Systemic amyloidoses comprise a growing group of disorders caused by the extracellular deposition of misfolded proteins in various organs such as heart, liver, kidney, skin, eyes, lungs, and nervous system, thereby resulting in different clinical manifestations [1]. Cardiac involvement varies among types of amyloidosis, most commonly found in immunoglobulin light chain (AL) and transthyretin (ATTR) amyloidosis [2]. Infiltration of the human heart by amyloid deposits is associated with a high morbidity and poor prognosis [3, 4]. Therefore, diagnosis of cardiac involvement at the early stages and initiation of a targeted therapy (if possible) may tremendously affect individual prognosis.

Cardiac amyloidosis (CA) is characterized by rapid progressive heart failure, arrhythmias, orthostatic dysregulation, and conduction abnormalities [5]. Due to the accumulation of amyloid in the myocardial interstitium, relaxation and compliance of the heart muscle are impaired, resulting in a restrictive form of cardiomyopathy [6, 7] that is also called “stiff heart” syndrome [8]. Noteworthy, amyloid fibrils cannot only deposit in the atrial and ventricular walls, in the valves and the conduction system, but also accumulate in the vessel walls of the coronary and microvascular system [9]. In this context, infiltration and accumulation of amyloid in coronary vessel walls may result in impaired vasodilation, microinfarction, luminal obliteration, and eventually reduced myocardial perfusion [10].

In contrast to CA, other forms of hypertrophic cardiomyopathy (HCM) are more frequent [11]: In particular, “conventional” HCM that is mostly caused by mutations in genes encoding proteins of the cardiac sarcomere is an important differential diagnosis in patients with hypertrophied left ventricles not caused by arterial hypertension [12]. Patients with such “conventional” HCM forms can be either asymptomatic or show symptoms of heart failure (HF), chest pain, or arrhythmias [13]. Histologically, “conventional” HCM forms are characterized by myocardial fibrosis, disarray, and small vessel disease [14]. Noteworthy, cellular architecture is disorganized [15], and different patterns of fibrosis may occur including perivascular fibrosis and microscopic replacement scars as a result of silent microvascular ischemia leading to cell death [16, 17].

Cardiovascular magnetic resonance (CMR) plays an important role in the diagnosis and differentiation of both pathological entities (CA and HCM) that are characterized by hypertrophied ventricular walls. In case of CA, late gadolinium enhancement (LGE) imaging reveals a characteristic pattern of diffuse LGE starting from the subendocardial layer of the myocardium and eventually involving all myocardial layers and segments [18‐22]. In contrast, the “conventional” HCM is characterized by a focally accentuated, rather patchy pattern of LGE in the most hypertrophied segments of the left-ventricular myocardium [23‐27].

In a recent study, we introduced a novel CMR parameter called “myocardial transit-time” (MyoTT) allowing a non-invasive and very quick assessment of coronary microvascular dysfunction (CMD) [28]. Based on the promising results of this previous study, we hypothesized that MyoTT could accurately measure the changes in the myocardial microvasculature and help to differentiate predominant intra-/perivascular changes from non-vascular interstitial processes that occur in the course of the aforementioned cardiomyopathies (CA and HCM). Therefore, the diagnostic yield of the novel CMR parameter MyoTT was assessed (in comparison to the other established CMR parameters) in both patients with CA and “conventional” HCM.

To the best of our knowledge, this is the first study that assesses the diagnostic yield of the novel CMR parameter MyoTT in both patients with CA and “conventional” HCM—in comparison to other established CMR parameters. The present study findings clearly show that mapping-based ECV is superior to MyoTT regarding the diagnosis of an “infiltrative” and predominantly “extracellular” disease such as CA. However, the present data also show that MyoTT is a very sensitive novel CMR parameter that allows both detection and characterization of cardiac diseases like “conventional” HCM that are characterized by less pronounced “extracellular” remodeling, but are rather dominated by “intracellular” and subsequent “intravascular” changes. In this context, MyoTT may not only help in the appropriate diagnosis and quantification of the severity of intra-/microvascular changes, but also be used to elegantly and easily monitor the course of the respective cardiac disease.

The assessment of CMD in non-ischemic cardiomyopathies has potential clinical value in different cardiomyopathies [30]. Briefly, the extent and severity of CMD correlates with worsening heart failure and poor clinical outcomes [31, 32]. In particular, hypertrophic heart diseases are characterized by CMD, and both “conventional” HCM [33] and cardiac amyloidosis [34] are typical examples. Obviously, there is a continuous interplay between myocardial perfusion abnormalities (particularly in the microvasculature) and myocardial tissue structure/remodeling. Novel CMR-methods such as T1 mapping and ECV measurement offer a unique non-invasive tool for myocardial tissue characterization and represent increasingly attractive techniques for clinicians in the work-up of cardiomyopathies. Changes in native T1-time and ECV value allow the assessment and quantification of primarily extracellular changes in the human myocardium [35]. In this context, different native T1- and ECV values were measured for the “conventional” HCM [36] and CA [37] patients. However, mapping and ECV measurements neither allow to directly assess “intravascular” changes nor to assess the degree of CMD. In contrast, MyoTT is a novel CMR parameter that promises to easily assess “intravascular” changes and quantify the degree of CMD.

In the case of an infiltrative cardiomyopathy like CA, structural changes of the extracellular space (in particular enlargement of ECV due to amyloid deposition) are expected to precede potential intravascular changes, resulting in CMD [34]. In addition, not only external compression of the coronary microvasculature by extracellular amyloid deposits but also additional amyloid deposits in the coronary vessel wall can increase the degree of CMD and induce severe myocardial ischemia even in the absence of epicardial obstructive CAD [38]. Therefore, the finding that the highest MyoTT values (reflecting severe CMD) were obtained in CA patients is not surprising. However, in the present study, native T1 mapping and ECV showed a higher diagnostic yield in comparison to MyoTT regarding the identification of patients with CA. This finding nicely illustrates that mapping and ECV measurement represent ideal imaging tools for the detection of cardiac diseases that are characterized by a predominant extracellular enlargement and support the aforementioned explanation that CMD (assessed by MyoTT) represents a less pronounced result of this extracellular process.

In contrast to CA, the histological characteristics of “conventional” HCM comprise myocyte hypertrophy and disarray as well as diffuse interstitial and perivascular fibrosis [39]. Coronary resistance increases in HCM not only due to “intracellular” enlargement with subsequent decrease in “extracellular” space but also due to vessel wall hypertrophy with subsequent reduction in luminal area, resulting in myocardial ischemia, myocyte death, and replacement fibrosis [17]. Noteworthy, the extracellular changes that are found in patients with advanced HCM are at least in part the result of abnormalities in the coronary microvasculature. Hence, the present finding that MyoTT is a sensitive parameter to differentiate patients with the conventional HCM from controls is not surprising and is backed up by the knowledge that the relative severity of CMD in relation to extracellular changes is more pronounced in HCM compared to CA. However, it must be emphasized that native T1 and ECV mapping are more useful techniques for the work-up of LV hypertrophy of unknown origin than MyoTT and provide a more reliable diagnosis of cardiac amyloidosis than MyoTT per se.

As shown in our previous study [28] and confirmed in the present one, the severity of CMD correlates with longitudinal strain in both HCM and CA. These findings are in line with the previous data that suggest an association between LV deformation behavior and myocardial ischemia in HCM patients [40]. Accordingly, the presence of both impaired longitudinal strain and CMD is frequently observed in CA patients, since an impaired longitudinal strain is partially due to disturbed microvascular function: the majority of longitudinal fibers are located in the subendocardium that in turn is more susceptible to (microvascular) ischemia [34]. Hence, the finding of a substantial correlation between MyoTT to longitudinal strain is of great interest: since abnormal myocardial deformation was shown to be associated with a higher rate of adverse cardiac events in HCM patients [41] and a worse survival in CA patients [42], a similar prognostic value can be deduced for the novel CMR parameter MyoTT. However, future studies are needed to prove this hypothesis.

It should be emphasized that a direct comparison regarding the diagnostic yield of MyoTT vs. routine CMR work-up (comprising cine- and LGE-imaging) for CA and/or HCM was not performed. Since the diagnostic value of the aforementioned routine CMR sequences in the assessment of unclear LV hypertrophy is already high, it is fair to assume that the addition of MyoTT will add only little to overall diagnostic certainty.

CA comprises different subtypes dependent on the precursor protein. For the purpose of this hypothesis-generating pilot study, no distinction was made between the different types of CA (AL and ATTR), because the underlying mechanism of cardiac involvement seems to be similar [43]. In addition, since CA is a rare disease, the size of our study group is limited [44]. Patients with obstructive CAD were excluded to minimize the risk of affecting measurement of MyoTT. Finally, the practical limitations of our novel MyoTT approach were already described in detail in our previous study [28].

MyoTT provides additive information to the data that can be obtained from parametric mapping and strain measurement. The relative severity of CMD (measured by MyoTT) in relationship to extracellular changes (measured by ECV) is more pronounced in HCM compared to CA—in spite of a higher absolute MyoTT value in CA patients. Hence, MyoTT may improve our understanding of the interplay between extracellular/intracellular and intravasal changes that occur in the myocardium during the disease course of different cardiomyopathies.