Wild-type Transthyretin Research Articles

Effects of tafamidis on serial [99mTc]Tc-DPD scintigraphy in transthyretin amyloid cardiomyopathy.

The relevance of repetitive [99mTc]Tc-DPD scintigraphy in wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) remains unclear. We investigated the impact of tafamidis on cardiac [99mTc]Tc-DPD uptake, clinical, and laboratory markers at 6 and 12months, and correlated 12months [99mTc]Tc-DPD uptake regression with survival. This single-center study enrolled 39 ATTRwt-CM patients. Upon treatment initiation with tafamidis, patients underwent follow-up [99mTc]Tc-DPD scintigraphy, and clinical and laboratory evaluations at 6months (n = 6) and 12months (n = 13), or both (n = 20). Tafamidis resulted in a significant decline in Perugini score (6months p = 0.008, 12months p < 0.001), and (semi-)quantitative [99mTc]Tc-DPD uptake (total cardiac uptake: baseline 816 [522-933]cps, vs. 6months 634 [502-734]cps, p = 0.003, vs. 12months 523 [108-754]cps, p = 0.001). Clinical and laboratory improvements were observed (NYHA: 6months p = 0.007, 12months p = 0.033; NT-proBNP: baseline 2586 [1271-5561]ng/L, vs. 6months 2526 [1109-4786]ng/L, p = 0.016, vs. 12months 2340 [1411-4749]ng/L, p = 0.012). In Kaplan-Meier analysis, a decrease in right ventricular [99mTc]Tc-DPD tracer uptake equal to or greater than the median value at 12months (-30%) was associated with improved survival (log-rank p = 0.021). Tafamidis in ATTRwt-CM resulted in significant reductions of cardiac [99mTc]Tc-DPD uptake, NYHA class, and cardiac biomarkers at 6 and 12months. Regression of right ventricular [99mTc]Tc-DPD uptake at 12months was associated with improved survival.

Unusual hypertrophic cardiomyopathy: case report of an early onset wild-type ATTR amyloidosis accompanied by a chromosomal duplication involving the MYH6 and MYH7 gene

BackgroundHypertrophic cardiomyopathy (HCM) is characterized by an increased left ventricular (LV) wall thickness and LV mass. With an estimated prevalence of 1:200–500, HCM is among the most common genetically determined cardiac diseases. Functionally, enhanced tissue stiffness and reduced elasticity, combined with diastolic dysfunction and myocardial fibrosis, can eventually lead to life-threatening arrhythmias and impaired blood flow through the heart chamber. Typical symptoms associated with HCM include atrial fibrillation (AF), syncope, ventricular fibrillation, and cardiac arrest. At the molecular level, various genetic and/or non-genetic etiologies can lead to HCM.Case summaryIn this case, we report on a 60-year-old male patient with severe, progressive hypertrophic cardiomyopathy (HCM) in an uncommon and ambivalent setting. Right ventricular (RV) biopsy and multi-phase skeletal scintigraphy diagnosed transthyretin amyloidosis with cardiac involvement. Sanger sequencing of the transthyretin gene revealed a wild-type sequence. Phenotypically, the patient initially presented with syncopal episodes, atrioventricular (AV) block, and atrial fibrillation. Subsequently, bilateral carpal tunnel syndrome and polyneuropathy developed. However, the progressive and early onset of left ventricular hypertrophy did not align with the typical presentation of HCM in the context of ATTR. Therefore, next-generation sequencing (NGS) analysis revealed a rare chromosomal duplication in both cardiac myosin genes, MYH6 and MYH7. Consequently, two distinct and rare disease entities co-occurred in this patient, both ultimately leading to HCM.DiscussionTo date, no other case featuring wild-type transthyretin amyloidosis (wtATTR) concurrently with a chromosomal duplication affecting both cardiac myosin heavy chain genes has been reported in the literature. This highlights the extreme rarity of this condition, making it challenging to ascertain the extent to which a presumably mutated hybrid myosin gene construct or the TTR amyloid fibrils contribute to stiffness, tissue fibrosis, and cardiac dysfunction. Ultimately, both effects converged in this case, leading to the same cardiac disease with an exacerbated phenotypical outcome of hypertrophic cardiomyopathy (HCM). While early onset wtATTR is an uncommon clinical finding, another significant clinical condition was identified in this patient, marked by an unusual copy number variation (CNV) in the genes MYH6 and MYH7.

A case series of patients with cardiac amyloidosis evaluated at a Colombian university hospital

BackgroundIn Colombia, the characteristics of cardiac amyloidosis (CA)—including wild-type transthyretin amyloidosis (ATTRwt), immunoglobulin light chain amyloidosis (AL), and genetic variant transthyretin amyloidosis (ATTRv)—are underexplored.MethodsThis case series at a Colombian university hospital analyzed demographic, clinical, laboratory, radiological, and genetic data of CA patients diagnosed between 2018 and 2022. Patients with incomplete data underwent further testing.ResultsOf 24 identified patients, 14 were included after exclusions. The majority were male (73.3%), with an average age of 70.6 years. ATTRv and AL were equally prevalent (42.8%), followed by ATTRwt (14.2%). The p.Val142Ile TTR mutation was found among all ATTRv patients. Most presented with functional capacity NYHA I-II and common electrocardiographic findings included low voltage, atrial fibrillation, and first-degree AV block. Echocardiography and cardiac magnetic resonance imaging revealed ventricular hypertrophy, diastolic dysfunction, reduced longitudinal strain, and late myocardial enhancement.ConclusionsAL and ATTRv were the most common causes of CA followed by ATTRwt. This distribution, along with the clinical, and radiological characterization is consistent with previous reports of other regions. The p.Val142Ile mutation was the only one found in patients with ATTRv, suggesting a strong African genetic influence. These findings enhance our understanding of CA in the region.

Cardiac amyloidosis: when to suspect and how to confirm.

Diagnosing cardiac amyloidosis (CA) is challenging because of its phenotypic heterogeneity, multiorgan involvement requiring interaction among experts in different specialties and subspecialties, lack of a single noninvasive diagnostic tool, and still limited awareness in the medical community. Missing or delaying the diagnosis of CA may profoundly impact on patients' outcomes, as potentially life-saving treatments may be omitted or delayed. The suspicion of CA should arise when "red flags" for this condition are present, together with increased left ventricular wall thickness. The diagnosis of CA requires amyloid typing and differentiation between the two most common forms, light chain (AL) and either mutated or wild-type transthyretin cardiac amyloidosis (ATTR-CA), which is critical to guide a specific treatment. Scientific societies worldwide focus on the importance of red flags, and on the prompt initiation of the diagnostic process with bone tracer uptake and the search of a monoclonal protein. An extra-cardiac or endomyocardial tissue biopsy is needed when a monoclonal protein has been detected and/or cardiac bone tracer uptake is absent or weak. Finally, all patients diagnosed with ATTR-CA should undergo genetic testing to search for TTR gene mutations.

Feasibility of the Absolute Quantification and Left Ventricular Segmentation of Cardiac Sympathetic Innervation in Wild-type Transthyretin Amyloidosis Cardiomyopathy with [123I]-MIBG SPECT/CT: the I-NERVE study.

Cardiac sympathetic neuronal dysfunction is an early marker in wild-type transthyretin amyloidosis cardiomyopathy (ATTRwt-CM). [123I]-MIBG imaging evaluates cardiac sympathetic innervation but lacks volumetric activity quantification in current methods. This study aims to quantify cardiac sympathetic neuronal dysfunction in ATTRwt-CM using [123I]-MIBG SPECT/CT and correlate findings with functional and structural cardiac parameters from echocardiogram and cardiac magnetic resonance imaging (CMR). We conducted a single-center, descriptive, cross-sectional study to quantify absolute myocardial sympathetic function in ATTRwt-CM using [123I]-MIBG SPECT/CT. Retrospective reconstruction allowed for absolute tracer-uptake quantification of the left ventricle, overall and segmented, in kBq/mL, SUV and percentage of the injected dose (%ID). Echocardiography, CMR, and bone scintigraphy were performed according to clinical standards. Segmented [123I]-MIBG SPECT/CT values were correlated with global longitudinal strain (GLSS) on echocardiography, native-T1, and extracellular volume (ECV) on CMR using SPECT/CT fused with CMR. Twenty-nine ATTRwt-CM patients (75.8±6.6 years, 90% male) were prospectively included. All exhibited cardiac sympathetic neuronal dysfunction, with a median late heart-to-mediastinum ratio of 1.69[1.45-1.89] and a washout rate of 22.7% (16.4-27.3%). SUVmean, SUVpeak, SUVmax and %ID were 1.80 ± 0.78, 3.84 ± 1.41, 4.46 ± 1.68 and 0.46 ± 0.18 respectively, correlating with semi-quantitative [123I]-MIBG measures. No correlations were found with GLSS on echocardiography or native T1 and ECV on CMR. The current study demonstrates the feasibility of volumetric quantification of [123I]-MIBG SPECT/CT in ATTRwt-CM. SUVmean, SUVpeak, SUVmax and %ID correlate with semi-quantitative measures but not with key cardiac parameters on echocardiography or CMR. This confirms the sensitivity of [123I]-MIBG SPECT/CT to different aspects of cardiac function or pathology. EudraCT ref. 2020-003350-72, retrospectively registered 20 March 2023. https://classic. gov/ct2/show/NCT05776212.

Predictors of mortality by an artificial intelligence enhanced electrocardiogram model for cardiac amyloidosis.

We aim to determine if our previously validated, diagnostic artificial intelligence (AI) electrocardiogram (ECG) model is prognostic for survival among patients with cardiac amyloidosis (CA). A total of 2533 patients with CA (1834 with light chain amyloidosis (AL), 530 with wild-type transthyretin amyloid protein (ATTRwt) and 169 with hereditary transthyretin amyloid (ATTRv)] were included. An amyloid AI ECG (A2E) score was calculated for each patient reflecting the likelihood of CA. CA stage was calculated using the European modification of the Mayo 2004 criteria for AL and Mayo stage for transthyretin amyloid (ATTR). Risk of death was modelled using Cox proportional hazards, and Kaplan-Meier was used to estimate survival. Median age of the cohort was 67 [inter-quartile ratio (IQR) 59, 74], and 71.6% were male. The median overall survival for the cohort was 35.6months [95% confidence interval (CI) 32.3, 39.5]. For AL, ATTRwt and ATTRv, respectively, median survival was 22.9 (95% CI 19.2, 28.2), 47.2 (95% CI 43.4, 52.3) and 61.4 (95% CI 48.7, 75.9) months. On univariate analysis, an increasing A2E score was associated with more than a two-fold risk of all-cause death. On multivariable analysis, the A2E score retained its importance with a risk ratio of 2.0 (95% CI 1.58, 2.55) in the AL group and 2.7 (95% CI 1.81, 4.24) in the ATTR group. Among patients with AL and ATTR amyloidosis, the A2E model helps to stratify risk of CA and adds another dimension of prognostication.

Prognostic impact of hypertension and diabetes in patients with cardiac amyloidosis.

Hypertension and diabetes may increase the risk of adverse events in the general population and patients with cardiomyopathies, however, their role in patients with cardiac amyloidosis (CA) is still unclarified. to evaluate the effect on phenotype and clinical outcomes of hypertension and diabetes in patients with CA. Data from 5 Italian Amyloidosis Referral Centres were used to describe clinical characteristics and outcomes of patients with CA based on the presence of a history of hypertension and diabetes. The study includes 887 patients with CA (311 light chain CA, 87 hereditary transthyretin CA, 489 wild-type transthyretin CA). Median age was 75 years (67-81), and 692 (78 %) were men. Five hundred-seven (57 %) patients had hypertension, 127 (14 %) had diabetes. In multivariable linear regression analysis, hypertension was associated with an increased interventricular septal thickness (coefficient 0.63,95 % CI 0.2-1.06), and augmented E/e' ratio (1.92,95 % CI 0.55-3.29). On Cox regression, diabetes was independently associated with death and heart failure hospitalizations (HR 1.45,95 % CI 1.05-1.99, p = 0.02). Patients with hypertension present a more severe phenotype with increased LV wall thickness and more severe diastolic dysfunction compared to non-hypertensive. The presence of diabetes in this cohort is associated with an increased risk of adverse outcomes.

Differential diagnosis of hypertrophic cardiomyopathy, fabry cardiomyopathy and transthyretin cardiac amyloidosis: insights from right ventricular strain imaging echocardiography

Abstract Introduction Timely differential diagnosis between hypertrophic cardiomyopathy (HCM), Fabry cardiomyopathy (FC) and wild-type transthyretin cardiac amyloidosis (ATTR-CA) is crucial for appropriate treatment and family screening. Right ventricle (RV) involvement is common in these diseases, making the systematic RV assessment essential. Two-dimensional speckle-tracking echocardiography (2D-STE) offers potential for precise RV myocardial mechanics evaluation, however its utility in distinguishing these conditions remains uncertain. Methods This study retrospectively compared matched controls (n=30) with three patient cohorts of nonobstructive HCM (n=30), ATTR-CA (n=30) and FC (n=30) referred to cardiomyopathy consultation between 2014 and 2021. Two blinded researchers independently performed morfofunctional echocardiographic evaluation of RV and 2D-STE analysis of RV myocardial strain. Receiver operating characteristic (ROC) analysis assessed the diagnostic performance of these parameters. Inter- and intra-observer reproducibility used Bland-Altman analysis and intraclass correlation coefficients. Results Male gender predominated in all groups (ATTR-CA 50%; FC 63%; HCM 63%). ATTR-CA patients were older when compared to FC and HCM (Median [IQR]: 84 [5] vs. 64.5 [18.75] vs. 57 [18.25] years, p&amp;lt;0.001) and had higher NT-proBNP (Median [IQR]: 5841 [11742] vs. 467 [1203] vs. 812 [857] pg/ml, p&amp;lt;0.001). ATTR-CA patients had the highest RV wall thickness (RVWT) in comparison to FC (9.0 vs. 7.4 mm, p=0.001) and HCM (9.0 vs. 5.5 mm, p&amp;lt;0.001). Patients with ATTR-CA had lower TAPSE (p=0.001), RV S’ (p=0.001), and RV-FAC values (p=0.003) compared to FC, with no significant differences compared to HCM. RV global longitudinal strain (RV-GLS) and RV free wall strain (RV-FWS) were significantly reduced in ATTR-CA (11.6% ± 4.7 and 15.5% ± 7.6) comparing to FC (19.3% ± 3.2 and 24.7% ± 3.9) and HCM (18.9% ± 3.1 and 25.6% ± 5.2) (p&amp;lt;0.001). RV systolic dysfunction according to RV strain analysis (RV-FWS &amp;lt;23%) led to substantial reclassification and increased prevalence in all groups (ATTR-CA: 37% to 87%; FA 0% to 20%; HCM: 3% to 27%). In ROC analysis, RV-GLS emerged as the most effective parameter for distinguishing ATTR-CA from FC (AUC 0.91; 95% CI 0.81-0.97, p&amp;lt;0.001) with an optimal cut-off of 15.0% yielding 83% sensitivity and 93% specificity. RVWT was the best discriminative parameter for distinguishing ATTR-CA from HCM (AUC 0.98; 95% CI 0.90-0.99, p&amp;lt;0.001; optimal cut-off of 6.5mm; 97% sensitivity, 90% specificity) and FC from HCM (AUC 0.91, 95% CI 0.81-0.97, p&amp;lt;0.001; optimal cut-off of 6.5mm; 83% sensitivity, 90% specificity). RVWT and strain parameters analyses were consistent Intra- and inter-observer with excellent agreement. Conclusion This study underscores the importance of RV thickness and RV-GLS for the differential diagnosis of HCM from phenocopies.

Clinical significance of the estimation of pulmonary-right ventricular uncoupling in patients with transthyretin amyloid cardiomyopathy.

There are few data on the prognostic impact of pulmonary-right ventricular (RV) uncoupling in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). Among the 174 patients who were diagnosed with ATTRwt-CM at Kumamoto University Hospital from 2002 to 2021, 143 patients who met the current Japanese guideline and had sufficient information for two-dimensional speckle tracking echocardiography were retrospectively analysed. During a median follow-up of 1209 days, 39 cardiac deaths occurred. Compared with patients in the non-event group, those in the cardiac death group were significantly older (79.3 ± 6.7 vs. 76.4 ± 6.2, respectively; P < 0.05). Additionally, RV global longitudinal strain (RV-GLS)/systolic pulmonary artery pressure (sPAP), an index of pulmonary-RV uncoupling, was significantly lower in patients in the cardiac death group vs. the non-event group [0.29 (0.18-0.35) vs. 0.40 (0.29-0.57), P < 0.01]. Multivariate Cox proportional hazards regression analysis demonstrated that RV-GLS/sPAP was significantly associated with cardiac death after adjusting for tricuspid annular plane systolic excursion/sPAP (P < 0.01), sPAP (P < 0.05), and conventional prognostic factors including age and hospitalization for heart failure (<0.01), laboratory finding including high-sensitivity cardiac troponin T, and B-type natriuretic peptide (P < 0.01). Receiver operating characteristic analysis showed that the area under the curve for RV-GLS/sPAP for cardiac death was 0.72 and that the best cut off value for RV-GLS/sPAP was 0.34 (sensitivity, 76%; specificity, 65%). In the Kaplan-Meier analysis, patients with ATTRwt-CM who had low vs. high RV-GLS/sPAP (cut-off value 0.34) had a significantly higher probability of cardiac death (P < 0.01). Pulmonary-RV uncoupling has significantly higher prognostic value compared with conventional prognostic factors in ATTRwt-CM.

Epidemiological perspectives of amyloidosis in Argentina: a cohort study analysing incidence and mortality patterns among a population affiliated to a medical care programme

BackgroundData on the epidemiology of amyloidosis are scarce worldwide, making it difficult to understand its true incidence and mortality.AimThe aim of this study is to estimate the incidence and mortality...

Amyloidosis and Heart Transplantation in a New Era.

The prognosis in patients with advanced cardiac amyloidosis (CA) remains poor. We sought to describe survival post heart transplantation (HT) in amyloid compared with non-amyloid recipients, highlight waitlist times within the new allocation system across three Organ Procurement and Transplantation Network (OPTN) regions, and describe multiorgan transplantation (MOT) in hereditary amyloidosis. This is a retrospective review of end-stage CA patients who underwent HT at Mayo Clinic from January 2007 to December 2020. Wait time was compared in the new versus old OPTN allocation era starting December 18, 2018 by Wilcoxon rank sum test. All-cause mortality for those with and without CA was compared using Kaplan-Meier estimates with log rank analysis, censoring December 16, 2022. Fifty-five patients with CA underwent HT between 2007 and 2020, 8 light chain amyloidosis (AL) (14.5%), 28 hereditary transthyretin (ATTRv) (50.9%), 17 wildtype transthyretin (ATTRwt) (30.9%), and 2 hereditary apolipoprotein A1 (AApoA1) amyloidosis patients (3.6%). No significant difference in overall survival post-transplant was seen in amyloid compared with non-amyloid (p = 0.816). Median time to HT was shorter in the new system, 45 days (IQR 24, 78) versus 174 days (IQR 76.5, 483.5), p = 0.006. There was a decline in MOT in hereditary amyloidosis over time with the concomitant rise in disease-targeted therapies. HT survival in CA patients was similar to non-amyloid patients. The new allocation system benefits this cohort with shorter wait times. There is less MOT in hereditary amyloidosis with increased utilization of disease-targeted therapy.

Prognosis of patients with wild-type transthyretin cardiac amyloidosis and non-sustained ventricular tachycardia.

Little is known regarding the prevalence and prognostic implications of non-sustained ventricular tachycardia (NSVT) in patients with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA). We aimed to investigate the prevalence of NSVT in patients with ATTRwr-CA, and the association of NSVT with sustained ventricular arrhythmias (VA) and all-cause mortality. In a cohort of ATTRwt-CA patients from 2011 to 2022 without prior sustained VA, we ascertained the presence and characteristics of NSVT during clinically indicated ambulatory Holter monitoring. Patients were stratified based on the presence of NSVT at baseline. The primary and secondary endpoints of sustained VA and all-cause mortality, respectively, were assessed during follow-up. The cohort included 217 patients with ATTRwt-CA (95% males, median age 75 years; median NYHA class 2). Baseline Holter monitoring demonstrated NSVT in 116 (53%) patients. During a median follow-up of 27 months (IQR 16-45) after the index Holter monitor, 11 (5.1%) patients reached the primary endpoint of sustained VA (incidence 1.8 per 100 person-years, all monomorphic VT), and 46 (21%) patients died. In univariable Cox proportional hazard model, NYHA class 3 or 4 heart failure (p = .048), the presence of NSVT (p = .04), the duration of longest NSVT run (p = .029), and the percentage of ventricular ectopy (p < .001) were associated with the primary outcome. When adjusting for age and NYHA class 3 or 4 heart failure, the presence of NSVT remained associated with the primary outcome (p = .03). All-cause mortality was not significantly different between patients with and without NSVT. A cutoff for ventricular ectopy burden of 0.5%, the median for all patients in this study, was associated with increased risk in sustained VA (log-rank p = .004) and mortality (log-rank p = .02). NSVT is highly prevalent among ATTRwt-CA patients undergoing clinically indicated Holter monitoring and may confer an increased risk of incident sustained VA.

Prospective Multicenter Screening With High-Sensitivity Cardiac Troponin T for Wild-Type Transthyretin Cardiac Amyloidosis in Outpatient and Community-Based Settings

High-sensitivity cardiac troponin T (hs-cTnT) was proposed as a simple and useful diagnostic tool for cardiac amyloidosis (CA). We performed exploratory systemic screening using hs-cTnT to detect wild-type transthyretin CA (ATTRwt-CA) in outpatient and community-based settings. This study was a prospective multicenter study including 8 internal medicine clinics in Kochi Prefecture, Japan. Consecutive individuals aged ≥70 years who visited those clinics as outpatients were enrolled. Patients with a prior diagnosis of CA or a history of heart failure hospitalization were excluded. We measured hs-cTnT levels in the enrolled individuals at each clinic, and those with elevated hs-cTnT levels (≥0.03ng/mL) received further detailed examination, including remeasurement of hs-cTnT. The diagnosis of ATTRwt-CA was confirmed by biopsy-proven transthyretin. Of 1,141 individuals enrolled in the study, 55 (4.8%) had elevated hs-cTnT levels. Of the 33 patients who underwent further examination, 22 had elevated hs-cTnT levels at remeasurement. Finally, 2 men were diagnosed with ATTRwt-CA. The prevalence of ATTRwt-CA was 9.1% (2/22) among patients with elevated hs-cTnT levels at two examinations, and at least 0.18% (2/1,141) in the whole study population. Measurement of hs-cTnT will help to screen for patients with undiagnosed ATTRwt-CA in primary care practice.

Predictors of Early Death in Patients With Wild-Type Transthyretin Cardiac Amyloidosis.

For the time being, tafamidis is the only approved treatment for wild-type transthyretin cardiac amyloidosis. However, benefits on all-cause death only emerge after ≈18 months. The current available staging systems are unable to specifically discriminate patients at high risk of death within 18 months from diagnosis, and the selection of patients who are expected to benefit from tafamidis is left to the clinical judgment of treating physicians, being often based primarily (and sometimes only) on age. We searched baseline variables able to discriminate patients at risk of death within 18 months. We randomly divided our prospectively maintained database in 2 cohorts, a testing (two thirds) and a validating (one third) set, respectively. We used the Eastern Cooperative Oncology Group-Performance Status as a simple scoring of frailty. We analyzed the clinical, laboratory and instrumental features of 691 consecutive wild-type transthyretin cardiac amyloidosis patients diagnosed between 2006 and 2021. Median follow-up was 43 months, and 367 patients (53%) died. Eighteen-month death was predicted by NT-proBNP (N-terminal pro-B-type natriuretic peptide; cutoff 4200 ng/L), cardiac troponin I (cutoff 92 ng/L), and age (cutoff 80 years). At multivariable analysis, Eastern Cooperative Oncology Group-Performance Status >1 along with the selected variables were independent prognostic determinants and outperformed New York Heart Association functional class. The combination of these variables identified standard- and high-risk patients (all variables above the cutoffs) with a median survival of 57 and 17 months, respectively (P<0.001). This was confirmed in the validation set. A simple scoring system including age, cardiac biomarkers, and Eastern Cooperative Oncology Group-Performance Status identifies subjects with cardiac wild-type transthyretin cardiac amyloidosis at high risk of early death.

Right ventricular coupling predicts cardiopulmonary fitness in cardiac transthyretin amyloidosis.

Wild-type transthyretin cardiac amyloidosis (ATTRwt) is an infiltrative disease leading to restrictive cardiomyopathy. We aimed to characterise exercise capacity in ATTRwt and to identify predictors of cardiopulmonary fitness, focusing on echocardiographic and clinical parameters. We studied 110 ATTRwt patients from a prospective single-centre registry (2020-2024) by cardiopulmonary exercise testing (CPET). Besides CPET, all patients underwent comprehensive clinical assessment including follow-up for mortality. In 32 patients follow-up CPET after 1 year was available. In ATTRwt, reduced aerobic capacity (pVO2 16 [13-18] ml/kg/min), and ventilatory inefficiency (VE/VCO2 slope 35 [30-43]) were common. In the multivariable regression analysis, we identified TAPSE/sPAP ratio as predictive for pVO2 (p = 0.019) and ventilatory efficiency (p = 0.004), while left ventricular ejection fraction or measures of left ventricular hypertrophy were not predictive. Concordantly, TAPSE/sPAP ratio assessed at baseline predicted pVO2 at 1-year follow-up (p = 0.009). Furthermore, patients with a TAPSE/sPAP ratio below the median of 0.38 mm/mmHg presented a higher risk of all-cause death (p = 0.009). In ATTRwt the TAPSE/sPAP ratio, a marker of right ventricular coupling, was an independent predictor of aerobic capacity assessed by CPET, at baseline and after 1 year, highlighting the importance of right ventricular assessment for risk stratification.

Multiple Red Flags of Cardiac Amyloidosis in a Single Patient: Clinical Manifestations of an Underdiagnosed Disease.

Cardiac transthyretin amyloidosis is an underdiagnosed disorder with significant diagnostic difficulties due to its non-specific clinical manifestations. It is caused by the deposition of protein aggregates with an abnormal tertiary structure in the extracellular matrix. Their accumulation leads to the development of hypertrophic and restrictive cardiomyopathy and, at a later stage, heart failure with preserved ejection fraction syndrome. Depending on the pathogenesis, there are different types of the disease-hereditary and age-related wild-type transthyretin amyloidosis. We present the case of an 85-year-old woman who was referred to the department with a two-month history of exertional dyspnea in New York Heart Association functional class II. After reviewing the initial findings, several red flags for cardiac amyloidosis (CA) were identified. Following the diagnostic algorithm, scintigraphy was performed and showed significant radioisotope accumulation in the myocardium, confirming the suspected disease. In this manuscript, we present the current recommendations and diagnostic pathway, discussing in detail both available and emerging treatment options. As early diagnosis is essential to prevent the development of serious complications, we would like to highlight the pitfalls in diagnosing CA and emphasize the need to be aware of its variable clinical presentation and red flags.

Progression and prognostic significance of electrocardiographic findings in patients with cardiac amyloidosis.

This study aimed to evaluate the change of the main electrocardiographic (ECG) characteristics and their prognostic role across the main subtypes of cardiac amyloidosis [light-chain amyloidosis (AL) and hereditary (ATTRv) and wild-type transthyretin amyloidosis (ATTRwt)]. This multicentre, retrospective study was performed in six referral centres for cardiac amyloidosis. Clinical and ECG data were collected at the first and last evaluations. Three hundred fifty-six patients were included (AL, n=105; ATTRv, n=50; ATTRwt, n=201). The median age was 76 (67-81) years, and 271 (74%) were men. At baseline, patients with ATTRwt showed a higher prevalence of conduction abnormalities compared with those with AL [first-degree atrioventricular block, n=51 (40%) vs. n=13 (34%), P<0.01; left bundle branch block, n=23 (11%) vs. n=2 (2%), P<0.01], and patients with AL more often had low QRS voltage [n=58 (55%); in ATTRv, n=17 (34%); in ATTRwt, n=67 (33%), P value<0.01] and T wave inversion compared with those with ATTR [n=39 (37%); in ATTRv, n=9 (18%); in ATTRwt, n=37 (18%)]. After a median follow-up of 15 (8-26) months, the adjusted differences in mean PR, QRS interval, total, peripheral, and precordial QRS scores were similar across subtypes of amyloidosis (P value for linear regression>0.05). The adjusted odds ratios for the development of right bundle branch block were higher in AL compared with ATTRwt [odds ratio 4.7 (95% confidence interval 1.5-15), P<0.05]. QRS duration at baseline remained independently associated with patient survival in the overall population even after adjustment for relevant clinical variables [hazard ratio 1.78 (95% confidence interval 1.13-2.8), P<0.01]. The progression of the ECG abnormalities seems similar across amyloidosis subtypes. QRS duration could be a marker of more advanced disease.

The effect of trimetazidine on cardiac haemodynamics and mitochondrial function in wild-type transthyretin amyloidosis.

Wild-type transthyretin cardiac amyloidosis (ATTRwt) is a cardiomyopathy causing myocardial hypoperfusion and impaired cardiac mitochondrial function. Trimetazidine is an antianginal agent used in patients with stable angina pectoris, which improves cardiac contractility and mitochondrial function. The aim of the study was to investigate the effect of trimetazidine on invasive haemodynamics and cardiac mitochondrial function in ATTRwt. In a randomized, double-blind, placebo-controlled, crossover trial, 22 patients with ATTRwt received 4weeks of trimetazidine and placebo in randomized order. After each treatment period followed examinations with endomyocardial biopsies taken for high-resolution respirometry and right heart catheterization at rest and during a cardiopulmonary exercise test. The primary endpoint was mean pulmonary artery wedge pressure (mPAWP) during peak exercise. The secondary endpoint was cardiac mitochondrial oxidative phosphorylation capacity. Exploratory endpoints were echocardiographic parameters, cardiac biomarker levels and quality of life. Trimetazidine did not significantly reduce mPAWP during peak exercise (31±12 vs. 31±13mmHg, P=0.61) or improve the cardiac mitochondrial oxidative phosphorylation capacity (73.4±7.7 vs. 75.3±7.7pmol O2/(mg*s), P=0.81) compared with placebo, nor did treatment with trimetazidine improve ejection fraction (P=0.93), global longitudinal strain (P=0.23), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (P=0.92) or the patients' quality of life (P=0.98). In ATTRwt, treatment with trimetazidine did not improve mPAWP or cardiac mitochondrial oxidative phosphorylation capacity compared with placebo.

Cardiac Elastography with External Vibration for Quantification of Diastolic Myocardial Stiffness.

Heart failure is an increasing global health problem. Approximately 50% of patients with heart failure have preserved ejection fraction (HFpEF) and concomitant diastolic dysfunction (DD), in part caused by increased myocardial stiffness not detectable by standard echocardiography. While elastography can map tissue stiffness, cardiac applications are currently limited, especially in patients with a higher body mass index (BMI). Therefore, we developed cardiac time-harmonic elastography (THE) to detect abnormal diastolic myocardial stiffness associated with DD. Cardiac THE was developed using standard medical ultrasound and continuous external vibration for regionally resolved mapping of diastolic shear wave speed (SWS) as a proxy for myocardial stiffness. The method was prospectively applied to 54 healthy controls (HC) (26 women), 10 patients with moderate left ventricular hypertrophy (mLVH) (5 women) and 45 patients with wild-type transthyretin amyloidosis (wTTR) (4 women), 20 of whom were treated with tafamidis. 10 healthy participants were re-investigated after 2-6 months to analyze test-retest reproducibility by intraclass correlation coefficients (ICC). Myocardial SWS was measured with good reproducibility (ICC=0.82) and showed higher values in wTTR (3.0±0.7 m/s) than in mLVH (2.1±0.6 m/s) and HCs (1.8±0.3 m/s, all p<0.05). Area-under-the-curve values were 0.991 and 0.737 for discriminating wTTR and mLVH from HCs, respectively. SWS was reduced in patients after tafamidis treatment (2.6±0.6 m/s, p=0.04), suggesting the potential value of THE for therapy monitoring. SWS was quantified in the septum, posterior wall and an automatically masked region (here stated for the septal region). Cardiac THE detects abnormal myocardial stiffness in patients with DD with high penetration depth, independent of BMI and region selection. Based on standard ultrasound components, cardiac THE is cost effective and has the potential to become a point-of-care method for stiffness sensitive echocardiography.

Wild-type transthyretin cardiac amyloidosis and aortic stenosis: Can carpal tunnel syndrome help distinguish the chicken from the egg?

The frequent association between transthyretin wild-type (TTRwt) cardiac amyloidosis (CA) and aortic stenosis (AS) suggests a bidirectional relationship: TTRwt-CA could induce AS and vice versa. Systemic manifestations may highlight this interaction: systemic amyloidogenesis would lead to systemic symptoms, CA, and AS, whereas the myocardial stresses induced by degenerative AS might promote local amyloidogenesis without systemic symptoms. Carpal tunnel syndrome (CTS) is the most frequently reported extracardiac symptom. Through a comparison of TTRwt-CA patients with and without CTS, we sought to determine whether CTS serves as a reliable indicator of systemic involvement and its impact on cardiac and valvular characteristics. A total of 411 consecutive patients with TTRwt-CA were included. CTS, present in 70.3%, was associated with a younger age (80 vs. 84 years, p<0.001), more extracardiac symptoms, and advanced CA, with greater cardiac remodeling and a higher heart-to-mediastinum ratio (1.63 vs. 1.54; p=0.012) compared to patients without CTS. AS was present in 21% and 31% of patients with and without CTS, respectively (p=0.024). Except for AS, these associations remained significant after adjusting for confounding factors. In severe AS, patients with CTS exclusively exhibited low-flow low-gradient (LFLG) AS and less severe class of aortic valvular calcium score (5.6% vs. 60%; p=0.006) compared to those without CTS. Our findings suggest that CTS may delineate two phenotypes in TTRwt-CA: a systemic phenotype associated with advanced CA and poorly calcified LFLG AS, and a cardiac phenotype characterized by less severe CA and a mixed pattern of highly calcified AS, suggesting disparate pathophysiologies.