“Cardiomyopathy refers to a myocardial disorder characterized by structural and functional abnormalities in the heart muscle. This condition manifests without the presence of coronary artery disease (CAD), hypertension, valvular disease, or congenital heart disease (CHD) that would typically account for the observed myocardial abnormalities.” This situation, therefore, represents a common crossroad in which many pathologies (cardiac-specific, systemic, familial, acquired disease) that can affect the heart will lead. Advances in knowledge in fields as diverse as genetics, biology, pathological anatomy, and imaging techniques have been expanding the complex of diseases that can cause cardiomyopathy, defining new entities or the underlying substrate of some that were previously of unknown cause. Beyond these multiple entities and etiological mechanisms, the various cardiomyopathies converge in the way they manifest in the heart and, in this sense, previous statements already proposed classifying them based on both anatomical and functional modifications [10]. The 2023 ESC Guidelines for the management of cardiomyopathies are new guidelines introduced to tackle all the multidimensional aspects of the disease in a single document covering all the patient journey, from the first onset, through initial assessment and diagnosis, to management, highlighting the importance of a multiparametric approach. The concept of the phenotype-based approach is reinforced and five main cardiomyopathies are defined: hypertrophic (HCM), dilated (DCM), non-dilated left ventricular (NDLVC), arrhythmogenic right ventricular (ARVC), and restrictive (RCM) [8]. Non-invasive imaging, including ultrasound-based techniques, cardiac magnetic resonance imaging (CMR), CT, and nuclear techniques ([18F]FDG PET/CT and bone scintigraphy, represent the backbone of the diagnosis and the follow-up strategy since they allow the assessment of both cardiac morphology and function.

In this context, one of the diseases in the spotlight of the nuclear medicine community is cardiac amyloidosis. Cardiac amyloidosis may share the phenotype of hypertrophic cardiomyopathy and restrictive cardiomyopathy. The diagnosis might be reach using invasive and non-invasive diagnostic criteria, this latter being accepted only for transthyretin amyloidosis (ATTR). The demonstration of amyloid fibrils within samples of cardiac or extracardiac tissues and the typical imaging features of cardiac amyloidosis on echocardiography or CMR are the diagnostic pillars of AL amyloidosis. In patients with clinical suspicion (the so-called red flags), suggestive imaging findings at ECHO and/or CMR, and exclusion of monoclonal protein, the demonstration of grade 2 or 3 myocardial uptake at SPECT/CT with bone seeking radiopharmaceuticals (i.e., 99mTc-pyrophosphate (99mTc-PYP), 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD), or hydroxymethylene diphosphonate (99mTc-HMDP)) allows a definitive diagnosis of cardiac ATTR. Bone scintigraphy has a class I recommendation for the diagnostic work-up in patients suspected of cardiac amyloidosis [11]. False negative scans may rarely occur in certain hereditary ATTRv genotypes and early stages of the disease, while false positives may be due to AL long-term chloroquine use, recent myocardial infarction, or excessive intracardiac blood-pool activity (due to early acquisitions or improper radiopharmaceutical preparation). The uptake of bone seeking radiopharmaceuticals is present in both wild-type and mutated ATTR; therefore, TTR genetic testing is mandatory and recommended in all ATTR cardiomyopathy regardless of age since 5% of men older than 70 years (and 10% of women) have ATTRv.

Specific amyloid PET tracers are currently under investigation, but not yet a clinical standard [12]. Amyloidosis is an emerging area of therapeutic developments with several new drugs in the phase of research and early clinical use, such as new TTR stabilizers, TTR silencers, and TTR degraders, the latter having the potential to reverse the disease process and even restore cardiac function. However, the guidelines are not currently providing any recommendations for cardiac amyloidosis patients’ follow-up and therapy monitoring by nuclear imaging procedures.

Another setting where [18F]FDG PET have demonstrated an invaluable role is the identification of myocardial inflammation due to active cardiac sarcoidosis and other atypical forms of myocarditis. However, it should be underlined that a positive [18F]FDG PET is not specific for active sarcoidosis unless other inflammatory cardiomyopathies and physiologic myocardial uptake are ruled out. On the contrary, a negative PET scan does not exclude the presence of inactive/chronic form of sarcoidosis. Therefore, in the 2023 ESC Guidelines, [18F]FDG PET has a class IIa level C recommendation in the diagnostic work-up of patients with cardiomyopathy in whom cardiac sarcoidosis is suspected. Although of value in patient follow-up, monitoring cardiac sarcoidosis with [18F]FDG PET is not currently part of the indication of the current ESC Guideline. However, the combination of CMR and PET findings can be synergistic, and PET-MR will surely play an important role in the future in this context.

Despite the assessment of microvascular dysfunction with H215O or 13NH3 rest/stress PET might play an important role as predictor of adverse outcome [13] in patients with HCM, DCM, and Anderson–Fabry disease, those imaging modalities are not currently included as a mean to reach an aetiological diagnosis (e.g., in distinguishing phenocopies) and are still confined to the research setting.

Nuclear medicine has evolved to a more consolidated role in the field of cardiac imaging, positioning with full title existing validated techniques in the international clinical guidelines, a pivotal step for our community. New developments are already at the horizon and will secure further improvements. As examples, the long-axial field-of-view (LAFOV) digital PET/CT systems enabling a larger anatomical coverage and a significant increase in system sensitivity [14] would facilitate the evaluation of diseases that are not confined to a single organ, rather involving the hearth as part of a more complex systemic diseases. Artificial intelligence is already a reality, potentially impacting on the value of [18F]FDG PET/CT in PVE diagnosis [15]. Therefore, let us get ready to become even more mature soon.