bluuebunny/crossref_metadata_2025 huggingface dataset:
CMR predictors of favourable outcome in myocarditis: a single-centre experience
Authors: Baritussio A , Simeti G , Ocagli H , Giordani A S , Basso C , Rizzo S , De Gaspari M , Motta R , De Conti G , Perazzolo Marra M , Tarantini G , Iliceto S , Gregori D , Marcolongo R , Caforio A L P
Published: November 2023

Background

Cardiovascular magnetic resonance (CMR) has emerged as the most accurate, non-invasive method to support diagnosis of clinically suspected myocarditis and has proved to risk-stratify patients with both ischemic and non-ischemic cardiomyopathies.

Purpose

We aimed to assess the diagnostic and prognostic role of CMR at diagnosis in patients with clinically suspected or endomyocardial biopsy (EMB) proven myocarditis.

Methods

We enrolled consecutive single-centre patients with EMB-proven or clinically suspected myocarditis (defined in keeping with the World Health Organization and the European Society of Cardiology (ESC) criteria) undergoing CMR at diagnosis. Extent of late gadolinium enhancement (LGE) was quantified with the full width at half maximum method. Pre-specified outcome was defined as NYHA class > I and echocardiographic left ventricular ejection fraction (LVEF) < 50% at follow-up.

Results

We included 207 patients (74% male, median age 36 years; 25% EMB-proven). CMR showed the highest diagnostic sensitivity in myocarditis patients with infarct-like presentation. Myocardial oedema was found in 63% of patients and LGE in 93%, with a more diffuse distribution in EMB-proven myocarditis. Right ventricular LGE was more prevalent among EMB-proven myocarditis (8% vs 0, p<0.001) and in patients with arrhythmic presentation (12% vs 1% in patients with infarct-like or heart failure presentation, p=0.001). Outcome was met in 17 patients at any follow-up time point, more commonly in patients with larger biventricular volumes (end-diastolic left HR 1.02, right HR 1.04, p<0.001), CMR-based diagnosis of dilated cardiomyopathy (HR 40.7, p<0.001) and ischemic LGE (HR 56.4, p=0.005), while higher biventricular function (LVEF HR 0.89, p<0.001) and greater LGE extent (HR 0.73, p=0.033) at diagnosis had a protective effect.

Conclusions

Higher biventricular function and greater LGE extent on CMR at diagnosis predict more favourable outcome in myocarditis; LGE at diagnosis may represent oedema rather than fibrosis.
Comprehensive analysis of risk factors for the severity of immune checkpoint inhibitor-associated myocarditis in cancer patients
Authors: Tang X , Li Y , Shi R , Yang Z
Published: November 2023

Purpose

To explore the predictive significance of patients’ clinical features and examination results, including blood laboratory tests, echocardiogram, cardiovascular magnetic resonance (CMR), and electrocardiogram (ECG), for the severity of immune checkpoint inhibitors (ICIs)-associated myocarditis.

Methods

Data from a real-world cohort of 81 cancer patients who developed ICI-associated myocarditis after immunotherapy were retrospectively analyzed. Myocarditis of Common Terminology Criteria for Adverse Events (CTCAE) grades 3-5 and the development of the major adverse cardiovascular event (MACE) were set as endpoints. Logistic regression was used to evaluate each parameter’s value in predicting myocarditis of grades 3-5 and MACE.

Results

Eventually, CTCAE grades 3-5 and MACE developed in 43/81 (53.1%) and 28/81 (34.6) cases, respectively. The occurrence of CTCAE grades 3-5 (HR, 95%CI: 4.48, 2.02-9.91, p<0.001) and MACE (HR, 95%CI: 16.21, 6.93-37.94, p<0.001) were strongly related to patients’ overall survival from ICI-associated myocarditis to death. The likelihood of CTCAE grades 3-5 and MACE increased with the accumulation of organs affected by the ICI-associated adverse events and initial clinical symptoms. Concurrent systematic therapies during ICI treatment did not raise the risk of myocarditis severity, while prior chemotherapy did. Apart from the classical cardiac markers, such as myoglobin, brain natriuretic peptide, and troponin T, a higher neutrophil ratio was also related to poorer cardiac outcomes, whereas a higher lymphocyte and monocyte ratios were predictors of favorable cardiac outcomes. Besides, the CD4+ T cell ratio and CD4/CD8 ratio were negatively related to CTCAE grades 3-5. Several cardiovascular magnetic resonance parameters were associated with myocarditis severity. In contrast, the predictive value of echocardiography and electrocardiogram was weak.

Conclusions

This study comprehensively evaluated the prognostic value of different patients’ clinical factors and examination results and discovered several predictors of severe ICI-associated myocarditis, which will facilitate early detection of severe ICI-associated myocarditis in patients receiving immunotherapy.
Sequential activation of DNA viruses by the RNA virus SARS-CoV-2 in patients with long COVID syndrome
Authors: Gyongyosi M , Hasimbegovic E , Lukovic D , Zlabinger K , Spannbauer A , Samaha E , Bergler-Klein J , Hengstenberg C , Mucher P , Haslacher H , Breuer M , Strassl R , Riesenhuber M , Nitsche C , Zelniker T A
Published: November 2023

Background

Reactivation of Epstein-Barr virus (EBV) has been suggested to play role in long lasting multiorgan symptoms several months after the initial COVID-19 illness.

Purpose

The aim of our prospective study was to 1) to evaluate the reactivation of DNA viruses of EBV, Cytomegalovirus, Herpes simplex, Varicella zoster and Parvovirus-B19 by SARS-CoV-2 in patients with the diagnosis of long-COVID syndrome, 2) to investigate the effect of supposed virus reactivation on clinical conditions and long COVID syndromes.

Methods

Patients with long COVID syndrome were prospectively included into the Vienna PostCoV Registry between March 15th 2021 and September 30th 2021. - The time between COVID-19 infection and first clinical visit was 219±98 days (7±3 months). Clinical symptoms were documented and patients were divided into symptoms-oriented subgroups with dominantly respiratory, cardiovascular or neuropsychologic complaints. Qualitative and quantitative viral IgG and IgM titer of the selected DNA viruses of n=105 patients were compared with age and sex-matched healthy (non-infected, non-vaccinated, n=105) controls, who had neither spike- nor nucleocapsid antibodies, nor clinical history of COVID-19 disease.

Results

Long Covid patients had significantly higher cumulative number of IgM positivity of the DNA viruses (18.1% vs 6.7%, p=0.02), and significantly elevated quantitative EBV IgG (420±296 vs 339±282 mg/dL, p=0.033) and Parvo-B19 IgM (0.28±0.29 vs 0.03±0.12 mg/dL, p<0.001) titer as compared to healthy controls. Significantly more patients with long COVID symptoms had an EBV IgG titer above the detection limit as compared with healthy controls (40% vs 28%, p=0.018), suggesting EBV virus reactivation and chronic EBV infection. EBV IgG titer was significantly higher in patients with dominant respiratory symptoms, while elevated Parvo-B19 IgM titer was observed in patients with dominant cardiovascular complaints. In patients with long-COVID syndrome the quantitative EBV IgG titer increased with the time between infection and blood sampling (logarithmic correlation, p=0.011), suggesting the subclinical continuous EBV activation by the SARS-CoV2 RNA virus, while the quantitative Parvo-B19 IgM titer decreased linearly during the observation period.

Conclusions

In this study of patients with long-COVID syndrome, SARS-CoV-2 infection apparently activated certain types of DNA viruses (EBV, and Parvo-B19), as demonstrated by the significantly higher incidence of cumulative IgM positivity, and elevated EBV IgG and parvovirus-B19 IgM titers, in long-COVID patients compared to healthy controls.
Association between anti-cardiac autoantibodies in acute myocarditis and downstream clinical outcomes
Authors: Iacob A , Lota A , Bakula A , Sattler S , Prasad S
Published: November 2023

Introduction

Myocarditis is an inflammatory heart muscle disease that can result in cardiac dysfunction and arrhythmias. Its aetiology includes infectious, toxic or autoimmune causes. Myocarditis is responsible for sudden cardiac death in young adults (1) and can result in heart failure due to dilated cardiomyopathy in 20% of patients (2). The pathogenesis of myocarditis may involve immune system dysregulation leading to a cascade of inflammation and myocardial damage (3). For those patients that rapidly progress to end-stage dilated cardiomyopathy, an important dilemma is whether there is any prospect of heart function recovery. Therefore, there is an unmet need for a better understanding of key causal pathways and for developing a biological signature of disease progression.

Hypothesis

The progression of acute myocarditis depends on a persistent adaptive immune response against the heart, leading to ongoing inflammation, myocardial fibrosis and ultimately tissue destruction and remodelling.

Aims

We sought to explore anti-cardiac IgG serum levels, their temporal profile throughout follow up and their association with clinical and imaging data, in patients presenting with acute myocarditis.

Methods

We prospectively recruited 80 patients with a clinical diagnosis of acute myocarditis. We measured their total anti-cardiac IgG levels at admisssion, 3- and 12-months follow-up using an enzyme-linked immunosorbent assay (ELISA). We explored the association between the anti-cardiac IgG levels, cardiac MRI parameters (CMR) and clinical data.

Results

We detect an adaptive immune response against the heart in a subgroup of patients with acute myocarditis. 20% of patients develop high systemic titres of anti-cardiac IgG (OD threshold >0.65), within the first 7 days of presentation (Figure 1a). These patients continue to have persistent and significantly higher anti-cardiac IgG levels at 12 months (Figure 1b). Importantly, patients that mount a strong initial adaptive immune response against the heart, are more likely to show evidence of persistent oedema on CMR at 12 months(Figure 1c). Clinical event rates in our cohort have remained low at five-year follow-up. A small signal exists to indicate potentially higher rates of persistent symptoms (70% vs 47%), hospitalisations for heart failure (12% vs 8%) and new heart failure diagnosis (18% vs 11%), in patients that mount a strong adaptive immune response compared to those that do not.

Conclusion

A subset of patients with acute myocarditis develops a strong and persistent adaptive immune response against the heart. This may be associated with more myocardial oedema on cardiac MRI, persistent symptoms and higher rates of heart failure diagnoses and hospitalisations.

Further work

Plasma proteomics (targeted and un-targeted discovery) with validation in myocardial tissue. Analysis of CMR data with a focus on fibrosis assessment. ELISA for IgG subtypes and total IgG against myosin and troponin I.
Role and prognostic relevance of cardiac magnetic resonance imaging in the assessment of left ventricular non-compaction cardiomyopathy: review and meta-analysis
Authors: Gegenava T , Gegenava M
Published: November 2023

Background

Left ventricular non-compaction (LVNC) is a heterogeneous myocardial disorder characterized by prominent myocardial trabeculation with deep inter-trabecular recesses, thin epicardial layer of compacted myocardium and extensive non-compacted inner muscular layer. Although several diagnostic criteria have been proposed, prediction of major adverse cardiovascular and cerebrovascular events (MACCE) still remains challenging in patients with LVNC.

Objectives

Objectives of our study were to perform systemic review and meta-analysis of published literature evaluating role and prognostic significance of the late gadolinium enhancement (LGE) in cardiac magnetic resonance imaging (CMR) study, its association with MACCE and characteristics of CMR derived feature-tracking (FT) strain analysis in patients with LVNC.

Methods

The objectives, literature search strategies, inclusion and exclusion criteria, outcome measurements, and methods of statistical analysis were analyzed according to an established protocol of the cochrane collaboration steps and meta-analysis of observational studies in epidemiology recommendations (MOOSE). Case control studies with evaluated prevalence of LGE in LVNC cardiomyopathy patients with and without MACCE and studies comparing FT strain: left ventricular global longitudinal (LV GLS), global circumferential (GCS) and global radial (GRS) strain between patients with and without LVNC has been included in the analysis.

Results

A total of 936 papers were collected according to our searching criteria, of those 9 studies including 416 LVNC cardiomyopathy patients with MACCE and 673 LVNC patients without MACCE and with evaluated LGE (including three studies with LVNC and heart failure), also 6 studies including 267 LVNC patients and 283 controls with evaluated FT LV GLS, GCS and GRS (measured in four studies) were selected. LGE was more frequently observed in LVNC patients with MACCE as compared to those without MACCE [RR (95 %CI) 2.52 (1.63 to 3.88); p<0.00001] (Fig.1). FT LV GLS was significantly more affected in LVNC patients compared to controls (St. mean difference (95 %CI): 1.40 (0.69 to 2.11); p<0.00001], as well as GCS and GRS (Fig. 2).

Conclusions

In patients with LVNC evaluated with CMR, LGE shows association with adverse cardiovascular and cerebrovascular events. CMR deformation indices: FT LV GLS, GCS, and GRS are significantly affected in patients with LVNC as compared to controls. This new CMR technique may be a complementary tool for timely detection and differentiation of LVNC cardiomyopathy and to avoid life threatening adverse events.Figure 1Figure 2
Prognostic value of the left ventricular mass index by magnetic resonance imaging in patients with hypertrophic obstructive cardiomyopathy undergoing septal myectomy
Authors: Yang Q , Hao C , Zhu C , Zhao S , Yang S , Wang S
Published: November 2023

Research background

Traditional risk factors for hypertrophic cardiomyopathy (HCM) have limited ability to predict poor survival outcomes in the medium to long term after surgical septal myectomy (septal myectomy) in patients with hypertrophic obstructive cardiomyopathy (HOCM) undergoing septal myectomy. Additionally, there is a lack of studies reporting the relationship between left ventricular mass index (LVMI), an index of ventricular remodeling in hypertrophic obstructive cardiomyopathy, and medium to long-term prognostic outcomes after septal myectomy.

Research methods: From June 2011 to July 2016, 490 patients with HOCM who completed preoperative cardiac magnetic resonance (CMR) were retrospectively enrolled for mid- to long-term follow-up. The study's primary endpoint included all-cause death. Secondary endpoints included cardiac death and adverse cardiovascular events. Furthermore, CMR measures were applied to study the risk factors for mid- and long-term adverse endpoint events after septal myectomy treatment.

Study results: 486 patients with HOCM completed follow-up and were included in the final analysis. Twenty-one patients (4.3%) died during follow-up (median 73.6, maximum 105.6 months), and 66 patients (16.3%) had an adverse cardiovascular event during follow-up. In the Cox proportional risk regression model, the most significant predictor of all-cause mortality after septal myectomy was CMR-LVMI (risk ratio 1.009, 95% confidence interval 1.003-1.015, P=0.018). In receiver operating characteristic (ROC) analysis, LVMI > Cutoffpredicted all-cause death analyzed separately by male and female subgruop(P<0.05). In Cox proportional risk regression models (incorporating age, maximum septal thickness, left atrial diameter, left ventricular end-diastolic dimension, left ventricular ejection fraction, LV outflow tract peak pressure, pulmonary hypertension, LGE positive and LVMI), the most significant predictor after surgical septal resection was LVMI measured by CMR (hazard ratio 1.025, 95% confidence interval 1.009-1.040, P=0.002). From ROC analysis, LVMI >cutoff accurately predicted the occurrence of all-cause mortality analysed separately by male and female (P<0.05). Additionally, K-M survival curve plots suggested that patients with HOCM above the LVMI threshold group had lower all-cause mortality-free survival (Log-rank: P=0.0.025), hear failure related mortality-free survival (Log-rank: P=0.0.014) in the medium to long term after septal myectomy.

Conclusions

An elevated preoperative left ventricular myocardial mass index suggests adverse ventricular remodeling and is an independent predictor of poor survival outcomes in patients with HOCM in the medium to long term after septal myectomy.ROC analysis of LVMI for all cause deathK-M survival curve devided by LVMI level
The efficacy and safety of direct oral anticoagulants compared with vitamin K antagonist in patients with hypertrophic cardiomyopathy and atrial fibrillation: a systematic review and meta-analysis
Authors: Lyu S , Zhu J , Wang J , Wu S , Yang Y
Published: November 2023

Background

The benefit-risk profile of direct oral anticoagulants (DOAC) therapy in patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF) have not been well established yet.

Purpose

This study aimed to evaluate the efficacy and safety of DOAC compared with vitamin K antagonists (VKA) in patients with HCM and AF.

Methods

PubMed, EMBASE, the Cochrane Library and clinicaltrials.gov were searched to identify studies comparing DOAC with VKA in patients with HCM and AF.

Results

Five studies involving 8103 patients were included in this meta-analysis. Compared to the VKA group, the DOAC group displayed a significant lower risk of all-cause death [RR (95%CI): 0.44 (0.35-0.55)]. Meanwhile, DOAC therapy group was similar to VKA therapy in reducing ischemic stroke [RR (95%CI): 0.65 (0.33-1.28)] and thromboembolic events [RR (95%CI): 0.95 (0.74-1.22)]. The incidence of major bleeding [RR (95%CI): 0.69 (0.44-1.07)] were comparable between the two groups.

Conclusion

In patients with HCM and AF, DOAC therapy were superior or non-inferior to VKA therapy in reducing the risk of all-cause death and thromboembolic events, without increasing bleeding risk. Further RCTs are needed to provide more evidence for DOAC therapy in this population.Efficacy and safety endpoints in DOAC th
Outcomes in patients with hypertrophic cardiomyopathy developing left ventricular systolic dysfunction after septal reduction therapy
Authors: Bataiosu D , Lee D Z J , Montazeri M , Billia F , Ralph-Edwards T , Rakowski H , Chan R
Published: November 2023

Background

In hypertrophic cardiomyopathy (HCM), systolic dysfunction (SD), defined by a left ventricular ejection fraction (LVEF) <50% is associated with a poor prognosis. After septal reduction therapy (SRT), anticipated alterations in left ventricular geometry and septal desynchrony may lead to reduction in LVEF. The prognostic significance of a reduction in LVEF <50% following SRT has not been established.

Purpose

To investigate the relationship between new development of SD post SRT and outcomes in HCM patients.

Methods

Of the 4110 HCM patients at our referral centre, 179 patients (4.4%) developed SD during follow up. The composite cardiac outcome was defined as the occurrence of new resuscitated cardiac arrest, ventricular tachycardia or ventricular fibrillation, and cardiac death after the onset of SD.

Results

Of the 179 patients who developed systolic dysfunction (SD), 67 patients developed it after undergoing septal reduction therapy (SRT) (4 patients underwent alcohol septal ablation, and 63 patients underwent septal myectomy). Both groups had similar characteristics with respect to age at the time of SD identification (59.9 ± 13.5 years vs. 59.6 ± 14.2 years, P=0.88), gender (76% men vs. 66% men, P=0.18), and genotype (24% had pathogenic or likely pathogenic variants vs. 28%, P=0.07). Despite similar LVEF at the time of presentation with SD between the two groups (44.1 ± 4.2% vs. 44.4% ± 4.9%, P=0.75), patients who underwent SRT had a lower maximal wall thickness (17.4 ± 4.9mm vs. 19.2 ± 5.2mm, P=0.02), larger end-diastolic diameter (5.3 ± 0.8mm vs. 4.8 ± 0.8mm, P<0.001) and end-systolic diameters (3.8 ± 0.7mm vs. 3.2 ± 0.8mm, P<0.001) than patients without SRT. Furthermore, patients who underwent SRT had a longer QRS complex duration (162.3 ± 20.6ms vs. 125.1 ± 31ms, p<0.001) and lower brain natriuretic peptide (BNP) (359.3 ± 632.9pg/ml vs. 690.8 ± 841.8pg/ml, p=0.04) during follow up than patients without prior SRT. During a mean follow up of 4.7 ± 4.1 years, the incidence of the composite cardiac outcome was significantly lower in patients who underwent SRT than in patients without prior SRT (7.5% vs. 20.5%, P=0.02). Notably, there were no observed sudden cardiac deaths observed in those who developed SD post SRT.

Conclusion

The prognosis for patients with HCM who underwent SRT and subsequently developed SD was significantly more favourable than for those who did not have a history of SRT. Thus, changes in left ventricular geometry and LVEF after SRT may not necessarily translate into a worsened prognosis.
Prediction of acute heart failure events in patients with hypertrophic cardiomyopathy using RNA-Sequencing of plasma small non-coding RNAs
Authors: Akita K , Hasegawa K , Maurer M S , Tower-Rader A , Fifer M A , Topkara V K , Reilly M P , Shimada Y J
Published: November 2023

Background

Hypertrophic cardiomyopathy (HCM) often causes acute heart failure (HF) events, which lead to worse quality of life and prognosis of patients with HCM. The recent emergence of cardiac myosin inhibitors to treat HCM highlights the clinical significance of identifying patients with HCM at high risk of developing acute HF events. However, no tools are available to predict acute HF events in HCM. Furthermore, the underlying molecular mechanisms responsible for the development of HF in HCM remain uncertain. Plasma RNA-sequencing (RNA-Seq) determines concentrations of thousands of small non-coding RNAs (sncRNAs) and has the potential to predict acute HF events in HCM.

Purpose

To predict acute HF events in patients with HCM using RNA-Seq of plasma sncRNAs and to determine signaling pathways dysregulated in those who subsequently experience acute HF events.

Methods

In this prospective, multi-center cohort study of patients with HCM, we conducted RNA-Seq of 3,740 plasma sncRNAs on 390 patients with HCM. The primary outcome was acute HF event defined as unplanned hospitalization due to HF. We developed a sncRNA-Seq-based model with linear discriminant analysis to predict acute HF events using data from one institution (training set, n=271). We also developed a reference model using clinical parameters with significant differences between patients with and without acute HF events in the training set. Then we tested the predictive ability in samples from the other institutions (test set, n=119), comparing the area under the receiver-operating-characteristic curve (AUC) between a combined model using the reference model plus the sncRNA-Seq-based model and the reference model using the Delong’s test. We also performed pathway analysis of microRNAs significantly (i.e., nominal P<0.05) associated with acute HF events.

Results

During a median follow-up time of 2.5 (interquartile 1.7–4.9) years, a total of 37 patients in the training set (14%) and 15 in the test set (13%) experienced an acute HF event. The model combining the reference model with the sncRNA-Seq-based machine learning model developed in the training set significantly outperformed the reference model (AUC 0.86 [95% confidence interval (CI) 0.74–0.97] vs. 0.68 [0.52–0.85], P=0.01, Figure) in the test set. The pathway analysis exhibited that both known pathways related to fibrosis, inflammation, and cell proliferation (e.g., the TGF-β signaling pathway) and novel pathways (e.g., the mTOR signaling pathway) were dysregulated with false discovery rate <0.01 in patients with HCM who subsequently experienced acute HF events (Table).

Conclusions

This study serves as the first to demonstrate the ability of plasma sncRNA-Seq to predict acute HF events in patients with HCM. Patients who subsequently experienced acute HF events exhibited dysregulation of both known and novel pathways.FigureTable
Clinical significance and genetic basis of hypertrophic cardiomyopathy with apical phenotype: comparison of pure-apical form and distal-dominant form
Authors: Sugiura K , Kubo T , Yamada T , Inoue S , Nomura S , Ochi Y , Baba Y , Hirota T , Morita H , Yamasaki N , Doi Y , Komuro I , Kitaoka H
Published: November 2023

Background

Apical hypertrophic cardiomyopathy (apical HCM) is a variant of HCM first reported in Japan. The definition of apical HCM in the Japanese Circulation Society guideline is left ventricular hypertrophy limited to the level of the apex below the papillary muscle level. On the other hand, apical HCM in Western countries often includes hypertrophy that extends to the ventricular septum beyond the true LV apex. Although these variations may have different clinical characteristics and prognoses, they are often considered the same. Therefore, we previously proposed two phenotypes of apical HCM. Pure-apical form follows the definition of the JCS guideline. Distal-dominant form is defined as demonstrating apical hypertrophy extended to the ventricular septum without basal septal hypertrophy. However, the clinical significance and genetic basis of these phenotypes have not been reported. This study aimed to clarify clinical differences and yield of genetic testing in apical phenotype of HCM.

Methods

Regarding clinical presentation and prognosis, we retrospectively investigated 111 consecutive HCM patients with apical phenotype. HCM-related adverse events were defined as HCM-related death and nonfatal HCM-related events: heart failure admission, embolic stroke admission, and sustained ventricular tachycardia with hemodynamic instability or appropriate implantable cardioverter-defibrillator discharge. Furthermore, we performed a genetic analysis including 145 genes associated with cardiomyopathy in 69 unrelated patients within the cohort.

Results

In the cohort, 60 patients were pure-apical, and 51 were distal-dominant. The age at diagnosis was about 60 years, and the majority were male in both groups. The comorbidity rate of hypertension did not indicate a statistically significant difference. During the follow-up period of 10.3 ± 6.9 years, the occurrence of HCM-related adverse events was significantly higher in the distal-dominant group than in the pure-apical group (log-rank p=0.007). Detection rate of pathogenic or likely pathogenic variants in sarcomeric protein-encoding genes was significantly higher in the distal-dominant group than in the pure-apical group (21% vs. 3%; p=0.044).

Conclusions

Two phenotypes of apical HCM should be recognized and distinguished clinically because they have different prognoses and genetic features.
Sudden cardiac death in childhood RASopathy-associated hypertrophic cardiomyopathy: validation of HCM Risk-Kids model and predictors of events
Authors: Boleti O , Norrish G , Field E , Tollit J , Zenker M , Wolf C , Kaski J P
Published: November 2023

RASopathies represent an important proportion of hypertrophic cardiomyopathy (HCM) cases presenting in childhood. Despite this, there are no published risk factors for sudden cardiac death (SCD) in this cohort of patients. Our primary aim was to validate the HCM Risk-Kids model in children with RASopathy-associated HCM and to investigate additional predictors of SCD in a cohort of 169 patients from 15 international paediatric cardiology centres (UK, Ireland and Germany). Eleven (6.5%) patients experienced a SCD equivalent event [5 (45.5%) an aborted cardiac arrest; 3 (27.3%) SCD; 2 (18.2%) sustained ventricular tachycardia (VT); and 1 (9.1%) appropriate implantable cardioverter-defibrillator (ICD) shock] at a median age of 12.5 months (IQR 7.7-28.64). The calculated SCD equivalent event incidence was 0.78 (95% CI 0.43 – 1.41) per 100 patient years. Six patients (54.54%) with a SCD equivalent event were in the low-risk category according to the HCM Risk-Kids model. Harrell’s C index was 0.5959 (95% CI 0.26-1.22) with a sensitivity of 9.09%, specificity of 63.92%, positive predictive value of 1.72%, and negative predictive value of 90.99%; there was poor distinction between the different risk groups. Unexplained syncope (HR 102.63 (95% CI 14.94 – 704.99), p<0.001) and non-sustained VT [NSVT (HR 5.67 (95% CI 1.30 – 24.70), p=0.021)] were independent predictors of SCD. The HCM Risk-Kids model should not be used for patients with RASopathy-associated HCM but NSVT and unexplained syncope appear to be predictors of SCD in this population. Larger multicentre collaborative studies are required to further investigate predictors of SCD in this group of patients.
Arrhythmic risk stratification in patients with left ventricular ring-like scar
Authors: Parisi V , Graziosi M , Lopes R L , Pasquale F , De Luca A , Targetti M , Tini G , Torlasco C , Ditaranto R , Chiti C , Crotti L , Olivotto I , Merlo M , Elliott P , Biagini E
Published: November 2023

Background

Myocardial fibrosis assessment with late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR) has recently emerged as an independent predictor of major adverse events in patients with non-ischemic cardiomyopathy. Several studies have examined different locations and extension degrees of LGE, and the so called "ring-like pattern" has been related with an increased incidence of ventricular arrhythmias, in patients with dilated cardiomyopathy (DCM), but also in patients with preserved systolic function.

Purpose

To describe clinical, electrocardiographic, echocardiographic, CMR and genetic features of the left ventricular (LV) ring-like scar phenotype and to evaluate which characteristics may be associated with the risk of sudden cardiac death (SCD).

Methods

Patients diagnosed with LV ring-like scar were identified at 6 referral Centres. Diagnosis was based on: 1) ring-like LGE LV pattern, defined as at least 3 contiguous segments with subepicardial/midwall LGE in the same slice with or without fatty infiltration; or 2) pathology examination of explanted hearts/autoptic cases suffering from sudden cardiac death (SCD). Moreover, patients must have an additional inclusion criterion: a positive genetic test, or ≥1 patient in the same family with an ascertained cardiomyopathy. Major adverse arrhythmic cardiac events (MAACE), defined as a composite of SCD, aborted SCD, and sustained ventricular tachycardia (SVT), were the primary study endpoint.

Results

The final cohort comprised 129 patients (male 59.7%, median age at diagnosis 44 years). During a median follow-up of 3.4 years (IQR 1.2 – 64.), MAACE occurred in 31 patients (24%). Nearly 70% of the patients had a likely pathogenic/pathogenic mutation, mostly in desmoplakin (DSP) and filamin-C (FLNC) genes (65% and 19%, respectively). Sex, QRS width, and LGE in LV anterior wall and/or apex, were the only independent predictors of the outcome events (HR: 0.329, 95% CI: 0.119-0.916, P = 0.033; HR: 1.036, 95% CI 1.019-1.053, P < 0.001; HR 4.270, 95% CI 1.337-13.630, P = 0.014, respectively). A significant interaction between sex and LGE in anterior wall/apex was observed, being this regions associated with MAACE only in male patients (p for interaction = 0.033). Although related to the arrhythmic endpoint at the Kaplan-Meier survival curves, neither DCM echocardiographic phenotype, nor LV ejection fraction ≤35% remained statistically associated to MAACE at the multivariate analysis. Age, genetic mutations, right ventricular involvement, proband status, LV-LGE extension (number of segments) were not statistically related to the study endpoint.

Conclusions

In this selected cohort of patients with LV ring-like scar and either a genetic test or family history, malignant arrhythmic events were predicted by male sex, QRS width and LGE in anterior wall and/or apex.Graphical Abstract
Genotype influences end-stage heart failure occurrence in dilated cardiomyopathy
Authors: Cannie D , Bakalakos A , Protonotarios A , Syrris P , Lorenzini M , Guttmann O , O'mahony C , Savvatis K , Lopes L , Sekhri N , Mohiddin S , Elliott P
Published: November 2023

Introduction

A monogenic cause of a dilated cardiomyopathy (DCM) phenotype is found in upto 37% of patients [1].

Purpose

Evaluate the influence of genotype on end-stage heart failure (ESHF) outcomes in DCM.

Methods

Consecutive patients carrying variants from the 3 most prevalent DCM genotypes in a database from a cardiomyopathy unit (TTN, DSP and LMNA) and with features of DCM at baseline were retrospectively recruited. Consecutive DCM patients returning a negative result from a next generation DCM panel were recruited for comparison. ESHF was defined as left ventricular assist device implantation, heart transplantation or heart-failure related death. The incidence of ESHF was compared between genotypes during follow-up.

Results

493 patients from 445 families (311 (63.1%) males, presenting at a median [IQR] age of 50.8 years [37.3 – 59.8]) with a median follow-up of 46.5 [28.1 – 88.2] months were recruited (Table 1). 26/493 (5.3%) of patients had ESHF by last evaluation. The highest incidence of ESHF was seen in LMNA variant-carriers and the lowest in genotype-negative patients (Figure 1). In a multivariable Cox model including age at presentation, sex and proband status, LMNA variant-carriage was associated with an increased risk of ESHF (HR 9.7 [4.6 – 20.6], p < 0.001) and genotype-negative status was associated with a reduced risk of ESHF (HR 0.08 [0.02 – 0.41], p = 0.002)

Conclusions

Genotype impacts the incidence of ESHF in patients with DCM. Close monitoring with early initiation of heart failure therapies is essential to mitigate this risk, particularly in LMNA variant-carriers.Table 1Figure 1
Myocardial Stiffness evaluation by shear wave elastography in transthyretin amyloidosis with and without cardiac involvement
Authors: Comte de Alencar Neto A C , Caio Reboucas Fonseca Cafezeiro C R F C , Bruno Vaz Kerges Bueno B V K B , Joao Henrique Rissato J H R , Viviane Tiemi Hotta V T H , Aristoteles Comte De Alencar Filho A C A F , Fernando Linhares Pereira F L P , Katia Couceiro K C , Carlos Eduardo Rochitte C E R , Joao Marcos Bemfica Barbosa J M B B , Jose Soares Junior J S J , Felix Jose Alvarez Ramires F J A R , Roberto Kalil Filho R K F , Wilson Mathias Junior W M J , Fabio Fernandes F F
Published: November 2023

Introduction

Cardiac involvement (CI) in hereditary transthyretin amyloidosis (ATTRh) occurs by deposition of amyloid fibrils in the heart, resulting in stiffening and diastolic dysfunction. Shear wave elastography, non-invasively and without the emission of ionizing radiation, quantitatively assesses tissue stiffness, a passive component of diastole, complementing the complex echocardiographic assessment.

Objective

To evaluate myocardial stiffness, through diastolic myocardial elasticity (DME), in ATTRh patients with and without CI and a healthy control group (CG).

Methodology

Prospective, cross-sectional study, 60 patients divided into 3 groups: ATTRh with CI (n:20), ATTRh without CI (n:20) and GC (n:20). DME was evaluated in the septal wall of the left ventricle (LV) (basal, middle, and apical segments) and in the free wall of the right ventricle (RV). They were also submitted to 2D-ECO, EKG, troponin, BNP, 6-minutes-walking test and pyrophosphate-labeled scintigraphy (Tc-99m-PYP). Data were analyzed using a one-way ANOVA, verifying myocardial stiffness, measured by DME, among the 3 groups. Then, pairwise comparisons were adjusted using Tukey's technique.

Results

DME was a significant factor for distinguishing between groups when analyzed in the parasternal long axis (PLAX) basal septum (p=0.013), parasternal short axis (PSAX) basal septum (p=0.03) and in the PLAX RV free wall (p=0.004). Was observed in the apical septum segment similar stiffness between groups, suggesting a pattern of apical preservation. In the post hoc evaluation, DME in the basal septum region was significantly higher among the ATTRh with CI group than in the control group, but without significant difference between ATTRh with CI and ATTRh without CI, suggesting that the latter group has intermediate values between the sick patient and the healthy patient. Also, right ventricle DME in ATTRh with CI was greater than in the other two groups (Table 1 and Figure 1). In a regression model, the results indicate that 17.2% of the DME variance can be attributed to 3-hour scan uptake on the Tc-99m-PYP (R2=0.172, F (1-36) =7.2, p< 0.011), estimated by the equation: 3-hour scan uptake = 0.91 +0.078 x DME.

Conclusion

Myocardial stiffness is increased in ATTRh with CI, showing a decreasing pattern of stiffness in the apex direction, suggesting a pattern of apical preservation. Cardiac elastography has the potential to be an important tool in the assessment of cardiac involvement in systemic amyloidosis.
A biopsy-based pilot clinical study: monitoring the effectiveness of tafamidis treatment of patients with transthyretin amyloid cardiomyopathy
Authors: Elsanhoury A , Diekmann S , Kuehl U , Klein O , Willner M , Kelle S , Klingel K , Tschoepe C
Published: November 2023

Background

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a rare and progressive disease associated with high mortality. It is caused by the accumulation of TTR amyloid protein in various tissues, including the myocardium. Tafamidis is currently the only approved therapy for ATTR-CM. The results of the phase III ATTR-ACT trial showed lower rates of mortality and hospitalization, besides lower rate of decline for both quality of life (QoL), and 6-minute walk test (6mwt) distance [1]. Whether the reported clinical outcomes represent a change in myocardial ATTR-accumulation and remodeling remains unclear. Here we monitor the clinical outcome and the corresponding myocardial histological changes of tafamidis-treated patients using endomyocardial biopsy (EMB).

Methods

Eleven patients with EMB-proven ATTR-CM, 10 wild type, 1 hereditary, 9 males, 2 females age= 77±9 years, were prescribed with 61 mg tafamidis once daily indefinitely. The course of the disease was evaluated via EMB, 99mTc-DPD scintigraphy, cardiac magnetic resonance imaging (cMRI), echocardiography, 6mwt, Minnesota QoL questionnaire and serum N-terminal pro brain natriuretic peptide (NT-proBNP) analysis, at baseline and after 321±72 days of treatment (ethics application number EA2/140/16). EMBs were examined via immunohistochemistry and Imaging mass spectrometry. All patients received standard heart failure medications. Paired clinical measurements were compared via paired t test for parametric data or Wilcoxon rank test for non-parametric data.

Results

Following the course of treatment, EMB ATTR-positive area measured via immunohistochemistry increased by 7.7±9.5% (p<0.05). Myocardial CD3+ and CD68+ cell counts remained within normal limits. The EMB peak intensities of ATTR, collagen and macrophage migration inhibitory factor, measured via imaging mass spectrometry were increased by 23% (AUC= 0.677, p<0.001), 25% (AUC= 0.620, p<0.001) and 18% (AUC= 0.609, p<0.001), respectively. Echocardiography measured left ventricular (LV) ejection fraction and LV end-diastolic diameter, as well as 6mwt distance, QoL and serum NT-proBNP showed no significant changes. cMRI did not show any significant changes in fibrosis/amyloidosis markers (N=9). 99mTc-DPD scintigraphy-derived Perugini score (N=10) improved by one-point in two patients and remained stable in the rest. The New York Heart Association (NYHA) functional class improved in one patient and remained stable in 10/11 patients.

Conclusion

Our findings demonstrate, for the first time, the persistence of myocardial ATTR-accumulation and remodeling despite a clinically stable disease course. Whether this finding is relevant in terms of disease-progression or indicate a need for more intensive treatment warrants further investigation.
Prognostic value of different echocardiographic and cardiac magnetic resonance parameters in patients with AL amyloidosis
Authors: Hernandez Martos A , Eiros Bachiller R , Gonzalez Calle V , Alejo Alonso E , Puig Moron N , Gallego Delgado M , Perez Sanchez P , Hernandez Hidalgo M , Mateos Manteca M V , Sanchez Fernandez P L , Villacorta Arguelles E
Published: November 2023

Introduction

Light chain amyloidosis (AL) is a systemic disease, highlighting its infiltration at the myocardium. Recent advances in imaging have increased the suspicion of cardiac involvement. Current risk stratification models are based exclusively on serum biomarkers.

We studied the prognostic value of echocardiographic and cardiac magnetic resonance (cMRI) parameters in a cohort of patients with a confirmed diagnosis of AL amyloidosis.

Methods

Retrospective observational study of consecutive patients diagnosed with AL amyloidosis by the Hematology Department in our center between 1999-2022. All had to have quantification of biomarkers (free light chains -dFLC-, NTpro-BNP and troponin T -TnT-) and transthoracic echocardiography (TTE) at diagnosis, collecting clinical and epidemiological characteristics and complementary tests.

Results

Of a total of 71 diagnoses of AL amyloidosis, 39 patients who met the inclusion criteria were selected, most diagnosed in the last 5 years. The mean age was 65.2 ± 12.9 years old, 56.4% male. The sample was divided according to the Mayo Clinic risk stratification model, into low (I-II, 33%) and high (III-IV, 67%) risk stages. Cardiac imaging variables were analyzed using Bootstrap statistics increasing the database to 150 patients (Table 1). Among echocardiographic variables, patients in the high-risk groups had greater systolic dysfunction of both ventricles, diastolic dysfunction, myocardial thickness, and pericardial effusion was observed more frequently. Among patients with cMRI (53.8%), we highlight the presence of an interventricular septal thickness ≥12 mm (47.6%) and a late gadolinium enhancement (LGE) in the left ventricle (66.6%, LV), most with a diffuse subendocardial pattern. In our cohort, the presence of LGE, greater maximum LV thickness, and increased LV extracellular volume (ECV) were significantly associated with the Mayo Clinic high-risk stages groups.

Finally, a global longitudinal strain > -11.5% by TTE, and a T1 mapping > 1042 ms or ECV > 49% by cMRI, were significantly associated with a reduction in overall survival (Figure 1).

Conclusions

There are cardiac imaging variables that have prognostic implications and could have a role in risk stratification of patients with AL amyloidosis. Its inclusion in new risk stratification models along with serum biomarkers should be considered.Table 1Figure 1
Echo-derived hemodynamic categorization for risk stratification in transthyretin cardiac amyloidosis
Authors: Cantone A , Dal Passo B , Sanguettoli F , Fabbri G , Maio D , Arzenton M , Vitali M , Tolomeo P , Pavasini R , Campo G , Serenelli M
Published: November 2023

Background

Transthyretin cardiac amyloidosis (TTR-CA) is a rare disease characterized by the deposition of abnormal proteins in the heart, which can lead to heart failure (HF) and death. Echocardiography provides valuable diagnostic and prognostic information in CA, but indices of left ventricular performance alone cannot thoroughly characterise patients with restrictive cardiomyopathy. Evaluating the hemodynamic profile by studying the forward flow and left ventricular filling pressure (LVFP) already proved its value in stratifying disease severity in patients with heart failure (HF).

Purpose

This study evaluated the prognostic relevance of a non-invasive hemodynamic categorization of TTR-CA patients based on the estimation of stroke volume index (SVi) and systolic pulmonary artery pressure (PAPs).

Methods

Baseline clinical, transthoracic echocardiogram and laboratory data were collected prospectively in patients with diagnosed TTR-CA. Patients were classified into four groups based on forward flow (SVi < or ≥30 ml/m2) and systolic pulmonary artery pressure (PAPs ≥ or <40 mmHg). The four profiles obtained were Profile-A, normal-flow, normal-pressure; Profile-B, low-flow, normal-pressure; Profile-C, normal-flow, high-pressure; Profile-D, low-flow, high-pressure. We assessed the incidence of the composite endpoint of cardiovascular death and HF hospitalization accordingly to the hemodynamic profile. We performed univariate and multivariate Cox regression using profile A as a reference for HR estimation (profile A corresponding to HR=1).

Results

Fifty-nine patients were enrolled in the analysis (Table). Over a mean follow-up of 35.9 months (IQR 11.7 - 51.2 months) 23 patients met the composite endpoint (10%, 23%, 43%, 60% for Profile A, B, C and D respectively). Compared to Profile A, Profile D showed the greatest risk of CV mortality and HF hospitalization (HR 10.17), followed by Profile C (HR 6.77) and B (HR 3.45), with P-value=0.015. The C-statistic for the model was 0.72. Kaplan-Meier curves confirmed that patients with PAPs >40 mmHg and SVi< 30 ml/m2 presented the highest risk of the composite endpoint (Log-rank P = 0.010) (Figure). Hemodynamic profiling remained an independent predictor of outcome even after adjusting for the NAC stage (Profile B, HR 2.26; Profile C, HR 6.96; Profile D, HR 17.13; P-value=0.0012).

Conclusions

The proposed echocardiographically-derived hemodynamic classification based on forward-flow and LVFP estimation is useful for TTR-CA patients risk stratification. Patients with low SVi and high PAPs have the greatest risk of CV death and HF hospitalization, even after adjustment for NAC stage. These findings highlight the importance of early detection and monitoring of hemodynamic changes in TTR-CA patients for tailored management and to improve outcomes.Table.Figure.