cell for sequencing on ONT GridION Mk1 running MinKNOW control software. FASTQ files were aligned to hg38 using minimap2. Variants were called using Clair3 and phased using WhatsHap. Integrative Genomics Viewer (IGV) was used for visualization of the phased variants.

Results

We successfully phased all the multiple DSG2 variants found in the 15 proband. A typical result of amplicon-based LRS was shown in Figure B. It was IGV screen shot of reads at DSG2 containing c.874C>T (p.R292C) and c.1481A>C (p.D494A). The reads colored in red belonged to one haplotype, while the ones in blue belonged to the other. Each of the two variants was on different color reads, indicating they were compound heterozygous variants. Using LRS, we confirmed all the 15 probands had compound heterozygous variants in DSG2. Overall, the 62 probands (40.5%) with DSG2 variants were recessive variant carriers (Figure A).

Conclusions

Japanese ARVC was mainly caused by autosomal recessive variants in DSG2. Clarifying the zygosity of causative variants is crucial for the diagnosis in recessive diseases including Japanese ARVC. Amplicon-based LRS was helpful for phasing the multiple DSG2 variants directly without genetic testing of the parents.Figure AFigure B
Natural course and effect of tafamidis treatment in real-life octogenarians with wild-type transthyretin cardiac amyloidosis: an international multi-centre analysis
Authors: Debonnaire P , Dujardin K , Verheyen N , Pouleur A C , Droogmans S , Claeys M , El Haddad M , Christiaen E , Zach D , Buytaert L , Jacobs A , Buysschaert I , Trenson S , Van Hoeyweghen R , Tavernier R
Published: October 2024

Background and aims

In real-life, wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is increasingly diagnosed in elderly patients above 80 years old. Nevertheless, specific data on natural course and outcome under tafamidis treatment in octogenarians are particularly scarce. We aimed to study tafamidis impact on mortality and its determinants in real-life ATTRwt-CM octogenarians.

Methods

International multi-centric cohort study of 710 consecutive ATTRwt-CM patients, stratified between octogenarians and non-octogenarians at diagnose and tafamidis naive or treatment. Mean follow-up was 2.2±1.8 years to all-cause mortality endpoint.

Results

The cohort consisted of 58.3% octogenarians (median 84 years, 74.2% male). Before tafamidis availability, natural course in octogenarians (148/257) versus non-octogenarians (109/257) was poor with 41% three-year and 70% five-year mortality versus 19% and 42%, respectively (p<0.001). Since tafamidis availability, 70.1% (253/361) octogenarians were initiated on tafamidis, less than 83.7% (231/276) non-octogenarians (p<0.001). Tafamidis discontinuation was similar (octogenarians 11.4%, non-octogenarians 7.9%, p=0.260). Overall tafamidis treated octogenarians had better survival than untreated octogenarians (p<0.001) and untreated non-octogenarians (p=0.026), with 23% three-year and 51% five-year mortality. Tafamidis treatment related to lower mortality in octogenarians (HR 0.37, 95%CI 0.20-0.67, p=0.001), after correcting for age, NAC stage and NYHA class, the other independent predictors. Propensity-score matching for those variables in 218 subjects confirmed tafamidis mortality benefit in octogenarians (p<0.001). Octogenarians had poorer survival under tafamidis, when initiated at ≥90 years old (p<0.001), NAC stage ≥3 (p=0.001) or NYHA class ≥3 (p=0.055).

Conclusions

Tafamidis treatment in real-life octogenarians independently improves survival, with better effect of early initiation at lower disease stage and age.Structured graphical abstractDistributions within age category
Endomyocardial biopsy in the diagnosis of cardiac sarcoidosis
Authors: Malkonen H , Lehtonen J , Poyhonen P , Uusitalo V , Mayranpaa M I , Kupari M
Published: October 2024

Background

Definite diagnosis of cardiac sarcoidosis (CS) requires proof of sarcoid granulomas in the heart. Endomyocardial biopsy (EMB) is considered a risky procedure with poor sensitivity (<25%) in CS (1), although comprehensive studies on its diagnostic performance are not available.

Purpose

We investigated the sensitivity, complications, and prognostic significance of EMB in a large cohort of patients with CS to help to choose diagnostic strategy when the disease is suspected.

Methods

We analysed the data of 260 consecutive patients diagnosed with CS in 1988-2022 at our institution. All met the diagnostic criteria of the Heart Rhythm Society (1). The use, findings, and complications of EMB were retrospectively noted in addition to patients’ demographics, presenting phenotype, diagnostic examinations, and future serious cardiac events. The data were retrieved from hospital records and an ongoing CS registry (2). Advanced imaging studies (cardiac magnetic resonance, positron emission tomography) were re-analysed and the follow-up information was updated until June 2023. EMB’s performance was assessed also in 30 cardiac transplant recipients having CS at the histopathologic study of the explanted heart.

Results

Of the 260 patients (mean age 49, 60% females), 216 (83%) underwent diagnostic EMB, 48 with repeat procedures. The sensitivity of EMB was 38%, rising to 49% after repeats. The predictors of positive EMB (Table 1) included the presenting phenotype and characteristics of the activity, extent, and location of myocardial involvement. Presentation with ventricular tachyarrhythmia, left ventricular (LV) ejection fraction ≤45%, elevation of cardiac troponins, and presence of middle or apical LV septal late gadolinium enhancement on magnetic resonance imaging were independent predictors (p<0.05) of positive biopsy. The sensitivity of EMB was directly related to the count of the predictors present (Figure 1). The rate of procedural complications was 9.7% overall and 0.7% for major events. One pericardial effusion needed drainage, but no deaths or long-term sequels followed the biopsies. Minor complications included 10 paroxysms of ventricular tachycardia and 6 small pericardial effusions. The 10-year rate (95% CI) of the composite of cardiac death, end-stage heart failure, or ventricular tachyarrhythmia was 55% (44-67%) with positive EMB vs 29% (17-44%) with negative EMB (p<0.001). When adjusted for the presenting phenotype and LV ejection fraction, EMB did not predict outcome events. In the 30 patients with CS in explanted hearts, the sensitivity of EMB, including the repeats, was 60%.

Conclusion

The sensitivity of EMB is better than usually presented in CS and the higher the more extensive myocardial involvement is. Risk of serious complications is <1%. In patients with suspect CS, the pre-test likelihood and value of positive EMB should be weighed against the procedural risks in shared decision-making when choosing the diagnostic pathway.
Health-related quality of life and prognosis in cardiac sarcoidosis
Authors: Raak-Tarkiainen J , Lehtonen J
Published: October 2024

Background

Cardiac sarcoidosis (CS) is characterized by inflammatory myocardial disease, often leading to conduction disturbances, ventricular tachycardias, and heart failure. While factors like initial symptoms, LVEF, and troponin levels are known prognostic indicators, the impact of CS on health-related quality of life (HRQoL) is not well-understood. Additionally, limited data exists on the predictive value of FDG-PET in CS.

Purpose

This study aimed to assess HRQoL in CS patients and investigate its prognostic relevance concerning cardiac events.

Methods

Patients diagnosed with CS completed the RAND-36 general health-related questionnaire, covering eight dimensions. Clinical data were obtained from the Finnish myocardial inflammatory diseases registry. Follow-up data on cardiac events, including life-threatening ventricular tachyarrhythmias (VT/VF), heart transplant, left ventricular assist device (LVAD) implantation, pericardial tamponade, or death, were collected over 36 months.

Results

Of the 240 CS patients surveyed, 179 (75%) were female, with a median age of 56 [IQR 48 – 64]. CS patients reported significantly lower RAND-36 scores across all dimensions compared to the general Finnish population. Over the 3-year follow-up, 38 (16%) patients experienced cardiac-related adverse events, including VT/VF (26 cases), deaths (8 cases), heart transplants (2 cases), LVAD implantation (1 case), and pericardial tamponade (1 case).

We divided CS patients into those without adverse event (N=202) and with adverse events (N=38). Interestingly, in four dimensions of PF 70.0 [50.0-90.0] vs 60.0 [33.8-80.0], p=0.019, RP 50.0 [0.0-100.0] vs 0.00 [0-56.3], p=0.002, MH 76.0 [59.0-88.0] vs 66.0 [51.0-84.0], p=0.036, and SF 75.0 [50-100] vs 62.5 [37.5-78.1], p=0.037 were significantly lower scores in the event group.

Univariate Cox regression analysis (Table 1) revealed that physical functioning (PF) and role-physical (RP) dimensions, along with certain clinical factors, such as younger age, higher NYHA classification, elevated proBNP levels, lower hemoglobin levels, and the main manifestation of the disease as ventricular tachyarrhythmia, independently predicted adverse cardiac events. In the multivariate analysis, lower role-physical scores and younger age remained independent prognostic factors for adverse cardiac events.

Conclusions

Patients with CS demonstrated lower HRQoL compared to the general Finnish population. This study enhances our understanding of prognosis in CS and underscores the predictive value of HRQoL in identifying future adverse cardiac events, highlighting its relevance in the clinical management of these patients.
Sustained paradoxical vasodilation and blood pressure lowering in response to sympathetic stimulation as markers of disease severity and poor survival in primary AL amyloidosis.
Authors: Patras R , Petropoulos I , Theodorakakou F , Delialis D , Georgiopoulos G , Angelidakis L , Gavriatopoulou M , Kokkotis P , Manios E , Terpos E , Dimopoulos M A , Kastritis E , Stamatelopoulos K
Published: October 2024

Background

AL patients present sustained paradoxical vasodilation in response to sympathetic stimulation by cold pressor test (CPT). The clinical relevance of this finding is unknown.

Purpose

We investigated the association between CPT-induced vascular and hemodynamic responses with clinical characteristics of the disease in AL amyloidosis.

Methods

We consecutively recruited 113 newly diagnosed patients with AL amyloidosis before treatment initiation. High resolution ultrasonography was used to measure the maximum vasodilation of the brachial artery in response to a cold stimulus and 3 minutes after its withdrawal. Systolic (SBP) and diastolic blood pressure (DBP) were measured at the same timepoints. Clinical and laboratory makers of autonomic dysfunction were also measured in a subgroup of the population. All-cause and cardiovascular (CV) mortality were defined as end-points of the study.

Results

Sustained vasodilation post CPT (%pCPT) was associated with markers of autonomic dysfunction, namely dipping status (p<0.05) and sudomotor dysfunction (p=0.064) and with NYHA stage, baseline NTproBNP and heart failure (p<0.05 for all). DBP%pCPT was associated with the neuropathy symptom scale (NSS Autonomous, p=0.032), while SBP%pCPT was inversely associated with Mayo stage. Vasodilation%pCPT was independently associated with CV death (adjusted HR=1.154, p=0.017) while both DBP%pCPT (HR=0.955, p=0.027) and SBP%pCPT (HR=0.947, p=0.04) were independently associated with all cause death (adjusted for the core model including age, sex, SBP, Mayo stage and nerve involvement). Overall survival was worse in AL patients who demonstrated a decrease in SBP%pCPT than in those who exhibited an increase or kept it stable (log rank test, p=0.024). The same applies to DBP%pCPT(log rank test, p=0.002). Regarding CV death, Vasodilation%pCPT above 5.86% was associated with increased risk of CV death (log rank test, p=0.002).

Conclusions

In AL amyloidosis, sustained paradoxical vasodilation and decreased SBP and DBP in response to sympathetic stimulation were associated with autonomic dysfunction, more severe cardiac involvement and poor survival.
Long-term outcomes in patients with dual pathology aortic stenosis and cardiac amyloidosis referred for valve intervention
Authors: Patel K , Autherith M , Scully P , Koschutnik M , Dona C , Halavina K , Kammerlander A , Menezes L , Pugliese F , Fontana M , Lloyd G , Mascherbauer J , Moon J , Nitsche C , Treibel T
Published: October 2024

Background

The coexistence of aortic stenosis (AS) and cardiac amyloidosis (CA) is common. If treated with transcatheter aortic valve implantation (TAVI), patients with the combined phenotype (AS-CA) have a comparable short term survival to those with lone AS, whereas data on longer term outcomes is currently lacking.

Purpose

This study aimed to evaluate the clinical outcomes of AS-CA compared to lone AS over a 5-year follow-up.

Methods

Using a prospective, multicentre, observational, case-control design, we screened consecutive patients with severe AS referred for TAVI for co-existing CA. CA screening included blinded 99mTc-DPD bone scintigraphy (Perugini Grade-0 negative, 1-3 increasingly positive) with additional SPECT/CT and light chain assessment prior to intervention. Transthyretin CA (ATTR) was diagnosed by bone scintigraphy and unremarkable light chain assessment, light-chain CA (AL) by endomyocardial biopsy. Mortality (all-cause and cardiovascular [CV]) and hospitalisation for heart failure (HHF) were captured as clinical endpoints.

Results

376 patients (83±7 years, 52% female, EuroSCORE-II 4.9±2.9) were recruited, of which 43 (11.4%) had AS-CA (42 ATTR, 1 AL). Compared to lone AS, patients with AS-CA were older with higher cardiac biomarkers (NT-proBNP, high-sensitive Troponin-T) and a higher prevalence of atrial fibrillation. Heart team decision yielded valve replacement in 320 (85%) and conservative management in 56 (15%) patients, without differences between AS-CA and lone AS.

Over a median follow-up of 5.4 (Q1: 4.9; Q3: 5.7) years, 230 (61.1%) patients died and 67 (17.8%) experienced HHF (with a total HHF number of 91). AS-CA was associated with higher all-cause mortality (crude HR 1.64, 95%CI 1.15-2.35; log-rank, p=0.006), which remained significant after multivariate adjustment for clinical confounders (EuroSCORE-II, valve replacement; adjusted HR 1.63, 95%CI 1.15-2.32; p=0.006). AS-CA was not associated with CV mortality (log-rank, p=0.18) or time to first HHF (log-rank, p=0.43), but the rate of HHF was significantly higher in AS-CA compared to lone AS (5.7 versus 3.5 per 1,000 patient years, p=0.022).

Conclusions

Among elderly patients referred for TAVI, long-term outcomes of AS-CA are characterized by higher mortality and a higher rate of heart failure hospitalisations compared to patients with lone AS. Studies evaluating the role of CA-specific treatments are warranted in this population.
Prognostic staging system correctly identifies high risk groups in cardiac transthyretin amyloidosis treated with tafamidis
Authors: Mueller M , Brand A , Mattig I , Spethmann S , Messroghli D , Hahn K , Landmesser U , Heidecker B
Published: October 2024

Background

The development of different multiparametric staging systems improved the risk assessment of cardiac transthyretin amyloidosis (ATTR-CA) patients substantially. However, to date, all staging systems were validated in treatment-naive ATTR-CA patients. The introduction of tafamidis led to significant changes in the disease trajectory of ATTR-CA, indicating that it may also have an impact on the prognostic accuracy of these staging systems.

Purpose

Thus, we sought to assess whether the prognostic value of the National Amyloidosis Centre (NAC) staging system, currently considered as the most accurate, is sustained in ATTR-CA patients treated with tafamidis.

Methods

This retrospective observational study included ATTR-CA patients treated with tafamidis. Patients were continuously followed from treatment initiation to time of death. NT-proBNP and eGFR data collected at baseline were used to stratify patients into low (stage I), intermediate (stage II) and high-risk (stage III) subgroups according to the NAC staging system. Kaplan-Meier analyses were conducted to illustrate overall survival. Differences in overall survival between subgroups were assessed by log rank tests. P-values <0.05 were considered statistically significant.

Results

A total of 166 ATTR-CA patients (95.2% wild-type) were enrolled. 81 (48.8%), 51 (30.7%) and 34 (20.5%) patients were stratified into stages I, II and III, respectively. Median follow-up was 539 [323-865] days, during which 20 deaths were recorded. Overall survival of the subgroups over time is demonstrated in figure 1. The probability of overall survival was significantly lower for patients in stage III compared to patients in stages I (log rank; p=0.002) and II (log rank; p=0.031). However, no differences in the probability of overall survival were identified between patients in stage I and II (log rank; p=0.679).

Conclusions

In this cohort of ATTR-CA patients treated with tafamidis, the NAC staging system effectively identified patients at elevated risk of mortality. However, the distinction in survival rates between low- and intermediate-risk groups was less pronounced, suggesting that tafamidis may have a stronger prognostic impact in these groups.Overall Survival across NAC Stages
ATTR cardiac amyloidosis after lumbar spinal stenosis- a prospective cohort study
Authors: Eldhagen P , Tzortzakakis A , Sorensson P , Lund L H , Westermark P , Soderstrom L , Berg S
Published: October 2024

Background

Systemic wild type transthyretin (ATTRwt) amyloidosis is underdiagnosed and generally diagnosed in manifest cardiac disease. Lumbar spinal stenosis (LSS) might be an early sign of ATTRwt and a possible screening target for early diagnosis.

Aim

To characterize patients with transthyretin amyloid deposits in ligamentum flavum six years after surgery for lumbar spinal stenosis, and assess prevalence of undiagnosed cardiac amyloidosis.

Materials and methods

In this prospective cohort study, 21 patients who had surgery for LSS in 2016-2018 and grade 3-4 ATTR deposits in ligamentum flavum, without manifest cardiac amyloidosis (CA) were followed up in 2022-2023, including biomarkers and multimodality cardiac imaging.

Results

Median age at follow-up was 79 years and 62% were male; 16% (3/19) of patients had DPD-scintigraphy and were diagnosed with ATTRwt cardiac amyloidosis. 48% (10/21) had a history of other tenosynovial conditions that associate to ATTRwt amyloidosis. on echocardiography.

Conclusion

In this prospective cohort study, 16% of patients were diagnosed with ATTRwt cardiomyopathy after a median of six years following surgery for lumbar spinal stenosis. These findings strengthen the hypothesis that LSS is a possible manifestation of ATTRwt amyloidosis and that analysis for amyloid in connective tissue and subsequent cardiac follow-up is of value.
A novel risk-stratification model that predicts long-term clinical outcomes in patients with recurrent pericarditis
Authors: Kumar A , Abdullah Yesilyaprak A Y , Ankit Agrawal A A , Beni Verma B V , Muhammad Furqan M F , Alveena B Syed A B S , Muhammad Majid M M , Danny L Rayes D L R , Tom Kai Ming Wang T K M , David Chen D C , Paul C Cremer P C , Allan L Klein A L K
Published: October 2024

Background

Recurrent Pericarditis (RP) is condition associated with significant debility and morbidity. Previous studies have identified variables such as elevated C-Reactive protein, corticosteroid usage, and presence of delayed hyper-enhancement (DHE) on cardiac magnetic resonance imaging are associated with recurrence. To date however, there is no established model for risk stratifying outcomes in these patients, therefore we attempted to develop a model that could predict long-term outcomes in patients with RP and stratify them into groups based on risk.

Methods

A total of 365 consecutive patients with RP from 2012-2019 were retrospectively examined. Our primary outcome was clinical remission (CR) defined as symptom resolution in addition to complete cessation of all anti-inflammatory therapy. We employed 5 survival models: CoxPH, RSF, SSVM, GBSA and XGBoost with Cox loss function to determine the likelihood of achieving CR within 5 years and to stratify patients into specific risk groups. We divided the dataset into training (70%) and test (30%) sets. Model training and optimization of the training set occurred via 5-fold cross validation. Model evaluation and selection was based on C-index. Finally, we employed an explainable artificial intelligence approach, SHapley Additive exPlanations to generate both individual and global explanation of the models decision.

Results

Amongst the cohort, the mean age was 46 ± 15 years, 205 (56%) were female, and the main etiology was idiopathic in 223 (61%). CR was achieved in 118 (32%) patients. The final model included steroid dependency, total number of recurrences, pericardial DHE, age, etiology, gender, ejection fraction and heart rate as its most important parameters. We observed similar CR rates across three risk score ranges and accordingly stratified patients into low (n=62), intermediate (n=154), and high-risk (n=149) groups. Scores of 3 or lower were categorized as low risk, with CR rates exceeding 90%. Scores of 4 to 7 were associated with CR rates of 50%. Scores of 8 or higher were deemed high-risk, with CR rates notably below 10%. Overall, the model predicted the outcome with C-index of 0.800 on the test set and exhibited a significant ability in stratification of patients into low-, intermediate-, and high-risk groups (log-rank test; P <0.0001).

Conclusion

We created a novel risk prediction model that can aid in predicting rates clinical remission in patients with recurrent pericarditis as well as aid in stratification into low, medium, and high risk groups. This risk prediction model may be helpful in diagnosis and management of these complicated patients.Figure 1