Cardiac TTR Amyloidosis Clinical Trial
Official title:
Tc99m-PYP Scintigraphy in Order to Establish Incidence of Cardiac Transthyretin Amyloidosis Among Patients With Otherwise Unexplained Cardiomyopathies
Cardiac amyloidosis is a multi-organ syndrome, which usually presents as restrictive
cardiomyopathy (RCM). Transthyretin (TTR) amyloidosis (or ATTR) is a subtype of amyloidosis
which frequently involves heart. Cardiac ATTR, though infrequently diagnosed during
lifetime, may represent a prevalent cause of RCM, especially in elderly. Several medications
that can limit progression of the disease are currently under investigation. Presently the
golden standard for diagnosis of ATTR is endomyocardial biopsy (EMB) which may entail severe
adverse complications causing under-diagnosis of ATTR.
Several papers support the evidence that Tc99m-labeled tracers can be used to detect
myocardial deposits of TTR amyloid. It was suggested that Tc99m scintigraphy might be a
highly sensitive diagnostic tool for cardiac ATTR. In this study the patients with otherwise
unexplained cardiomyopathy or heart block will undergo Tc99m scan, which will establish the
incidence of this largely underdiagnosed condition in the population.
Amyloidosis is a multi-organ syndrome, which usually presents as a restrictive
cardiomyopathy (RCM). Transthyretin (TTR) amyloidosis is a subtype of amyloidosis, further
subdivided into familial type and senile type. Its pathophysiology consists primarily of
abnormal precipitation of transthyretin - a protein that normally acts as transporter for
thyroid hormone and retinoids - in tissues. TTR amyloidosis frequently involves heart,
bringing about the same clinical and pathophysiological picture of RCM. Another presentation
of TTR Amyloidosis can be atrio-ventricular block or bundle-branch block [1].
There is evidence that the cardiac TTR amyloidosis, though infrequently diagnosed during the
lifetime, may represent a widespread cause of restrictive cardiomyopathy especially in
elderly. An autopsy study in octogenarians having suffered of heart failure with preserved
left ventricular ejection fraction (HFpEF) suggested that up to 25% of them had TTR amyloid
deposit in myocardium, though a negligible minority of them had been diagnosed with TTR
amyloidosis during their lifetime [2-3]. HFpEF is a very widespread diagnosis, which
represents a considerable burden of morbidity, and usually harbours populations of patients
poorly responding to treatment. Most of patients with the diagnosis of HFpEF have little or
no explanation concerning the aetiology of their disease, especially if they do not respond
to conventional treatment. Most of them can benefit only from symptomatic treatment which
does not alter the course of the disease. Thus a more widespread diagnosis of TTR
amyloidosis could have been very promising as to a better management of this hard-to-treat
patient population.
Several medications that can limit progression of TTR amyloidosis are currently under
investigation. Until now, the golden standard for diagnosis of the disease was
endomyocardial biopsy (EMB) which may entail several adverse complications and thus limit
widespread diagnosis. Since amyloidosis is a multi-organ disease, extra-cardiac biopsy was
proposed as a surrogate tissue diagnosis, though in TTR amyloidosis its sensitivity is below
50% [4].
Recently several papers support the evidence that Tc99m-labeled pyrophosphate (PYP) and
bisphosphonates when injected intravenously localize to myocardial deposits of TTR amyloid.
It was thus suggested that Tc99m scintigraphy might be a highly sensitive and specific
diagnostic tool for cardiac TTR amyloidosis [5-9]. It was shown that almost the only source
of false positive Tc99m scintigraphy is primary amyloidosis, which is a different entity,
with worse prognosis, different treatment, although frequently involves heart as well [10].
Primary amyloidosis can be diagnosed by means of demonstration of monoclonal immunoglobulin
peak in serum and immunoglobulin light chains in serum and urine [11]. Therefore, the
specificity of Tc99m scan for TTR amyloidosis can be brought to an extraordinary level, with
virtually negligible false positive rate, if primary amyloidosis is excluded prior to
referral to Tc99m scan. The other entity where false positive uptake of Tc99m in myocardium
can be observed is acute myocardial infarction. Currently the Tc99m-PYP scan is utilised as
bone scan according to guidelines in order to diagnose wide spectrum of diseases such as
stress fractures or metastatic bone disease.
At present the mentioned hypothesis that TTR amyloidosis might be a widespread cause of
HFpEF has not been established in a clinical trial due to the fact that until now the most
accurate diagnosis of TTR amyloidosis required an invasive procedure with possible adverse
outcomes while the extra-cardiac biopsy had low diagnostic yield. Advent of a novel,
possibly as accurate, yet non-invasive diagnostic tool opens new opportunities to set such
study.
The incidence of both familial type and senile type TTR amyloidosis among patients with
diagnosis of otherwise unexplained heart failure or heart block will be evaluated in this
study by means of Tc99m scan using SPECT technology as described above. The hypothesis is
that if the incidence of TTR amyloidosis within the population of patients suffering of
HFpEF is as high as it was demonstrated by the autopsy studies, then we will be able to
establish the diagnosis in a larger cohort of patients. This will make new developments in
the research of the disease, such as treatment and outcome driven trials, possible.
Establishing the diagnosis of TTR amyloidosis in patients with HFpEF will improve our
decision-making ability regarding the patients' treatment, for example preventing
unnecessary invasive measures in patients with comorbidities demanding such measures, the
alternative diagnoses being unrevealed.
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