Raquel Machado

Myocardial fibrosis is a major pathological component of cardiac remodelling and contributes to ventricular stiffness, impaired myocardial function, heart failure progression, and arrhythmic vulnerability across a broad spectrum of cardiomyopathies. In hypertrophic cardiomyopathy (HCM), fibrotic remodelling encompasses both diffuse interstitial matrix expansion and focal replacement fibrosis and is closely associated with disease severity and adverse clinical outcomes. Cardiac magnetic resonance (CMR), using late gadolinium enhancement (LGE) and quantitative parametric mapping, is central to non-invasive myocardial tissue characterization. LGE primarily identifies focal areas of replacement fibrosis and scar, whereas native T1, T2, and extracellular volume (ECV) mapping provide complementary information on diffuse myocardial and interstitial tissue abnormalities, including extracellular matrix expansion. However, these techniques characterize the structural and tissue-level consequences of myocardial injury and remodelling rather than directly visualizing the cellular processes underlying fibroblast activation. Fibroblast activation protein inhibitor positron emission tomography (FAPI PET) has emerged as a promising molecular imaging approach for assessing active fibroblast-mediated tissue remodelling. By targeting fibroblast activation protein (FAP), a cell-surface serine protease upregulated in activated fibroblasts and myofibroblasts. FAPI radiotracers may provide a molecular readout of accessible FAP expression that complements structural and tissue characterization by CMR. This review examines the cellular and molecular mechanisms underlying active myocardial remodelling, with particular emphasis on transforming growth factor-β1 (TGF-β1)/Smad signalling, fibroblast-to-myofibroblast transition, FAP expression, and extracellular matrix turnover. We critically evaluate the current clinical evidence for FAPI PET/CT and hybrid PET/CMR across cardiomyopathies, focusing on HCM while also considering ischemic, inflammatory, infiltrative, and other non-ischemic forms of cardiac remodelling. Particular attention is given to the relationship between myocardial FAPI uptake, CMR tissue characterization, ventricular function, circulating biomarkers, and calculated arrhythmic risk. Although initial studies support the complementary value of FAPI PET and CMR for characterizing active and established myocardial remodelling, the available evidence remains limited by small, predominantly single-centre cohorts, heterogeneous radiotracers and acquisition protocols, and the absence of validated quantitative thresholds or prospective outcome data. Larger longitudinal studies are required to determine whether FAPI PET can provide incremental prognostic information or serve as a reproducible imaging biomarker for disease progression and therapeutic response.

Background/Objectives: Idiopathic carpal tunnel syndrome (CTS) can frequently precede the clinical diagnosis of transthyretin cardiac amyloidosis (ATTR-CA). This study aimed to comprehensively characterize the standard and advanced echocardiographic phenotype in a screening cohort of patients with CTS assessed for concurrent ATTR-CA. Methods: Thirty-three patients with idiopathic CTS underwent comprehensive standard and advanced echocardiography. The presence of concurrent ATTR-CA was assessed using ^99mTc-DPD scintigraphy, allowing the stratification of the cohort into an amyloidosis group and a non-amyloidosis control group for comparative analysis. Results: Based on scintigraphy, 8 patients (24.2%) were diagnosed with presumptive ATTR-CA, acknowledging that AL amyloidosis was not systematically excluded, while 25 served as scintigraphy-negative controls. Standard echocardiography revealed greater wall thickness and worse diastolic function (p < 0.001) in the scintigraphy-positive group. Advanced imaging demonstrated profound left ventricular (LV) mechanical dysfunction, with severely reduced global longitudinal strain (p < 0.001) and a high prevalence of apical sparing (p < 0.001). Non-invasive myocardial work (MW) analysis showed a marked reduction in Global Constructive Work (p = 0.005) and Global Work Index (p = 0.017) in scintigraphy-positive patients, despite a relatively preserved LV ejection fraction. Multi-chamber strain analysis unmasked a pan-cardiac myopathy in the amyloid group, characterized by severe impairment of right ventricular (RV) global strain (p = 0.004) and profound depression of both left (p = 0.002) and right (p < 0.001) atrial reservoir strains. Conclusions: In patients with CTS, positive scintigraphy is characterized by severe, afterload-adjusted LV mechanical failure and profound biatrial and RV dysfunction. Advanced multi-chamber strain and MW indices show potential as non-invasive markers to help identify previously unrecognized pan-cardiac amyloid infiltration, guiding prompt diagnostic referral.

Background/Objectives: Idiopathic Carpal Tunnel Syndrome (CTS) can be an early manifestation of systemic amyloidosis, particularly transthyretin cardiac amyloidosis (ATTR-CA). The primary purpose of this retrospective case series was to describe the presence of amyloid deposits in tenosynovial tissue and explore potential cardiac involvement in patients undergoing carpal tunnel release surgery. Methods: From a cohort of 54 patients diagnosed with bilateral idiopathic CTS with surgical indication, 12 patients were selected for tenosynovial tissue samples, which were subsequently evaluated using Congo red staining and proteomic confirmation via mass spectrometry. Before the procedure, patients underwent a clinical assessment of medical history, electrocardiogram, and cardiac scintigraphy with Technetium-99 m 3,3-diphosphono-1,2-propanodicarboxylic acid (^99mTc-DPD). Transthoracic echocardiogram and cardiac magnetic resonance were subsequently performed in all patients with positive scintigraphy, while a subset of scintigraphy-negative patients underwent an echocardiogram. Results: Congo red staining identified amyloid deposits in 3 of the 12 patients (25%). Proteomic analysis confirmed ATTR amyloidosis deposits in 2 of these patients (17%). One of these 2 patients presented Perugini grade 3 uptake on cardiac scintigraphy, suspicious for ATTR-CA. Complete concordance across histology, proteomics, and cardiac imaging was observed in only 1 patient (8.3%). Three discordances were noted: one case of tenosynovial ATTR without evident cardiac disease, one patient with a discordant Congo red result likely reflecting low amyloid burden or tissue heterogeneity, and one with imaging findings suspicious for ATTR-CA despite a negative tenosynovial biopsy. Conclusions: Tenosynovial biopsy obtained during CTS surgery can reveal early amyloid deposition, which may precede overt cardiac involvement. The variability observed across findings underscores the need for a multimodal diagnostic approach that integrates histological, proteomic, and imaging data, thereby mitigating the risk of amyloidosis misclassification.

Background/Objectives: Fabry disease (FD) is a rare X-linked disease caused by the deficient activity of the enzyme α-galactosidase A. Cardiac involvement is particularly critical, often determining the disease prognosis. Epidemiological data on FD in Portugal are limited and inconsistent, highlighting the need for targeted screening. The F-CHECK study aimed to determine the prevalence of FD through the systematic screening of a Portuguese cohort of patients with unexplained cardiomyopathies. Methods: This multicenter observational study (NCT05409846) assessed the prevalence and clinical characteristics of FD in a Portuguese cohort (n = 409) of patients from 10 central hospitals who presented with unexplained cardiomyopathies, including idiopathic hypertrophic cardiomyopathy (HCM), left ventricular hypertrophy, dilated-phase HCM, and dilated cardiomyopathy with late gadolinium enhancement in the inferolateral segment. Screening was performed using dried blood spot assays to measure α-galactosidase A activity and/or by GLA gene sequencing in whole-blood samples. Results: FD was diagnosed in 14 patients, corresponding to a prevalence of 3.4%. FD diagnosis was significantly associated with systemic manifestations such as acroparesthesias (p = 0.027) and angiokeratomas (p = 0.003), as well as an increased risk of prior arrhythmic events (p = 0.021) and cerebrovascular disease (p = 0.016). Most FD patients (57%) presented a non-founder mutation in the GLA gene; however, they were pathogenically relevant. Conclusions: The observed 3.4% prevalence highlights the importance of systematic FD screening among Portuguese patients with unexplained cardiomyopathy, extending beyond classic hypertrophic presentations to dilated forms. Specific clinical signs, electrocardiogram findings, and cardiac imaging features can serve as valuable indicators to guide targeted genetic testing for FD.