bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence of stroke in patients with hypertrophic cardiomyopathy in stable sinus rhythm during long-term monitoring
Authors: Fumagalli C , Bonanni F , Beltrami M , Ruggiero R , Zocchi C , Tassetti L , Maurizi N , Zampieri M , Lovero F , Di Bari M , Marchionni N , Pieragnoli P , Cappelli F , Fumagalli S , Olivotto I
Published: October 2022

Background

Patients with hypertrophic cardiomyopathy (HCM) are at increased risk of atrial fibrillation (AF) and stroke, especially at an advanced disease stage. To date, however, the incidence and factors associated with cardioembolic events in HCM patients without AF remain unresolved.

Purpose

To determine the incidence of stroke in HCM patients in whom cardiac rhythm was monitored with a cardiac implantable electronic device (CIED). The association of stroke with left atrial (LA) enlargement was also examined.

Methods

Retrospective cohort study in an outpatient clinic in a tertiary HCM Referral Center.

All consecutive patients diagnosed with HCM and referred for CIED implantation with >16 years at diagnosis and >1 year follow-up post CIED implantation were reviewed. Severe LA dilatation was defined as a LA dimension (LAD) of >48mm at echocardiogram. Based on CIED monitoring, patients were classified as: Pre-existing AF (diagnosed with AF prior to CIED); De novo AF (diagnosed with AF after CIED implantation); Sinus Rhythm (SR): no episodes of AF. Incidence of stroke after CIED implantation was the primary outcome.

Results

A total of 185 patients (57% men, age: 54±17 years) were implanted with a CIED and were included. Pre-existing AF was present in 72 (36%) patients and de novo AF in 24 (13%); whereas 89 (48%) remained in SR. After 5 [2–9] years, stroke was reported in 19 (10.3%) patients: 7 occurred in patients with pre-existing AF (1.1%/year), 3 in patients with de novo AF (2.2%/year), and 9 in patients with SR (2.3%/year). No difference was captured by CHA2DS2-VASc score among rhythm categories. Patients with AF had larger LAD at baseline. Among patients in SR, those with a LAD>48mm had the greatest risk of stroke (4.8%/year vs 0.5%/year, p<0.01; Hazard Ratio [HR]: 8.56, 95% C.I. 2.03–36.15). At Cox multivariable regression analysis, LA (HR: 1.104, 95%C.I. 1.039–1.173, p=0.001) and AF (HR: 0.310, 95% C.I. 0.102–0.939, p=0.038) were associated with incident stroke.

Conclusions

In HCM patients with CIED long-term monitoring and no prior history of AF, stroke rates were similar in those with de novo AF or stable sinus rhythm. CHA2DS2-VASc considerably underestimated risk, whereas severe LA dilatation was a powerful predictor of risk, irrespective of AF.

Funding Acknowledgement

Type of funding sources: None.
Natural history of MYH7-related dilated cardiomyopathy
Authors: Frutos Seminario F , Ochoa J P , Navarro-Penalver M , Baas A , Bjerre J V , Zorio E , Mendez I , Lorca R , Verdonschot J A J , Garcia-Granja P E , Bilinska Z , Fatkin D , Fuentes-Canamero M E , Garcia-Pinilla J M , Garcia-Pavia P
Published: October 2022

Background

Variants in MYH7 are responsible for disease in 1–5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described.

Objectives

We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression.

Methods

We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% females, 35.6±19.2 years) recruited from 29 international centers.

Results

At initial evaluation, 106 patients (72.1%) had DCM (LVEF 34.5±11.7%). Median follow-up was 4.5 years (interquartile range: 1.7–8.0). 23.7% carriers who were initially phenotype-negative developed DCM. Disease penetrance by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years. Thirty-six percent of patients with DCM met imaging criteria for LV non-compaction. During follow-up, 28% showed left ventricular reverse remodeling (LVRR). Overall incidence of end-stage heart failure (heart transplantation or heart failure related death) was 11.6% at 5 years. Overall major ventricular arrhythmia rate was low (1.0% at 5 years) even among patients with LVEF ≤35% (2.1% at 5 years). LV non-compaction was more prevalent in patients with variants in head domain (S1) (44.2%) compared with other domains (P<0.001). No differences among domain groups were found regarding LVRR, major ventricular arrhythmias or end-stage heart failure.

Conclusions

MYH7-related DCM is characterized by early age of onset, high penetrance, low rate of LVRR, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, even among patients with severe systolic disfunction.

Funding Acknowledgement

Type of funding sources: None.
Population estimates of obstructive and non-obstructive hypertrophic cardiomyopathy in the UK and Germany
Authors: Schultze M , Zema C , Carroll R , Hurst M , Borchert J , Zhong Y , Krause T , Bluhmki T , Partington H , Osman F , Tome Esteban M
Published: October 2022

Background

While numerous publications have estimated the prevalence of diagnosed hypertrophic cardiomyopathy (HCM), none have quantified the real-world proportion of obstructive and non-obstructive HCM using nationally representative data sources in any European countries.

Purpose

To estimate the prevalence of diagnosed HCM and its subtypes in the UK and Germany.

Methods

Patients with HCM were identified in the UK from 01 Apr 2009 to 30 Oct 2020 and Germany from 2011 to 2019. UK patients with HCM were identified using electronic health records from the Clinical Practice Research Datalink (CPRD) primary care data linked with Hospital Episode Statistics (HES) secondary care data using ICD-10 (I42.1, I42.2), Read, Medcode, SNOMED, and OPCS codes. German patients with HCM were identified using a nationally representative administrative claims data pool (WIG2 Benchmark database) from several German Statutory Health Insurance (SHI)-insurances using ICD-10 and OPS codes. Obstructive HCM was identified as any obstructive HCM diagnosis, any HCM diagnosis with septal reduction therapy, and any HCM diagnosis and left ventricular outflow tract obstruction (LVOTO; not in German claims data). Non-obstructive HCM was any non-obstructive or unspecified HCM diagnosis without evidence of any obstructive HCM. Annual prevalence was calculated for each year in the respective study periods and average annual prevalence across the study period.

Results

The average annual prevalence rate of HCM was 4.15/10,000 in the UK and 8.61/10,000 in Germany, while the average annual prevalence rate of obstructive HCM was 2.84/10,000 in the UK and 4.18/10,000 in Germany (Table). The proportion of HCM that was obstructive HCM was 68% in the UK and 49% in Germany. The prevalence rates of diagnosed HCM and obstructive HCM tended to increase over time (Figure).

Conclusion

The prevalence of HCM, obstructive HCM and the proportion of HCM that is obstructive varied between the UK and Germany. The prevalence of HCM was generally consistent with previously published estimates. Although there are limitations with coding in administrative data, it is important to differentiate obstructive HCM from non-obstructive HCM given their unique treatments and disease progression and management, especially since at least 49–68% of HCM is obstructive.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): Bristol Myers-Squibb
Natural history of myocardial fibrosis in dilated cardiomyopathy
Authors: Rubis P , Dziewiecka E , Wisniowska-Smialek S , Banys P , Urbanczyk-Zawadzka M , Krupinski M , Mielnik M , Karabinowska A , Garlitski A
Published: October 2022

Background

It is commonly accepted that myocardial fibrosis (MF) is implicated in the pathology of dilated cardiomyopathy (DCM). However, MF is not a “fixed” abnormality but evolves over time. It is unknown what the natural history of MF is in optimally treated DCM patients.

Methods

This is a prospective, single-center, observational study. Between May 2019 and September 2020, 90 DCM (81 male, mean age 47.2±9.8 years, mean EF 34.5±12.2%) patients underwent cardiac magnetic resonance (CMR). All patients were optimally treated with heart failure approved medications (beta-blockers in 100%, ACE-I/ARNI/ARB – 98%, MRA – 95%). Both, replacement via late gadolinium enhancement (LGE) and interstitial via T1 mapping MF were assessed. Replacement MF was expressed as LGE mass and LGE extent, whereas interstitial MF as extracellular volume (ECV). Left ventricular (LV) matrix and cell volumes were calculated based on LV mass and ECV as: LV matrix volume = (LV mass/1.05 g/mL) × ECV and LV cell volume = (LV mass/1.05 g/mL) × (1 − ECV). After 12 months CMR studies with MF assessment were repeated.

Results

Overall, index LV end-diastolic and end-systolic volumes (LVEDvol, LVESvol) and LV mass significantly decreased, whereas EF increased during follow-up (Table 1). Both, LGE mass (8.7±8.1 vs. 8.6±7.7 g; p=0.6) and LGE extent (4.6±4.2 vs. 4.97±4.6%; p=0.14) were similar between two measurements. There was a trend towards ECV decrease between baseline and follow-up studies but it did not reach statistical significance (28.5±4.9 vs. 27.7±4.1%; p=0.09). LV matrix volume significantly decreased during follow-up (49.1±17.8 vs. 46.1±15.7 ml; p<0.05); however LV cell volume remained unchanged (123.1±35.6 vs. 119.7±39.6 ml; p=0.2).

Conclusions

Beneficial regression of LV volumes and improvement of systolic function is common in DCM over mid-term period (one year). Replacement fibrosis seems to be a “fixed” pathology without much room for improvement. On the other hand, interstitial fibrosis seems to be a subject for substantial change. Left ventricular cells compartment does not change over time. Two types of MF – replacement and interstitial behaved differently during follow-up. Interstitial MF is amenable for treatment, whereas replacement MF does not respond to currently available therapy.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was founded through the National Science Centre, Poland (grant number 2018/29/B/NZ5/02588) and the Department of Scientific Research and Structural Funds of Medical College, Jagiellonian University (grant number K/ZDS/007192)
Significance and distribution of aortic valve calcium score before TAVI
Authors: Viegas J M , Grazina A , Castelo A , Mendonca T , Rodrigues I , Ramos R , Fiarresga A , Cacela D , Ferreira R C
Published: October 2022

Introduction

Aortic valve calcium scoring by multislice computed tomography (MSCT) is an alternative load independent assessment of aortic stenosis severity. Recent studies have further demonstrated that aortic valve calcification load is related to adverse outcomes during and after transcatheter aortic valve implantation (TAVI), however reference values in this population are uncertain. This study aimed to assess aortic valve calcium in P referred for TAVI.

Methods

Retrospective analysis of consecutive patients (P) submitted to TAVI between 2014 and 2020 in a tertiary care centre. Clinical and echocardiographic characteristics, along with MSCT-derived aortic valve calcium score were collected.

Results

A total of 467 P were included, 57% female, median age 83 (9) years (minimum 45 and maximum 95 years-old). The prevalence of hypertension, dyslipidemia and diabetes was 83%, 69% and 36%, respectively. Chronic renal failure was present in 51%, atrial fibrillation in 34% and peripheral artery disease in 14%.

Considering the 346 P with aortic valve calcification quantified by MSCT, median calcium score was 2161 (1761) AU. Age did not correlate with valvular calcification (r=0.043, p=0.422). Male gender showed significantly higher calcium score (2800 (2093) vs 1850 (1584), p<0.001) (Figs. 1 and 2).

11P had bicuspid aortic valve disease, with this population being younger (75 (16) vs 83 (8) years, p=0.001), nonetheless displaying higher aortic valve calcium load (2800 (2599) vs 2112 (1788), p=0.025). A weak but statistically significant correlation between calcium score and maximum (r=0.366, p<0.001) and mean gradients (r=0.387, p<0.001) and aortic valve area (r=−0.120, p=0.047) was demonstrated. Valvular calcification was not significantly different in P with reduced ejection fraction (<50%) (p=0.388).

Conclusion

There are significant differences in aortic valve calcium score between men and women referred for TAVI. Higher maximum and mean gradients were associated with increasing valvular calcification. Age and left ventricle ejection fraction were not related. P with bicuspid aortic valve have distinct calcification characteristics. As calcification burden may influence preprocedural planning, this parameter should be incorporated in the general work-up and reference values in this population should be known.

Funding Acknowledgement

Type of funding sources: None.
Phenotypic variability of FLNC-related cardiomyopathy: insights from a novel Dutch founder variant
Authors: Schoonvelde S A C , Ruijmbeek C W B , Hirsch A , Van Slegtenhorst M A , Wessels M W , Von Der Thusen J H , Verhagen J M A , Michels M
Published: October 2022

Background

Truncating variants in filamin C (encoded by the FLNC gene) are an important cause of dilated cardiomyopathy (DCM). Recently, a new pathogenic FLNC variant c.6864_6867dup, p.(Val2290Argfs*23) was identified in a number of families with DCM in the south of the Netherlands.

Objectives

The aim of this study was to: (i) investigate whether this FLNC variant is a founder variant; and (ii) to evaluate the clinical phenotype of the affected individuals.

Material and methods

Genetic and clinical data from these FLNC carriers were retrospectively collected. To determine a possible founder effect, haplotypes were reconstructed. The geographical distribution and age of the variant were determined. Clinical characteristics and outcomes were retrieved from electronic medical records. Cardiac magnetic resonance imaging (CMR) studies were reviewed.

Results

In total 33 individuals from 9 families carrying this FLNC variant were identified. A shared haplotype spanning 2.1 Mb was present in all subjects that were haplotyped. The variant appears to have originated in the south of the Netherlands between 275 and 650 years ago.

Median age was 53 years (range 20–79). Nine (27%) individuals were male. The clinical presentation is heterogeneous, ranging from the presence of DCM with heart failure with reduced ejection fraction in 11 (33%) subjects (median age 57, range 36–79 years), to presentation with sudden cardiac death (SCD) in 1 subject at 28 years of age with LV dilation and fibrosis on pathology, without prior symptoms. Seven subjects (21%) had left ventricular (LV) dilation with normal LV function, and one had midrange LV function without dilation. Nine (27%) subjects had no cardiac abnormalities, with a median age of 56 (range 26–70).

CMR was available in 18 subjects and showed late gadolinium enhancement (LGE), indicating fibrosis, in 11 subjects (61%), including 2 with preserved LV function. The LGE was extensively present in epicardial and infrequently in the subepicardial LV segments, with ring-like distributions being observed in 4 (22%) of the assessed patients.

During follow-up 1 subject experienced SCD and 3 developed end-stage heart failure and underwent heart transplantation. Six (18%) subjects had asymptomatic non-sustained ventricular arrhythmias detected by Holter monitoring, and 4 (12%) subjects received an implantable cardioverter defibrillator for primary prevention and 1 for secondary prevention.

Conclusion

The c.6864_6867dup, p.(Val2290Argfs*23) pathogenic FLNC variant is a founder variant originating from the south of the Netherlands. The phenotype is characterized by extensive myocardial fibrosis, even in subjects with preserved LV function, making subjects prone to both arrhythmias and heart failure.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation
Myocardial ischaemia in cardiac amyloidosis: a change of perspective
Authors: Ioannou A , Chacko L , Kotecha T , Patel R K , Razvi Y , Porcari A , Venneri L , Martinez-Naharro A , Knight D , Brown J , Hawkins P N , Gillmore J D , Fontana M
Published: October 2022

Introduction

Cardiac involvement is the main driver of clinical outcomes in systemic amyloidosis; however many clinical observations are not explained by the concept of replacement of the interstitium by amyloid material. Preliminary studies support the hypothesis that myocardial ischaemia contributes to cellular damage.

Purpose

This study assesses the presence and mechanisms of myocardial ischaemia using cardiovascular magnetic resonance (CMR) with multiparametric mapping and histopathological assessment.

Methods

Ninety-two patients with cardiac amyloidosis (CA) (AL = 41, ATTR = 51) and 97 without CA (3-vessel coronary disease (3VD) = 47, unobstructed coronary arteries = 26, healthy volunteers (HV) = 24) underwent quantitative stress perfusion CMR with myocardial blood flow (MBF) mapping. Twenty-six myocardial biopsies and 3 explanted hearts with CA were analysed histopathologically.

Results

Stress MBF was severely reduced in patients with CA with lower values than patients with 3VD, unobstructed coronary arteries and HV (CA = 1.03±0.51 ml/min/g, 3VD = 1.35±0.50 ml/min/g, Unobstructed coronaries = 2.92±0.52 ml/min/g, HV = 3.14±0.69 ml/min/g; CA vs 3VD p=0.008, CA vs Unobstructed coronaries p<0.001, CA vs HV p<0.001). After adjustment for intracellular volume the MBF in patients with CA remained significantly lower than in HV (stress MBF/ICV: AL = 2.24±1.12, ATTR = 2.22±0.93, HV = 4.38±1.06; AL vs. ATTR p=1.000, AL vs HV p<0.001, ATTR vs. HV p<0.001). Myocardial perfusion reserve (MPR) was severely reduced in CA patients, compared to HV and patients with unobstructed coronary arteries, with the degree of reduction being comparable only to patients with 3VD (CA = 1.55±0.60, 3VD = 1.54±0.51, unobstructed coronaries = 2.78±0.70, HV = 4.08±0.86; CA vs 3VD p=1.000, CA vs unobstructed coronary arteries p<0.001, CA vs. HV p<0.001). Myocardial perfusion abnormalities correlated with amyloid burden, systolic and diastolic function, structural parameters and blood biomarkers (p<0.05). Biopsies demonstrated diffuse hypoxia with abnormal VEGF staining in cardiomyocytes and endothelial cells. Amyloid infiltration in intramural arteries was associated with severe lumen reduction in 20% of vessels, and severe reduction in capillary density.

Conclusion

CA is associated with severe myocardial ischaemia demonstrable by histology and CMR stress perfusion mapping. Histological evaluation indicates a complex pathophysiology, where systolic and diastolic dysfunction, amyloid infiltration of the epicardial arteries and disruption and rarefaction of the capillaries play a role in contributing to myocardial ischaemia.

Funding Acknowledgement

Type of funding sources: None.
Utility of advanced echocardiographic deformation measures to delineate cause of pathological left ventricular hypertrophy: value of a multiparametric approach
Authors: Lo A , Ruane L , Mew T , Mew C , Guppy-Coles K , Dahiya A , Ng A , Prasad S , Atherton J
Published: October 2022

Background

Early diagnosis of cardiac amyloidosis (CA) is warranted to initiate specific treatment and improve outcomes. Conventional echocardiography is unable to reliably differentiate CA from other causes of increased left ventricular (LV) wall thickness.

Purpose

To demonstrate the value of a multiparametric approach utilising both standard and advanced echocardiographic measures to distinguish CA from other pathological causes of increased LV wall thickness.

Results

Patients with HCM had the highest septal thickness, maximum LV wall thickness, septum/posterior wall (Sep/PW) thickness ratio and left ventricular outflow tract (LVOT) gradient and lowest PW thickness (p<0.0001) among all groups. Patients with CA had the lowest global longitudinal strain (GLS), tissue Doppler-derived myocardial systolic and diastolic velocities and LV ejection fraction (EF) (p<0.0001). EF strain ratio (EFSR=LVEF/GLS) and LV longitudinal strain (apex/base) ratio were highest (largest number) in CA patients (p<0.0001). Multivariate linear regression identified 5 independent predictors (PW thickness, Sep/PW thickness ratio, LVOT gradient, LV longitudinal strain (apex/base) ratio and GLS) that discriminated CA from other causes of increased LV wall thickness. A regression equation (using multivariate linear regression) {CA prediction value = (0.230*LS apex/base) − (0.002*LVOT gradient) − [0.068*(Sep/PW ratio)] + (0.007*PW thickness) + (0.022*GLS) + 0.189; r=0.667)} was derived which allowed reliable distinction of CA with a sensitivity of 92.3% and specificity of 91.2% at the optimal cut-off.

Conclusion

PW thickness, Sep/PW thickness ratio, LVOT gradient, LV longitudinal strain (apex/base) ratio and GLS are independent predictors of CA. We developed a multiparametric regression equation which allowed discrimination of CA from other causes of increased LV wall thickness. Future studies involving larger cohorts are required to validate these findings.

Funding Acknowledgement

Type of funding sources: None.
Incidence and risk factors for pacemaker implantation in light chain and transthyretin cardiac amyloidosis
Authors: Porcari A , Rossi M , Cappelli F , Canepa M , Musumeci B , Cipriani A , Tini G , Varra' G G , Argiro' A , Sessarego E , Sinigiani G , Di Bella G , Rapezzi C , Sinagra G , Merlo M
Published: October 2022

Background

The incidence and risk factors of pacemaker (PM) implantation in patients with cardiac amyloidosis (CA) are largely unexplored.

Purpose

We sought to characterise the trends in the incidence of permanent PM and to identify baseline predictors of future PM implantation in light chain (AL) and transthyretin (ATTR) CA.

Methods

Multicentre, retrospective, observational study. Consecutive patients with AL and ATTR-CA diagnosed or referred at participating Centres between 2017 and 2020 were included. Clinical data recorded within ± 1 month from baseline evaluation were collected from electronic medical records. The primary outcome of the study was the need for clinically-indicated PM implantation. Reversible causes of conduction system disease were systematically ruled out before PM implantation. Patients with PM (n=41) and/or permanent defibrillator in situ (n=13) at the time of CA diagnosis were excluded.

Results

The study population consisted of 405 patients: 29.4% AL, 14.6% variant ATTR and 56% wild-type ATTR; 82.5% were males, with median age 76 years. During a median follow-up of 33 months (interquartile range 21–46), 36 (8.9%) patients experienced the primary outcome: 10 patients with AL-CA, 2 with variant ATTR-CA and 24 with wild-type ATTR-CA (p=0.08). At multivariable analysis, history of atrial fibrillation (hazard ratio [HR] 3.80, p=0.002), PR interval (HR 1.013, p=0.002) and QRS >120 ms (HR 4.7, p=0.001) on baseline ECG were independently associated with PM implantation (Figure 1). In the individual patient, the contemporary presence of these 3 factors yielded the highest risk of PM implantation (HR 6.26, p=0.003).

Conclusion

In a large cohort of AL and ATTR-CA, the incidence of PM implantation was high accounting for ≈9% of patients in the 3 years following the diagnosis. History of atrial fibrillation, longer PR interval and QRS >120 ms identified CA patients at high-risk of future PM implantation (Figure 2).

CA patients with these features might need close monitoring during follow-up for the development of conduction system disease requiring PM implantation.

Funding Acknowledgement

Type of funding sources: None.
Long-term prognosis of patients with Perugini Grade 1 cardiac scintigraphy score
Authors: Itzhaki Ben Zadok O , Rhurman Shahar N , Vaturi M , Kandinov I , Kornowski R , Hamdan A
Published: October 2022

Background

A Perugini Grade 1 myocardial uptake on amyloid cardiac scintigraphy does not establish the diagnosis of amyloid transthyretin cardiomyopathy (ATTR-CA), and according to current position papers mandates an endomyocardial biopsy to rule in or rule out ATTR-CA. We aimed to investigate whether Perugini Grade 1 reflects an early stage of ATTR-CA or a false positive result thus obliviating the need for further evaluation.

Methods

Study population was comprised of consecutive ≥70 years old patients who underwent a baseline cardiac scintigraphy scan for the presumed diagnosis of ATTR-CA at our institution between the years 2017–2020 and had a Perugini Grade 1 score. Patients with Perugini Grade 2 or 3 comprised our control group. At the beginning of 2022, Perugini Grade 1 patients prospectively underwent a repeat follow-up evaluation which included clinical examination, echocardiography with strain parameters, cardiac biomarkers measurement and cardiac scintigraphy. Cardiac magnetic resonance (CMR) and genetic testing for ATTR-CA mutations were analyzed as well.

Preliminary results

Fifty patients were included in the baseline study cohort, of whom 44% (n=22) were females. A carpal tunnel syndrome history was present in 10 patients (20%). Baseline troponin T and NT pro-BNP levels were 23 (IQR 14,39) and 1557 (IQR 237, 5746) ng/L, respectively. Wall thickness by echocardiography was 12 (11, 15) mm and 8 patients (16%) had severe mitral annulus calcification. Left ventricular ejection fraction (LVEF) was 60 (IQR 50, 60)%. At a median follow-up of 31 (20, 35) months, 7 patients (14%) were diagnosed with plasma-cell dyscrasias and 6 patients (12%) were hospitalized for heart failure exacerbations. Follow-up troponin T and NT pro-BNP levels were 27 (IQR 21,46) pg/ml and 1158 (IQR 434, 7249) ng/L, respectively (p=NS compared to baseline). Wall thickness by echocardiography was 12 (12, 15) mm and LVEF was 60 (IQR 50, 60)% (p=NS compared to baseline). Follow-up cardiac scintigraphy demonstrated Perugini Grade 1 in all re-tested patients. Two patients and 14 patients (32% total) underwent an endomyocardial biopsy or CMR, respectively, for a definitive diagnosis. All 16 tests were incompatible with amyloid cardiomyopathy. Genetic data results will be added. All-cause survival was similar between patients with Perugini Grade 1 versus Grades 2 and 3 (log rank p=0.103).

Conclusion

At long-term follow-up, Perugini Grade 1 patients do not demonstrate progression of laboratory or imaging amyloid characteristics. This suggests that Perugini grade 1 reflects a false positive result for ATTR-CA rather than an early stage in the disease. Larger-scale data should further question the need for an endomyocardial biopsy in these patients.

Funding Acknowledgement

Type of funding sources: None.
Genetic and clinical characteristics of transthyretin cardiac amyloidosis in Koreans
Authors: Jeon K , Kim D , Choi J O , Kim K H , Park M S , Jeon E S
Published: October 2022

Background/Introduction

Transthyretin amyloidosis with mutations (aTTRv amyloidosis) have over 100 recognized pathogenic mutations of the TTR gene and its clinical manifestations are very heterogenous. Through the global THAOS (Transthyretin Amyloidosis Outcomes Survey) patient registry, different and several types of mutants and clinical differences have been identified. Awareness of aTTRv amyloidosis is now becoming somewhat significant amongst physicians all over the world. This is a detailed look at such efforts in Korea.

Purpose

We aimed to seek the geologic significance of aTTRv amyloidosis in South Korea.

Methods

This was an analysis of 638 Korean amyloidosis patients in a single center over a period of 16 years from 1995 to October 2021. 95 individuals were found with aTTR mutations.

Results

aTTRv amyloidosis constituted 14.8% (n=95) of amyloidosis patients, and the most commonly involved organ being the heart (61.7%, n=58). Unlike the rest of the world, the mixed phenotype was most common (51.0%, n=48) in Korea and the most universal mutation in Koreans were Asp38Ala, which only constitutes about 1.0% in the THAOS registry. Val30Met mutation, which comprises 76% of the mutation in the THAOS registry, was mostly associated the neurologic phenotypes. However, the same mutations in Korea mixed phenotypes with cardiac (38.4%) and neurologic (37%) symptoms.

Conclusion

aTTRv amyloidosis in Korea is different from other patients worldwide. The mixed phenotype was most common, emphasizing the need for heart failure management in the Korean population. Genotype wise, Koreans held a less common mutation of Asp38Ala. The most common mutation of Val30Met was more likely to be associated cardiac symptoms, which concurs with other studies that suggesting that geological features are more important than mutations itself.

Funding Acknowledgement

Type of funding sources: None.
Incidence and factors associated with de novo atrial fibrillation in patients with wild-type transthyretin cardiac amyloidosis
Authors: Fumagalli C , Zampieri M , Argiro' A , Musumeci B , Tini G , Di Bella G , Cipriani A , Porcari A , Canepa M , Merlo M , Sinagra G , Rapezzi C , Perfetto F , Cappelli F
Published: October 2022

Purpose

We described the incidence and ECG factors associated with de novo atrial fibrillation (AF) in patients diagnosed with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) to drive tailored arrhythmia screening.

Background

Data on the incidence rate and factors associated with de novo AF in patients with ATTRwt-CA is limited.

Methods

Multicenter, retrospective, observational cohort study performed in six referral centers for CA. All consecutive patients diagnosed with ATTRwt-CA between 2004 and 2020 with >1-year follow up (FU) were enrolled in the study and were divided into three groups according to presence of AF: (1) patients with “known AF”; (2) patients in “sinus rhythm” and (3) patients developing “de novo AF” during FU. Incidence and factors associated with AF in patients with ATTRwt were the primary outcomes.

Results

Overall, 266 patients were followed for a median of 469 days: 148 (56%) with known AF, 84 (31.6%) with sinus rhythm, and 34 (12.8%) with de novo AF. Age and gender were similarly distributed. At multivariable analysis, PR (Hazard Ratio [HR]: 1.008; 95% CI: 1.001–1.016), QRS (HR: 1.022; 95% CI: 1.002–1.043) and left atrial dilatation >50mm (HR: 3.429, 95% CI: 1.565–7.329) were associated with de novo AF at FU. Patients presenting with at least two risk factors (PR >200ms, QRS >120ms or LAD >50mm) had a higher risk of developing de novo AF compared to patients with no risk factors (HR 14.918; 95% CI: 3.242–31.646).

Conclusions

Incidence of de novo AF in patients with ATTRwt is 20.7%/year. Longer PR and QRS duration and left atrial dilation are associated with arrhythmia onset.

Funding Acknowledgement

Type of funding sources: None.
Cardiac amyloidosis is not a single disease: a multiparametric comparison between the light chain and transthyretin forms
Authors: Neculae G , Adam R , Jercan A , Badelita S , Draghici M , Stan C , Rosca M , Beladan C , Coriu D , Popescu B A , Jurcut R
Published: October 2022

Background

Systemic amyloidoses represent a heterogeneous group of diseases resulting from the deposition of misfolded proteins as amyloid fibrils into the extracellular matrix of different organs. Based on this precursor protein, cardiac amyloidosis (CA) can be most frequently classified as: light chain (AL) and transthyretin (ATTR) amyloidosis, with different management and prognosis.

Purpose

The purpose of this study is to establish a differential diagnosis algorithm targeted towards these two most frequent subtypes of CA. Although confirmation through invasive or non-invasive diagnostic algorithms is still mandatory for a final diagnosis, a series of clinical, paraclinical and imaging differences could possibly guide the choice for more complex diagnostic steps.

Methods

We prospectively included all consecutive patients with ATTR and AL evaluated between 2018 and 2022 in our center. All patients had a complete clinical, paraclinical and imaging evaluation including myocardial deformation study, and confirmation of the final diagnosis, according to the current international recommendations.

Results

The study population included 81 patients divided into 2 groups: ATTR (group 1, n=32: 30 variant and 2 wild type) and AL (group 2, n=49).

ATTR patients were younger (50.7±13.9 vs. 60.2±7.3 years, p=0.0001), had predominantly more neurological symptoms, milder cardiac symptoms and lower values of cardiac biomarkers than AL: NT-proBNP (3095±4433 vs. 10382±9008 ng/ml, p=0.001) and high sensitive troponin I (0.0129±0.01 vs 0.177±0.2 ng/ml, p=0.0002), with better renal function (mean GFR 84.74±26.9 vs. 64.5±29.45 mL/min, p=0.003). We found no significant differences in terms of ECG changes.

Moreover, at similar left ventricular (LV) wall thickness and ejection fraction, ATTR group had less pericardial effusions (53.6 vs. 86.8%, p=0.0027), better LV global longitudinal strain (−12.0±3.7 vs. −9.7±4.6%, p=0.03), RV strain (RVFW strain −19.7±6.2 vs. −14.5±11.0%, p=0.03) and also better reservoir and contractile function of the LA (LASr 17.2±12.3 vs. 11.2±7.4%, p=0.02).

Based on this multiparametric comparison we proposed a prediction algorithm to differentiate between the 2 forms of CA. A score of equal or more than 4 from a maximum of 9 points, has been able to differentiate between AL and ATTR with a sensitivity and specificity of 78 and 80%, respectively; AUC= 0.82.

Conclusions

CA is a complex entity and requires extensive testing through serum biomarkers, imaging, and invasive confirmation of amyloid infiltration in some cases. This study highlighted a series of non-invasive checkpoints, which can be useful in guiding the decision making process towards a more accurate and rapid differential diagnosis, in cases where a final diagnosis is crucial to be immediately established.

Funding Acknowledgement

Type of funding sources: None.
Sustained vasodilation after cold pressor test is an independent predictor of poor survival in primary AL amyloidosis
Authors: Patras R , Georgiopoulos G , Petropoulos I , Theodorakakou F , Delialis D , Angelidakis L , Gavriatopoulou M , Dimopoulou M A , Sianis A , Maneta E , Neofytou O , Terpos E , Dimopoulos M A , Kastritis E , Stamatelopoulos K
Published: October 2022

Background

Primary AL amyloidosis is a rare yet lethal systemic disorder. Dysfunction of the autonomous nervous system due to disease-related nerve infiltration is a common manifestation of AL amyloidosis. Previously published own work indicated that AL patients present sustained paradoxical vasodilation in response to sympathetic stimulus, as assessed by cold pressor test (CPT). The clinical relevance of this finding is unknown.

Purpose

We sought to investigate the relationship between CPT-induced vascular response and mortality in AL amyloidosis.

Methods

We consecutively recruited 97 newly diagnosed patients with AL amyloidosis. CPT of the brachial artery was performed before treatment initiation. All measurements were assessed using high resolution ultrasonography (14.0Mhz multifrequency linear array probe, Vivid 7 Pro; General Electric Healthcare, Milwaukee, Wisconsin, USA). The maximum vasodilation of the brachial artery was measured during the sympathetic stimulus and 3 minutes after withdrawal (sustained response). All-cause mortality was defined as the primary end-point of the study.

Results

Mean age was 66 years with prevalence of male gender. Sustained vasodilation (but not vasodilation during CPT) was associated with heart failure, NYHA stage, BNP and peripheral vascular involvement (p<0.05 for all). Sustained vasodilation after withdrawal of the sympathetic stimulus was significantly associated with mortality as assessed by Cox regression analysis (HR: 1.149, 95% CI 1.042–1.269, p=0.005). This association remained significant after adjustment for age, sex, systolic blood pressure (SBP), nerve involvement and Mayo stage (HR: 1.123, 95% CI 1.014–1.243, p=0.026). A sustained vasodilation ≥3.35% from pre-stimulus diameter was associated with shorter survival (log-rank test, p=0.022, Figure 1). No association between vasodilation during sympathetic stress and mortality was observed.

Conclusions

In AL amyloidosis, sustained paradoxical vasodilation in response to sympathetic stimulus was associated with poor survival. The clinical utility of this index of vascular autonomic dysfunction as a potential prognostic and therapeutic biomarker in AL amyloidosis merits further investigation.

Funding Acknowledgement

Type of funding sources: None.
Detection of arrhythmias in patients with cardiac amyloidosis using implantable ECG recorders
Authors: Taborsky M , Aiglova R , Fedorco M , Bradac P , Flasik J , Danek J , Schee A
Published: October 2022

Introduction

Cardiac Amyloidosis frequently results in congestive cardiac failure and arrhythmias, from a disruption in cardiac substrate with subsequent electro-mechanical remodeling. Arrhythmias are vary based on the amyloidosis type. Conduction defects and atrial arrhythmias are more prevalent in transthyretin amyloidosis compared with light chain amyloidosis, and this difference might be a reflection of the longer survival time in the former.

Methods

112 transthyretin amyloidosis (TTR) patients with completed underlying diagnosis including 99mTc-DPD scan, genetic testing and endomyocardioal biopsy (27%) without documented arrhythmias were randomized to standard clinical follow-up including arrhythmias or implantation of an ECG loop recorder (ILR). The classic FU took place in a heart failure clinic, and the group of patients with ILR was monitored by remote control with automatic daily report of the occurrence of arrhythmias by an independent organization. If an arrhythmia was detected, the patient was contacted immediately. The mean follow-up time for both groups was 17±7 months.

Results

The results are summarized in Table 1.

Conclusions

Currently, there is no consensus on the absolute benefit that ICDs in patients with cardiac amyloidosis. When non-sustained VT and syncope are captured and documented, ICD implantation for prevention of SCD in CA is most likely a reasonable approach. However, intensive monitoring of arrhythmias in patients with CA using ILR can lead to accurate and early detection of ventricular arrhythmias in particular and early initiation of ICD treatment as a prevention of SCD. Documentation of ventricular arrhythmias in CA patients was significantly higher by ILR (p<0.005) and was a clear predictor of patient survival (HR 2.51).

Funding Acknowledgement

Type of funding sources: None.
Transthyretin cardiac amyloidosis in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement: a single center experience
Authors: Scudeler L , Gallone G , Bongiovanni C , Bruno F , Landra F , Andreis A , Fava A , Pidello S , Raineri C , Giorgi M , D'Ascenzo F , Conrotto F , Alunni G , Rinaldi M , De Ferrari G M
Published: October 2022

Background

Even if prevalent among patients with severe aortic stenosis (AS), the clinical suspicion for transthyretin cardiac amyloidosis (ATTR-CA) remains difficult in this subset.

Methods

Consecutive severe AS patients undergoing transcatheter aortic valve replacement (TAVR) evaluation at a single center were prospectively included. Those with suspected ATTR-CA based on clinical assessment underwent 99mTc-DPD cardiac scintigraphy. The RAISE score, a novel screening tool with high sensitivity for ATTR-CA in AS, was retrospectively calculated to rule-out ATTR-CA in the remaining patients. Patients were categorized as follow: “ATTR-CA+”: patients with confirmed ATTR-CA at 99mTc-DPD cardiac scintigraphy; “ATTR-CA−”: patients with negative 99mTc-DPD cardiac scintigraphy or a negative RAISE score; c) “ATTR-CA indeterminate”: patients not undergoing ATTR-CA assessment with a positive RAISE score. The characteristics of ATTR-CA+ and ATTR-CA− patients were compared.

Results

Of 107 included patients, ATTR-CA suspicion was posed in 13 patients and confirmed in 6. Patients were categorized as follow: 6 (5.6%) ATTR-CA+, 79 (73.8%) ATTR-CA−, 22 (20.6%) ATTR-CA indeterminate. Excluding ATTR-CA indeterminate patients, the prevalence of ATTR-CA was 7.1%. As compared to ATTR-CA− patients, ATTR-CA+ patients were older, had higher procedural risk and more extensive myocardial and renal damage. They had higher left ventricle mass index and lower ECG voltages, translating into a lower voltage to mass ratio. Moreover, bifascicular block was more common. No difference in procedural outcomes and 1-year mortality was observed between groups.

Conclusions

Among severe AS patients, ATTR-CA is prevalent and presents with phenotypic features that may aid to differentiate it from lone AS. A clinical approach based on routine search of amyloidosis features may effectively lead to selective 99mTc-DPD cardiac scintigraphy with a satisfactory positive predictive value.

Funding Acknowledgement

Type of funding sources: None.
Right ventricular mechanics and its association with symptoms in transcatheter aortic valve replacement candidates: a three-dimensional echocardiography study
Authors: Ladanyi Z , Lakatos B K , Ruppert M , Fabian A , Ujvari A , Molnar B , Turschl T , Fejer C , Apor A , Nagy A I , Molnar L , Kovacs A , Merkely B
Published: October 2022

Aortic valve stenosis is one of the most prevalent valvular disease with significant clinical burden. While it is initially a disorder of the left ventricle (LV), long-term effects of the disease also affect the right ventricle (RV) as well. Nevertheless, data are scarce regarding the changes of RV mechanics and their association with symptomatic status of the patients. 3D echocardiography allows a more detailed assessment of the RV, which may unveil distinct changes of its morphology and function in this clinical setting.

Accordingly, our aim was to examine LV and RV mechanics in TAVR candidate patients with severe aortic stenosis using three-dimensional (3D) echocardiography.

Seventy patients (51% male, age: 80±6 years) were enrolled. Detailed medical history and symptomatic status were obtained. Beyond conventional transthoracic echocardiographic protocol, 3D loops were also acquired. We measured 3D LV and RV end-diastolic volume indexed to body surface area (EDVi), ejection fraction (EF) and global longitudinal (GLS) using dedicated software. Furthermore, we have determined 3D RV global longitudinal (RV GLS) and circumferential strain (RV GCS) using the ReVISION method.

LV EF (r=0.28, p<0.05) and LV GLS (r=−0.26, p<0.05) significantly correlated with age, while RV EF (r=0.21, p=0.11), RV GLS (r=−0.17, p=0.19) and RV GCS (r=−0.07, p=0.61) did not show association with it. 41% (n=29) of the patient population mentioned angina or had syncope. Patients with these symptoms had comparable LV EDVi (73±23 vs. 69±25 mL/m2, p=0.47), LV EF (47±15 vs. 51±10%, p=0.14) and LV GLS (−13.6±4.8 vs. −14.8±2.6%, p=0.25) to those who did not mention these complaints. On the other hand, patients with angina or syncope in their medical history had significantly lower RV EDVi (58±13 vs. 70±23 mL/m2, p<0.05), while having significantly higher RV EF (46±10 vs. 52±7%, p<0.05). Moreover, symptomatic patients had significantly lower RV GCS (−15.7±5.6 vs. −19.6±5.3%, p<0.01), while RV GLS did not differ (−15.8±4.8 vs. −17.4±4.1%, p=0.17).

Patients with severe aortic stenosis have marked changes in not only the LV, but the RV mechanics as well. While the symptomatic status does not seem to be associated with LV morphology and function, patients with angina or syncope had distinct changes in RV size and the contraction pattern of the chamber.

Funding Acknowledgement

Type of funding sources: None.
Safety of heart radiotherapy for malignant cardiac tumors: a short and long term study
Authors: Lestuzzi C , Cosei I , Navarria F , Viel E , Ravasel A , Fumagalli A , Miolo G M , Popescu B , Buonadonna A
Published: October 2022

Background

Radiotherapy (RT) may be used as a complementary or palliative treatment for selected cases of malignant cardiac tumors, and improves the overall and relapse-free survival in cardiac sarcomas (1–3). Its use is limited by the risk of radiation injury on the cardiac structures (4). Only few data about the safety of cardiac RT are available.

Purpose

This study aimed to assess the short and long term adverse cardiac effects in a cohort of patients with cardiac malignancies treated with RT directly on the heart.

Methods

We reviewed the clinical and echocardiographic data of 25 patients (pts) treated with cardiac RT from 2002 to 2021, using Intensity Modulated RT or Tomotherapy at doses of 25–59 Gy over 5–25 fractions for primary or metastatic tumors (21 sarcomas). The patients had ECG and echocardiogram (ECHO) before RT and weekly during the treatment. After RT, the cardiac surveillance included a visit with ECG and ECHO every 3 months for the first 2 years, every 6 months for 3 years, and yearly thereafter. We compared the left ventricular ejection fraction (LVEF) before RT and at the last available follow-up for all patients; for 12 pts whose radiation field included the right chambers, we analyzed also the right ventricular shortening fraction (RVSF) at the last available follow-up.

Results

The pts were 14 males, 11 females, aged 22 to 75 (median 54) when treated. The intent was adiuvant after R1 surgery in 12 pts, preoperative in 3, palliative or curative for metastatic or unresectable tumors or in patients refusing redo surgery or chemotherapy (10 pts). Anthracyclines chemotherapy was used in 19 pts. The radiation field included the left atrium and/or ventricle in 11 pts, the right heart in 9, both left and right structures in 3. Two pts were lost to follow-up after 36 and 50 months; 17 died, 3 to 175 months after RT (median 12), all for non-cardiac causes; 6 are alive (with complete local remission) 15 to 126 months (median 79) after completing RT. Acute toxicities were: atrial fibrillation in 2 pts, pericarditis in 2 (both reverted in one week with medical therapy) and temporary worsening of ventricular arrhythmias in one pt with myocardial metastases. At last follow-up no significant valvular or pericardial disease was evident; the LVEF was >50% in all pts (5–10% decreased -compared to baseline- in 2 pts, improved in 3, stable in the others) and the RVSF was >35%.

Conclusions

In our experience, RT may be used in the treatment of cardiac malignancies with little adverse effects both on short term and at a median follow-up of 13 months (and lasting up to >10 years).

Funding Acknowledgement

Type of funding sources: None.