bluuebunny/crossref_metadata_2025_split huggingface dataset:
The joint role of collagen turn-over biomarkers and late gadolinium enhancement to predict cardiovascular outcome in nonischemic dilated cardiomyopathy
Authors: Zlibut A , Agoston R , Orzan R I , Muresan I D , Horvat D , Agoston-Coldea L 
Published: October 2022

Abstract

Background
Myocardial scarring is a primary pathogenetic process in nonischemic dilated cardiomyopathy (NIDCM) which is responsible for progressive cardiac remodeling and heart failure, severely impacting the survival of these patients. Although several collagens turn-over biomarkers have been associated with myocardial fibrosis, their clinical utility is still limited. Late gadolinium enhancement (LGE) determined by cardiac magnetic resonance imaging (CMR) has become a feasible method to detect myocardial replacement fibrosis.

Purpose
We sought to evaluate the association between collagen turn-over biomarkers and replacement myocardial scarring by CMR and, also, to test their ability to predict outcome in conjunction with LGE in patients with NIDCM.

Method
We conducted a prospective study on 194 patients (48.7±14.3 years of age; 74% male gender) with NIDCM. CMR was used to determine the presence and extent of LGE. Several collagen turn-over biomarkers were determined at the diagnosis, comprising galectin-3 (Gal3), procollagen type I carboxy-terminal pro-peptide (PICP) and N-terminal pro-peptide of procollagen type III (PIIINP). A composite outcome (all-cause mortality, ventricular tachyarrhythmias, heart failure hospitalization) was ascertained over a median of 26 months. Of all, 17% (n=33) of patients reached the outcome: all-cause mortality (n=6), malignant ventricular tachyarrhythmia (n=14) and HF hospitalization (n=13).

Results
Gal3, PICP and PIIINP were considerably increased in those with LGE+ (p&lt;0.001), being also directly correlated with LGE mass (r2=0.42; r2=0.44; r2=0.31; all p&lt;0.001). Receiver operating characteristic (ROC) analysis revealed significant ability to diagnose LGE, with area under the ROC: 0.816 for Gal3, 0.705 for PICP, and 0.757 for PIIINP (all p&lt;0.0001). Kaplan-Meier analysis showed that at a threshold of &gt;13.8 ng/dL for Gal3 and &gt;97 ng/dL for PICP, they significantly predicted the outcome (HR=2.66, p&lt;0.001; HR=1.93, p&lt;0.002). Moreover, for a combined model of LGE+/Gal3+/PICP+, time-to-event analysis demonstrated the highest ability to predict composite outcome, as compared to any other models (p=0.004). Nevertheless, in multivariate analysis, after adjustment for covariates, only LGE+ and Gal3+ remained independent predictors for outcome (p=0.008; p=0.04).

Conclusion
In patients with NIDCM, serum collagen turn-over biomarkers such as Gal3, PICP and PIIINP are closely related to the presence and extent of LGE and can significantly predict cardiovascular outcome. The joint use of LGE with Gal3 and PICP significantly improved outcome prediction.

Funding Acknowledgement
Type of funding sources: None.
Different prognosis of ARVC patients between DSG2 and PKP2 variant carriers
Authors: Sonoda K , Nagase S , Aiba T , Kato K , Shiga T , Kusano K , Horie M , Ohno S 
Published: October 2022

Abstract

Background
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy mainly caused by desmosomal gene variants. In Europe and North America, pathogenic variants in PKP2 were identified in most of the ARVC patients. On the other hand, we have reported that the genetic backgrounds of ARVC in Japanese were different from those in European; pathogenic variants in DSG2 were predominant in Japanese. Genotype-phenotype correlations, however, have not been clarified yet.

Purpose
In this study, we aimed to examine whether the genotype affect the phenotype and outcome in Japanese ARVC patients.

Methods and results
This study included 167 Japanese ARVC patients who received genetic testing (128 males [77%]). Their median age at diagnosis was 44 [24–55] years old and median follow-up duration was 10 [4–21] years. We found 90 patients with pathogenic variants: 52 in DSG2 (31%), 30 in PKP2 (18%), 3 in DSP (1.8%), 1 in DSC (0.6%), 1 in JUP (0.6%) and 3 in DES (1.8%). The age of the first sustained ventricular arrhythmia (SVT) were older in the patients with DSG2 than those with PKP2 variants (48±15 years vs. 35±15 years, P=0.008) but younger in DSG2 variant carriers at the first hospitalization for heart failure (41 [22–61] years vs. 67 [61–74] years, P=0.03). The left ventricular ejection fractions of DSG2 variant carriers were significantly lower at diagnosis than that of PKP2 (52 [41–60] % vs. 61 [56–66] %, P=0.002). Kaplan-Meier survival curve for lethal arrhythmic events including SVT, ventricular fibrillation and sudden death revealed that the event rate of DSG2 variant carriers was significantly lower than that of PKP2 (log-rank test, P=0.02) (Fig. 1).
Among 11 patients who had both SVT and hospitalizations for HF, 7 PKP2 variant carriers had SVT first, then, hospitalized for HF (48 [35–53] years and 67 [55–71] years, P=0.02). Contrary, the clinical course of 4 DSG2 variants carriers were different from those with PKP2 (54 [40–68] years for SVT and 65 [56–70, P=0.1] years for HF) (Fig. 2).

Conclusion
The patients with DSG2, which is the major causative gene for ARVC in Japanese, show different phenotype and outcome from those with PKP2. We should examine the effect of variants on the prognosis of ARVC patients in more large population including various ethnics.

Funding Acknowledgement
Type of funding sources: None.
Global longitudinal strain and quantitative sensory testing in pre-symptomatic patients with mutation for transthyretin amyloidosis
Authors: Canciello G , Tozza S , Lombardi R , Nolano M , Todde G , Severi D , Borrelli F , Acampa W , Esposito G , Manganelli F , Losi M A 
Published: October 2022

Abstract

Background
Hereditary transthyretin (ATTRv) amyloidosis is a rare, autosomal dominant, and devastating disease. If untreated, the disease is fatal within 4–15 years from onset.
Thus, diagnosis in the early stages of ATTRv amyloidosis is crucial to start treatment and to prevent or delay disease progression. However, the diagnosis of symptomatic ATTRv amyloidosis in TTR gene mutation carriers may be challenging.

Purpose
We aimed identifying early indexes of cardiac and/or neurological involvement in pre-symptomatic subjects (carriers) harboring a TTR gene mutation.

Methods
Eight TTR-mutation carriers (mean age 51±9 years, 5 males) constituted the study populations. Mutations identified were: Val30Met in 4, and Phe64Leu in the remaining 4 patients. Patients underwent tactile and thermal quantitative sensory testing (QST), 99mTc-labeled bisphosphonate (HMDP) scintigraphy with the evaluation of Perugini score, and comprehensive echocardiogram with evaluation of global longitudinal strain (GLS).

Results
Table 1 reports results in overall patients. PADO indicates predicted age of disease onset. MWT indicates maximal wall thickness at echocardiography.
There was a strong and inverse correlation between the °C degree at HPT and GLS (r=−0.790; p=0.02, demonstrating that a worse HPT corresponded a better GLS (Figure 1).

Conclusion
GLS and QST findings support an early involvement of heart and small nerve fibers even many years before the PADO. Interestingly, cardiac impairment seems to not parallel that of small nerve fibers. An inhomogeneous accumulation of fibrils, as well possible different pathophysiological mechanisms in heart and nerve fibers, might result in a variable organ impairment at least in the earliest stage of disease.
Our observation needs to be tested in a wider population with such a rare disease.

Funding Acknowledgement
Type of funding sources: None.
Two-dimensional speckle-tracking echocardiography in tafamidis-treated patients with transthyretin amyloid cardiomyopathy: a glimmer of hope for viable therapy monitoring?
Authors: Rettl R , Duca F , Binder C , Dachs T , Cherouny B , Camuz Ligios L , Mann C , Schrutka L , Dalos D , Charwat-Resl S , Badr Eslam R , Kastner J , Bonderman D 
Published: October 2022

Abstract

Background
Treatment with Tafamidis in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) has been shown to have beneficial effects on the left ventricle (LV), as assessed by cardiac magnetic resonance (CMR) imaging. Although CMR represents the gold standard among imaging modalities, its limited availability in clinical practice makes it unfeasible for routine therapy monitoring.

Purpose
We aimed to determine Tafamidis-induced changes using two-dimensional (2D) speckle-tracking echocardiography and to identify echocardiographic imaging parameters that could be used for specific therapy monitoring.

Methods
We subjected a series of ATTR-CM patients to transthoracic echocardiography (TTE) at baseline and follow-up and compared patients treated with Tafamidis 61mg once daily (QD) to a historical control cohort treated with Tafamidis 20mg QD, as well as to a historical treatment-naïve control cohort reflecting the natural course of the disease.

Results
Patients receiving Tafamidis 61mg (n=62) or 20mg (n=21) QD showed stable measurements at follow-up [61mg: 8.5 months, 20mg: 7.0 months] in LV global longitudinal strain (GLS) (61mg: −11.75% vs. −11.58%, p=0.534; 20mg: −10.61% vs. −10.12%, p=0.309), right ventricular (RV) GLS (61mg: −14.18% vs. −13.72%, p=0.377; 20mg: −14.53% vs. −13.99%, p=0.452) and left atrial (LA) reservoir strain (LASr; 61mg: 8.80% vs. 9.42%, p=0.283; 20mg: 8.23% vs. 8.67%, p=0.589), whereas treatment-naïve ATTR-CM patients (n=54) had clear signs of disease progression at the end of the observation period [10.5 months; LV-GLS: −11.71% vs. −10.59%, p=0.001; RV-GLS: −14.36% vs. −12.99%, p=0.038; LASr: 10.67% vs. 8.41%, p=0.005]. Between-group comparison at follow-up revealed beneficial effects of Tafamidis 61mg on LASr (p=0.003), LV-GLS (p=0.030) and interventricular septum (IVS) thickness (p=0.006), resulting in clinical benefits (six-minute walk distance (6-MWD): p=0.006, NT-proBNP: p≤0.001), while patients treated with Tafamidis 20mg QD showed positive effects on LASr (p=0.039) but no differences in LV-GLS (p=0.274), IVS thickness (p=0.068) and clinical status (6-MWD: p=0.124, NT-proBNP: p=0.053) compared to the natural course.

Conclusion
Treatment with Tafamidis 61mg in ATTR-CM patients delays the increase in IVS thickness and the deterioration of LA and LV longitudinal function, resulting in significant clinical benefits compared with natural history. Serial TTE with 2D speckle-tracking imaging may be appropriate for disease-specific therapy monitoring.

Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): This work was supported by the Pfizer Inc. However, Pfizer Inc. did not have influence on study design, data processing, or statistical analysis.
Prevalence of amyloid transthyretin cardiomyopathy in elderly subjects from the general population: first results from the CATCH study
Authors: Aimo A , Vergaro G , Moscardini S , Puccianti D , Castiglione V , Gentile F , Fabiani I , Barison A , Agazio A , Picerni A , Poggianti E , Taddei C , Arzilli C , Passino C , Emdin M 
Published: October 2022

Abstract

Background
Amyloid transthyretin cardiomyopathy (ATTR-CM) has become treatable. Wild-type ATTR-CM is an age-related disorder. Establishing the exact prevalence of ATTR-CM in elderly subjects from the general population may be useful for healthcare providers and policy makers alike.

Methods
The Characterizing the burden of Amyloid Transthyretin CardiomyopatHy in the elderly (CATCH) study is a population screening on all subjects aged ≥65 years followed by general practitioners working in a part of Tuscany (Italy) where there is no cluster of variant ATTR. The study started on March 12, 2021 and is ongoing. The first step of the evaluation includes clinical history and physical examination, electrocardiogram, transthoracic echocardiogram, and blood sampling with measurement of N-terminal pro-B-type natriuretic peptide and high-sensitivity (hs) troponin T. The following elements are searched: 1) any clinical red flag of amyloidosis (history of carpal tunnel syndrome, lumbar spine stenosis, etc.), 2) interventricular septal thickness ≥12 mm or other echocardiographic red flags, 3) hs-troponin T higher than the upper reference limit (14 ng/L). Patients with any of these elements are referred to a second step including diphosphonate scintigraphy and the search for a monoclonal protein in the serum and urine. The standard diagnostic workup for CA is then followed until the diagnosis is confirmed or discarded.

Results
As of October 13, 2021, 514 subjects ≥65 years have been evaluated for possible participation. Among them, 135 (26%) could not be contacted, were reluctant to enter the study, died before being contacted, or were bedridden. Out of the other 379 subjects, 329 (87%) have already undergone the first step. Forty percent of individuals (n=132) have been referred to the second step. Thirteen subjects have declined (10%); 69 patients have undergone diphosphonate scintigraphy and the search for a monoclonal protein (while the other 50 are awaiting these exams). Two subjects showed an intense myocardial uptake of the diphosphonate tracer (Perugini score 2–3) and no monoclonal protein, and were then diagnosed with ATTR-CM. They were both women, aged 83 and 78 years, both mildly symptomatic for dyspnea (New York Heart Association II) and with unexplained hypertrophy. The search for TTR gene mutation was negative in the first case and is still ongoing in the second. Based on these preliminary data, the prevalence of ATTR-CM in the elderly population can be calculated as 2/266=0.8% (Figure 1).

Conclusions
The CATCH study is expected to enroll at least 1,000 subjects and will provide the first data on the epidemiology of ATTR-CM in elderly subjects. Based on an interim analysis, almost 1 in 100 individuals ≥65 years has ATTR-CM.

Funding Acknowledgement
Type of funding sources: None.
Multi-imaging characterisation of cardiac phenotype in different types of amyloidosis
Authors: Ioannou A , Patel R K , Razvi Y , Porcari A , Knight D , Martinez-Naharro A , Kotecha T , Venneri L , Chacko L , Hawkins P N , Gillmore J D , Fontana M 
Published: October 2022

Abstract

Background
Bone scintigraphy is extremely valuable when assessing patients with suspected cardiac amyloidosis (CA), but the clinical significance and associated phenotype of different degrees of myocardial tracer uptake across different types of amyloidosis is yet to be defined.

Purpose
We sought to define the phenotypes of patients with varying degrees of cardiac uptake on bone scintigraphy, across multiple types of systemic amyloidosis using extensive characterisation comprising of biomarkers, echocardiographic and cardiac magnetic resonance (CMR) imaging.

Methods
A total of 296 patients (117 immunoglobulin light-chain [AL] amyloidosis, 165 transthyretin [ATTR] amyloidosis, 7 apolipoprotein-A1-amyloidosis [AApoAI],and 7 apolipoprotein-A4-amyloidosis [AApoA4]) underwent deep characterisation of their cardiac phenotype.

Results
AL-amyloidosis patients with grade 0 myocardial radiotracer uptake spanned the spectrum of CMR findings from no evidence of CA to characteristic features of CA, while AL-amyloidosis patients with grade 1–3 always produced characteristic CMR features. In ATTR-amyloidosis the CA burden strongly correlated with myocardial tracer uptake (correlation between bone scintigraphy cardiac uptake and CMR derived extracellular volume: R=0.88, 95% CI [0.84–0.91], P&lt;0.001), except in patients with the Ser77Tyr variant. AApoAI-amyloidosis presented with grade 0–1 myocardial tracer uptake, and unique features of disproportionate right sided involvement such as disproportionate right ventricular (RV) and right atrial uptake on bone scintigraphy, RV free wall thickening, and tricuspid valve thickening and dysfunction. Within our cohort, AApoAIV-amyloidosis always presented with grade 0 myocardial tracer uptake, and characteristic features of CA on CMR. All AL-amyloidosis patients with grade 1 myocardial tracer uptake had characteristic CMR features of CA (n=48, 100%), while only ATTR-amyloidosis grade 1 patients with the Ser77Tyr variant had characteristic features of CA on CMR (n=5, 11.4%). Following the exclusion of Ser77Tyr and AApoAI, a CMR showing characteristic features of CA or an extracellular volume &gt;0.40 in a patient with grade 1 myocardial tracer uptake had a sensitivity and specificity of 100% for diagnosing AL-amyloidosis.

Conclusion
Deep characterisation of the cardiac phenotype in different types of amyloidosis, across a range of bone scintigraphy cardiac uptake grades has identified clear differences between each amyloidosis type. The distinctive characteristics in each cohort has allowed the development of a diagnostic pathway to help define the diagnostic differentials and the clinical phenotype in each individual patient, following comprehensive assessment with bone scintigraphy and CMR.

Funding Acknowledgement
Type of funding sources: None.
Unveiling cardiac amyloidosis, its characteristics and outcomes among patients with mitral regurgitation undergoing transcatheter edge-to-edge mitral valve repair
Authors: Nitsche C , Dona C D , Heitzinger G , Mascherbauer K M , Kammerlander A K , Dannenberg V D , Halavina K H , Traub-Weidinger T T W , Puchiner J P , Lamm G L , Hengstenberg C H , Fontana M F , Goliasch G G , Mascherbauer J M 
Published: October 2022

Abstract

Background
Mitral regurgitation (MR) and cardiac amyloidosis (CA) both primarily affect older patients. Data on co-existence and prognostic implications of MR and CA are currently lacking.

Purpose
We aimed to identify prevalence, clinical characteristics and outcomes of MR-CA compared to lone MR.

Methods
Consecutive patients undergoing transcatheter edge-to-edge repair (TEER) for MR were screened for concomitant CA at two Austrian centers using a multi-parametric approach including core-lab 99mTc-DPD bone scintigraphy and echocardiography, and immunoglobulin light-chain assessment. Transthyretin-CA (ATTR) was diagnosed by DPD (Perugini Grade-1: early infiltration; Grades-2/3: clinical CA) and absence of monoclonal protein, and light-chain-(AL)-CA via tissue biopsy. Mass spectroscopy was performed in case of conflicting immunohistochemical results. All-cause mortality and hospitalization for heart failure (HHF) served as composite endpoint.

Results
In total, 120 patients (76.9±8.1 years, 55.8% male) were recruited. Clinical CA was diagnosed in n=14 (11.7%; 12 ATTR, 1 AL, 1 combined ATTR/AL), and early amyloid infiltration in n=9 (7.5%). MR-CA had higher troponin levels, thicker left ventricular walls, and a higher prevalence of carpal tunnel syndrome and left anterior fascicular block compared to lone MR (all p&lt;0.05). Independent predictors of MR-CA were increased posterior wall thickness, and presence of left anterior fascicular block on ECG. Procedural success (MR reduction ≥1 grade) and periprocedural complications of TEER were similar in MR-CA and lone MR (p for all=n.s.).
After a median of 1.7 years, 25.8% had experienced death and/or HHF. MR-CA had worse outcomes compared to lone MR with regard to the composite endpoint (HR 2.2, 95% confidence interval [95% CI] 1.0–4.7, p=0.039), driven by a 2.5-fold higher risk for HHF (HR 2.5, 95% CI 1.1–5.9), but comparable mortality (HR 1.6, 95% CI 0.4–6.1; Graphical abstract).

Conclusions
Dual pathology of MR-CA is common in elderly MR patients undergoing TEER, and has worse post-interventional outcomes compared to lone MR. Given technical feasibility of TEER in MR-CA, valvular repair should be considered as an option to improve forward volume in a state with typically low output. Future studies should evaluate the prognostic benefits of TEER and CA-specific treatment in MR-CA.

Funding Acknowledgement
Type of funding sources: None.
Transthyretin amyloid cardiomyopathy: a 2-year single-centre experience
Authors: Rocha B , Amador R , Maltes S , Marques M , Oliveira C , Lopes P , Cunha G , Paiva M , Strong C , Abreu F , Pintao S , Aguiar C , Mendes M 
Published: October 2022

Abstract

Background
Transthyretin Amyloid Cardiomyopathy (ATTR-CM) is an under-diagnosed condition often presenting with Heart Failure (HF). We aimed to assess a cohort of patients with ATTR-CM and HF, focusing on the centre strategies to identify new cases, prognosticate and tailor treatment.

Methods
We conducted an all-comers single-centre prospective registry of consecutive patients with HF due to ATTR-CM followed in our centre from November 2019 to 2021. As per site protocol, diagnosis is established according to the algorithm by Gilmore et al. and all patients are assessed in our HF outpatient clinic at least twice yearly with systematic electronic chart data collection. We evaluated disease-modifying treatment and compliance with the current European Guidelines and CHAD-STOP management. A summary of this program is presented in the central figure.

Results
Overall, 60 patients were included (mean age 83±7 years; 80% male). ATTR-CM was confirmed by the non-invasive algorithm in all but 8 patients, in whom endomyocardial biopsy was positive. Of those undergoing genetic testing (n=30), 7 (23%) presented with the hereditary form of ATTR-CM (4 Val50Met and 3 Val142Ile mutations). The initial presentation was most often HF (n=43), atrial fibrillation (n=9), or “incidental” myocardial uptake on 99mTc-HMDP bone scintigraphy (grade 2) performed for cancer staging (n=5). Beta-blockers were reduced or stopped in 40 (67%) patients, all of whom improved in NYHA class and/or NT-proBNP (&gt;30% reduction) at 1–3 months. Tafamidis 61mg was started in 22 patients and 15 more currently await approval. Those initiated on or referred to tafamidis 61mg (n=37) had less severe HF, as per NYHA (class I-II – 94 vs. 50%, p=0.033) and performance status (e.g. Karnofsky score 80–100 – 79 vs. 21%, p=0.010). Of those already on tafamidis (n=22), NYHA class remained stable or improved in all but 1 patient. In the year following vs. preceding treatment there was 2 vs. 3 total HF hospitalizations. No drug-related severe adverse events were reported. Over a 2-year follow-up, 14 (23.3%) patients died, of whom 1 was on tafamidis (compassionate use for 19 months).

Conclusions
ATTR-CM recognition is improving in our dedicated rare disease program, possibly due to the implementation of several alert pathways. The identification of the disease at an earlier stage allows targeted treatment, compliant with the recommendations. Nonetheless, the rarity of this disease and the required expertise for its optimal management argues in favour of a national strategic plan based on referral centres for ATTR-CM.

Funding Acknowledgement
Type of funding sources: None.