STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

Not applicable.

BACKGROUND OF THE INVENTION

Cardiac amyloidosis (CA) is a progressive and fatal cause of heart failure with preserved ejection fraction (HFpEF) that has been grossly underdiagnosed [Ref. 1-4]. In one study, 17% patients with HFpEF who had no ante-mortem suspicion of CA were found to have CA at autopsy [Ref. 3]. A high prevalence (13.9 to 16%) of occult cardiac transthyretin related amyloid (ATTR) has also been noted in patients with aortic stenosis undergoing transcatheter aortic valve replacement (TAVR) [Ref. 5,6]. Amyloidosis is caused by a progressive extracellular deposition of insoluble fibrils that are composed of variety of serum proteins, leading to tissue destruction and organ function impairment [Ref. 7]. Amyloid is classified based on the protein that led to its deposition [Ref. 8]. The two most common types of cardiac amyloid that can cause heart failure are light chain amyloid (AL) and ATTR [Ref. 9-12]. It is essential to differentiate between these two types of amyloid as they are managed differently [Ref. 11,13,14]. The current gold standard for diagnosis of CA is endomyocardial biopsy (EMB) followed by mass spectrometry for amyloid subtyping on the biopsied tissue [Ref. 15,16]. Immunohistochemistry is also used for amyloid subtyping, with variable reliability [Ref. 15,17]. EMB is an invasive procedure and can lead to complications such as myocardial perforation, arrhythmias, pneumothorax and pulmonary embolization. The reported rate of complications ranges from less than 1 to 6 percent [Ref. 18,19]. In addition, these methods require significant expertise for both the vascular interventional procedure and the pathologic interpretation, which are not widely available. Therefore, there has been an unmet need for alternative non-invasive methods for diagnosing and differentiating between different types of cardiac amyloidosis. Noninvasive procedures like magnetic resonance imaging (MRI) and echocardiography can be helpful in differentiating restrictive cardiomyopathy caused by amyloid deposition from other types of cardiomyopathy, but neither imaging method can reliably differentiate between amyloid types [Ref. 20-26].

It has been known that cardiac amyloidosis can be detected by planar scintigraphy using bone seeking radiotracers like99mTc-3,3-diphophono-1,2-propanodicarboxylic acid (DPD),99mTc-methylene diphosphonate (MPD), and99mTc-pyrophosphate (PYP). However, these studies failed to recognize the need to differentiate ATTR from AL, and therefore concluded there was low sensitivity for detection of CA. Hence, its clinical use was not further studied [Ref. 27-30]. But with recent understanding that these radiotracers are highly sensitive and specific for ATTR CA [Ref. 31-34], there has been a reemergence in the interest for non-invasive diagnosis and differentiation of different types of cardiac amyloid. The currently used 2-D planar scintigraphy based heart to contralateral (HCL) ratio has shown an excellent diagnostic accuracy for detecting ATTR-CA. However, planar images have potential diagnostic limitations particularly in patients with bone pathologies, recent thoracic surgeries, myocardial infarction, cardiac trauma, renal failure and altered thoracic anatomy, which may lead to thoracic uptake of PYP unrelated to cardiac amyloid.

An alternative option to 2-D scintigraphy that has been recently studied has been to use SPECT/CT. In a recent study by Moore et al.,99mTc-DPD SPECT/CT was used for assessment of cardiac amyloidosis in 21 subjects with heart failure due to amyloid (8 AL and 13 ATTR) [Ref. 39]. In that study a semi-quantitative visual scoring of cardiac retention was evaluated in accordance with criteria proposed by Perugini et al. [Ref. 40]. The results of the study showed a 100% sensitivity (Sn) but only 75% specificity (Sp) for detection of ATTR-CA. Similar results were observed in this study with quantitative comparison of cardiac retention relative to bone retention (sternum) (Sn=94.1% and Sp=80%). Comparison of the cardiac radiotracer retention relative to bone retention was used in this study and is a standard technique.

In a different study, Yamamoto et al. [Ref. 41] described a quantitative method, the PYP score, based on SPECT alone. It was defined as the ratio of myocardial mean counts to ventricular cavity mean counts and was used to assess the utility of99mTc-PYP for evaluation for cardiac amyloidosis in 13 subjects with heart failure due to amyloid (1 AL, 3 ATTRm, and 8 ATTRwt) and 37 subjects with heart failure attributable to non-amyloid causes. The PYP score was found to have a Sn of 84.6% and Sp of 94.5% for differentiating cardiac amyloidosis from non-amyloid causes of heart failure.

What is needed therefore is an improved system and method for enhanced diagnosis of transthyretin-related cardiac amyloidosis in a subject.

SUMMARY OF THE INVENTION

The present disclosure overcomes the aforementioned shortcomings by providing systems and methods for enhanced diagnosis of transthyretin-related cardiac amyloidosis in a subject. The systems and methods use both SPECT imaging data as well as an anatomical imaging data, such as computed tomography (CT) data, to produce a combined image. Within the combined image, the radiotracer uptake between two volumes of interests are compared, one of which may represent the left ventricle of the subject and the other may represent the blood pool retention of the subject. Combining the anatomical imaging data with SPECT data enables better anatomical delineation and helps in avoiding areas with coronary or lymph node calcifications and overlying soft tissue and bony pathologies. Previous diagnostic systems have struggled to avoid such troublesome areas, which can often be missed without anatomical information that helps to provide better visual evaluation of cardiac radiotracer uptake. Further, because the comparison of the uptake may be made with the blood pool of the subject, patients with abnormal bone calcifications can still be accurately diagnosed. The culmination of these novel features allowed a diagnostic study using the methods and systems described herein to produce 100% Sp and 100% Sn results.

In one aspect, the present disclosure provides a method for diagnosing transthyretin cardiac amyloidosis in a subject. The method can comprise introducing a technetium-99m pyrophosphate radiotracer into a subject; acquiring single-photon emission computed tomography (SPECT) image data of a cardiac region of the subject based on the uptake of the radiotracer; acquiring anatomical image data of the cardiac region of the subject; combining the SPECT image data and the anatomical image data to produce a combined three-dimensional image of the cardiac region; and comparing the radiotracer uptake present within a first volume of interest and a second volume of interest, wherein both volumes of interest are located within the combined image of the cardiac region.

In another aspect, the present disclosure provides a method for diagnosing transthyretin cardiac amyloidosis in a subject. The method can comprise introducing a radiotracer into a subject; acquiring single-photon emission computed tomography (SPECT) image data of a cardiac region of the subject based on the uptake of the radiotracer; acquiring anatomical image data of the cardiac region of the subject; combining the SPECT image data and the anatomical image data to produce a combined three-dimensional image of the cardiac region; and comparing the radiotracer uptake present within a first volume of interest and a second volume of interest, wherein the first volume of interest is representative of the left ventricle of the subject and the second volume of interest is representative of the blood pool of the subject.

In yet another aspect, the present disclosure provides a system for diagnosing transthyretin cardiac amyloidosis in a subject. The system can comprise a source of technetium-99m pyrophosphate radiotracer; means for introducing the technetium-99m pyrophosphate radiotracer into a subject; a single-photon emission computed tomography (SPECT) system configured to acquire SPECT image data of a cardiac region of the subject based on the uptake of the radiotracer; an imaging system configured to acquire anatomical image data of the cardiac region of the subject; a processor configured to combine the SPECT image data and the anatomical image data to produce a combined three-dimensional image of the cardiac region and compare the radiotracer uptake present within a first volume of interest and a second volume of interest, wherein both volumes of interest are located within the combined image of the cardiac region.

Various other features of the present invention will be made apparent from the following detailed description, claims, and the drawings.

