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Page 4 of 13 Canepa et al. Vessel Plus 2022;6:30 https://dx.doi.org/10.20517/2574-1209.2021.106

CARDIAC AMYLOIDOSIS IN AT-RISK CONDITIONS: HEART FAILURE, AORTIC STENOSIS
AND HYPERTROPHIC CARDIOMYOPATHY
[4]
We have been learning by screening different conditions considered at risk of CA that the prevalence of
ATTR-CA in certain subgroups of cardiovascular patients might be higher than initially thought [Figure 1].
In particular, several studies have screened for CA patients with HF, with a particular focus on patients with
HF with preserved ejection fraction (HFpEF). Among the several studies that screened for ATTR-CA mixed
[17]
HF populations by means of bone scintigraphy [15,16] , cardiac magnetic resonance , endomyocardial
biopsy , or genetic testing , two pivotal ones with a prospective design and careful patients’ selection are
[19]
[18]
worth noting. The two studies together screened 169 HFpEF patients of a mean age of about 80 years using
bone scintigraphy [20,21] and found an average ATTR-CA prevalence of 15%. A larger multinational study is
ongoing (NCT 04424914) aiming at enrolling 2500 HFpEF patients older than 60 years and with left
ventricular hypertrophy, which will be screened for ATTR-CA by means of bone scintigraphy. This study
will offer an updated and more reliable estimate of the prevalence of this disease in this at-risk condition.

A similar prevalence of ATTR-CA has been noticed in another group of patients considered at risk of CA,
i.e., those with aortic stenosis (AS) undergoing interventional procedures of percutaneous valve
implantation or surgical valve replacement. A summary of CA screening studies published in this
population was recently presented by Rapezzi et al. in an editorial. However, considering the existence of
[22]
some overlap between study populations presented in different manuscript (see, e.g, Refs [23-26] ), we pulled
together data from three independent cohorts of 595 AS patients screened using bone scintigraphy [24,26,27] and
estimated an overall average prevalence of ATTR-CA of 11% . Notably, genetic TTR testing was not
[28]
routinely performed in these studies, and none found an independent significant impact of this new ATTR-
CA diagnosis on prognosis in these AS patients.

Another population considered at risk of CA is the one with hypertrophic cardiomyopathy (HCM)
diagnosed later in life. This was primarily highlighted in the study by Maurizi et al. investigating a cohort
[29]
of 343 consecutive patients referred with an initial diagnosis of HCM at age ≥ 40 years. They demonstrated
that the prevalence of CA in this sample linearly increased with the age of HCM diagnosis, ranging from 1%
at ages 40-49 years to 26% above 80 years, with the large majority of cases being ATTR-CA . Similarly, by
[29]
screening 114 patients with unexplained left ventricular hypertrophy (LVH) using cardiac magnetic
resonance and bone scintigraphy together, Cariou et al. found a 27% prevalence of ATTR-CA.
[30]

Overall, the above evidence confirms that at least one out of ten patients with HFpEF, AS, or HCM
diagnosed later in life might have an overlooked ATTR-CA, and systematic screening of patients with these
conditions using bone scintigraphy has been proposed by experts .
[4]

EVOLVING CONCEPTS IN THE EPIDEMIOLOGY OF THESE AT-RISK CONDITIONS
HFpEF
Although a unifying definition of HF is still under discussion , in developed countries, the prevalence of
[31]
[32]
known HF is generally reported at 1%-2% of the general adult population . Most studies estimated that
over half of patients diagnosed with HF have HFpEF and that this is rapidly becoming the most prevalent
form of HF, especially in the elderly [32-34] . Number of comorbidities and non-cardiovascular etiology have
generally been reported to be higher in patients with HFpEF than in those with HF and reduced ejection
fraction (HFrEF) . Accordingly, non-cardiovascular modes of death represent nowadays a more relevant
[35]
[36]
competing risk in HFpEF than in HFrEF . For these and other reasons, hospital admissions of elderly and
frail HFpEF patients are increasingly reported in internal medicine/geriatric wards as compared to
[43]
cardiology wards [37-42] , and this gap is expected to further broaden over time . Observational studies have