Cardiac Amyloidosis in HFpEF
Cardiac Amyloidosis in HFpEF
Heart failure with preserved ejection fraction (HFpEF) accounts for half of heart failure
 cases with heterogenous cause and variable presentations. The diagnosis of HFpEF required
 clinical signs and symptoms of HF, normal left ventricular ejection fraction (LVEF) and
 evidence of diastolic dysfunction. No treatment has been shown in recent major clinical
 trials having benefits in these patients. One major reason of the poor response to medical
 treatment is the heterogeneity of HFpEF, which contains many different underline causes. To
 identify the underlying causes of HFpEF may improve the diagnosis and treatment in these
 patients.

 Age-related amyloid deposition has first been reported in 1876 and the following autopsy
 studies showed the prevalence of senile cardiac amyloid is up to 25%. Recently, it has been
 recognized that the deposits in senile cardiac amyloid are derived from wild-type
 transthyretin (TTR). Transthyretin amyloidosis cardiac amyloidosis (ATTR CA) is caused by
 myocardial deposition of misfolded transthyretin protein. There are 2 types of ATTR
 classified by genetic mutation including wild-type ATTR (ATTRwt) and familial cardiac amyloid
 caused by TTR mutation (ATTRm).

 Multimodality techniques have been developed to assist in the diagnosis of the diagnosis of
 TTR. Among them, 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy
 is a non-invasive test and it can diagnose TTR from other cause diverse form of cardiac
 amyloidosis and cardiomyopathy. In the study of Gonzalez-Lopez et al, in 120 HFpEF patients,
 16 (13.3%) had positive 99mTc-DPD scan. Four patients with positive 99mTc-DPD scan received
 endomyocardial biopsy and confirmed cardiac amyloid deposition.

 ATTRwt could be an important cause of HFpEF and it was often under diagnosed. A recent study
 in Spain reported that 13% of patents over age of 60 years with HFpEF and left ventricular
 wall thickness of 12mm or more had ATTRwt. However, the prevalence of ATTRwt among patients
 with HFpEF is not well-established in Taiwan and Asia. The aim of this study is to determine
 the prevalence, clinical characteristics, risk factors and outcomes of ATTRwt related HFpEF
 patients in Taiwan.
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical situation
 with multiple underlying causes. The diagnosis of HFpEF is challenging which requires
 clinical signs/symptoms of HF, a normal or mildly impaired systolic function measured by left
 ventricular ejection fraction (LVEF), and evidence of diastolic dysfunction. There are no
 significant improvements in treatment of HFpEF in recent years and the results in the major
 clinical trials for HFpEF were disappointed. One major reason is the heterogeneity of HFpEF,
 which contains several diseases under the same entity.

 Small deposits of amyloid are found in the elder hearts in up to 25% of the autopsies. These
 deposits are mainly composed by wild-type transthyretin (TTR). Transthyretin amyloidosis
 cardiac amyloidosis (ATTR CA) is caused by myocardial deposition of misfolded transthyretin
 protein. It is classified into 2 groups by the genetics of Transthyretin amyloidosis (ATTR):
 wild-type (ATTRwt) or hereditary (hATTR or ATTRm). ATTR CA, irrespective of genotype, is an
 unrecognized mechanism underlying HFpEF. It was reported wild-type TTR might be an
 underdiagnosed cause of HFpEF. However, the prevalence of wild-type ATTR among patients with
 HFpEF is not well-established in Taiwan and Asia.

 One of the most convenient method to detect and diagnosis cardiac amyloidosis is
 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy6. In the study of
 Gonzalez-Lopez et al, in 120 HFpEF patients, 16 (13.3%) had positive 99mTc-DPD scan6. Four
 patients with positive 99mTc-DPD scan received endomyocardial biopsy and confirmed cardiac
 amyloid deposition6. In addition, technetium-99m TC pyrophosphate (PYP) scintigraphy is also
 very useful in diagnosis of cardiac amyloidosis.

 The propose of this study is to determine the prevalence of ATTRwt among elderly HFpEF
 patients in Taiwan. In this study, the investigators will recruit a cohort of HFpEF patients
 in Taiwan to define the number of patients who have cardiac amyloidosis by utilizing highly
 sensitive heart imaging and blood tests. The investigators will also explore differences in
 different risk factors as they relate to heart failure disease progression in cardiac
 amyloidosis. According our previous studies, the average age of HFpEF in Taiwan is 65 y/o. In
 this study, the investigators set age limitation as 60 y/o. However, because 5% ATTRwt were <
 60 y/o9, therefore, the investigators also recruit patients >50y/o with risk factors of
 ATTRwt.

 Hypothesis HFpEF is a heterogeneous clinical situation with multiple underlying causes.
 ATTRwt is an underdiagnosed cause of HFpEF but the prevalence is unknown in Taiwan. ATTRwt
 can be diagnosed non-invasively by 99mTc-PYP scintigraphy7. The investigators aimed to
 investigate the prevalence and clinical characteristics of ATTRwt among patients with HFpEF.

 Primary Objective(s) / Endpoint(s) Percentage of participants with ATTRwt among patients with
 HFpEF in Taiwan

 Secondary Objective(s) / Endpoint(s) To investigate the clinical and echocardiographic
 characters in ATTRwt patients and compare with HFpEF patients without ATTRwt

 Trial Population Eligible HFpEF patients with a LVEF of ≧50%, New York Heart Association
 (NYHA) class I-IV symptoms: Both in-patients or patients in clinics could be enrolled. These
 patients could be newly diagnosed or has been diagnosed. Study subjects will be
 pre-stratified according to left ventricular posterior wall thickness (LVPW) ≥12mm or less;
 number of subjects with LVPW ≥12mm should account for more than 50% of total subjects
 recruited in the final analysis.

 Sample Size and Sample Size Justification The study will prospectively evaluate the
 prevalence of ATTRwt among patients with HFpEF. Assume the expected 10% prevalence of ATTRwt
 in patients with HFpEF, the target recruitment of 260 HFpEF patients would yield 25 ATTRwt
 positive result, which would provide the prevalence estimate with associated 90% confidence
 interval at the range of +- 3%. The estimated enrolled time is 18 months.

 Key Inclusion Criteria

 1. Patient is ≥ 60 years old or 50 y/o with carpal tunnel syndrome or spinal stenosis

 2. Patient has been diagnosed as HFpEF in their medical history or newly diagnosed as
 HFpEF. They have HF symptoms with NYHA Classification of I-IV when diagnosis. The
 criteria of HFpEF is according to our previous studies10.

 3. More than 50% of them have LVPW ≥12mm (when diagnosis).

 4. Written informed consent could be obtained

 Key Exclusion Criteria

 1. Patients unwilling to join this projects

 2. Patients with unstable coronary artery disease, plan to receive coronary intervention
 within months.

 3. Patients has previous history of heart failure reduced ejection (HFrEF) with a LVEF
 <40%.

 Method

 1. Patients recruitment and study protocol The enrolled and exclusion criteria were
 mentioned above. The investigators will enroll 260 HFpEF patients (> 50% with LVPW
 thickness >12mm). After receiving informed consent, patients will receive NTproBNP, ECG,
 and echocardiography. Then the investigators will arrange 99mTc-PYP scan to detect the
 presence of amyloidosis. If patients have these data (ECG, NTproBNP, echocardiogram,
 99mTc PYP) within 6 months, the investigators will record and use this data and do not
 perform again. In patients with positive 99mTc-PYP scan, the investigators will detect
 urinary monoclonal light chain and serum monoclonal light chain. In addition, the
 investigators will arrange TTR genetic testing.

 2. Data Collection Delegated physicians or study personnel blinded to scintigraphy results
 will review the medical records of all patients. Demographic and clinical data will be
 collected during outpatient clinic visit.

 3. Scintigraphy Protocol Planar and single-photon positive emission computed tomography
 (SPECT) imaging with 99mTc-PYP was performed with a dual head Philips Precedence
 SPECT/CT camera (Philips Healthcare, Guildford, United Kingdom). Patients received 20 to
 25 mCi of 99mTc-PYP intravenously and images were obtained at 2 hours over 8 minutes
 duration.

 4. Genotype Testing The TTR mutation was confirmed by sequencing of the TTR gene following
 National Taiwan University Hospital established protocols. All 4 exons and their
 flanking intron regions of the human TTR gene were amplified by polymerase chain
 reaction (PCR). The amplicons were purified by the Gel/PCR DNA Fragments Extraction Kit
 (Geneaid, Taipei, Taiwan). Sequencing was performed at the corresponding exons by using
 the ABI3730 automatic DNA sequencer (Applied Biosystems, Foster City, CA).
Inclusion Criteria:

 -  Patient is ≥ 60 years old or 50 y/o with carpal tunnel syndrome or spinal stenosis

 -  Patient has been diagnosed as HFpEF in their medical history or newly diagnosed as
 HFpEF. They have HF symptoms with NYHA Classification of I-IV when diagnosis. The
 criteria of HFpEF is according to our previous studies.

 -  More than 50% of them have LVPW ≥12mm (when diagnosis).

 -  Written informed consent could be obtained.

 Exclusion Criteria:

 -  Patients unwilling to join this projects.

 -  Patients with unstable coronary artery disease, plan to receive coronary intervention
 within months.

 -  Patients has previous history of HFrEF with a LVEF <40%.