Cardiac transthyretin amyloidosis (ATTR-CA) is no longer a rare and silent entity but has rather become a diagnostic and therapeutic challenge for modern cardiology. We know that the extracellular deposition of misfolded amyloid protein in cardiac tissue has a significant impact on ventricular function. The article by Carvelli MV et al. invites us to look beyond amyloid deposition and explore its relationship with myocardial flow reserve (MFR) and global longitudinal strain, thereby evaluating the functional dimension that could predict ventricular deterioration. (1)

Previous literature has documented microvascular dysfunction in amyloidosis and other infiltrative cardiomyopathies using various noninvasive techniques, including positron emission tomography, the gold standard, (2,3)cardiac magnetic resonance imaging, transthoracic Doppler echocardiography, and contrast-enhanced echocardiography.

Using cadmium-zinc-tellurium (CZT-SPECT) detectors, the authors achieved simultaneous assessment of perfusion and amyloid distribution with a resolution that redefines the limits of nuclear imaging. The finding of reduced MFR in patients with ATTR-CA, even in the absence of epicardial coronary artery disease, supports the hypothesis that microvascular dysfunction is a key pathophysiological mechanism. (4) However, the most striking aspect of the study is what was not found: no correlation between the magnitude of amyloid deposition, global longitudinal strain and MFR.

This result invites us to rethink the paradigm. Is amyloid deposition the only relevant factor in the functional progression of the disease? Or are we facing a more complex interaction between inflammation, extrinsic compression, and tissue toxicity? The homogeneous distribution of amyloid observed in polar maps challenges the classic "Japan flag plot pattern" and suggests that functional deterioration may precede or even be independent of structural compromise.

The study also introduces a methodological innovation: the measurement of MFR using CZT-SPECT, an accessible, reproducible, and noninvasive technique. In this context, MFR emerges not only as a physiological marker but also as a potential tool to inform prognostic stratification and therapeutic follow-up. A reduction in MFR could anticipate symptoms of angina and functional deterioration or guide the initiation of specific therapies such as tafamidis.

In line with this perspective, it is worth mentioning the AMYTRE protocol, (5) conducted by Bastien Vançon et al., which aims to confirm coronary microvascular dysfunction and evaluate the effect of tafamidis on it. The primary outcome will be the variation of stress and rest myocardial blood flow and MFR between baseline and 24 months after tafamidis treatment.

In conclusion, this study marks a turning point in ATTR-CA research, despite its limited sample size. It reminds us that seeing the deposition is not enough; we must also understand its functional impact. The future of cardiology will combine diagnostic accuracy with physiological sensitivity. This paper is a significant step in that direction, inviting further exploration of the heart beyond its anatomy.