US Benchmarking Clinical Study

Inclusion Criteria

Inclusion Criteria Common to all three Study Arms:

• Male or female age ≥ 60 years
• Signed informed consent and able to comply with protocol

Inclusion Criteria Common to the Heart Failure with non-reduced left ventricular ejection fraction (LVEF) with or without transthyretin amyloid cardiomyopathy (ATTR-CM) Arms:

• Patients meeting the Universal Definition of Heart Failure \& HeartShare study criteria.
• LVEF >40% on the last available imaging study
• Left ventricular hypertrophy (LVH) defined as left ventricular mass index (mass/BSA) in female > 95 g/m², in male > 115 g/m² according to American Society of Echocardiography/European Association of Cariology (ASE/EAC) guidelines42 OR as interventricular septum (IVS) thickness ≥12 mm

Inclusion criterion specific to HF with non-reduced LVEF without ATTR-CM Arm:

• Negative (grade 0) Pyrophosphate (PYP) scintigraphy within 24 months prior to the enrolment in the study OR Simple Score \<643 OR negative endomyocardial biopsy

Inclusion criterion specific to HF with non-reduced LVEF with ATTR-CM Arm:

• ATTR-CM objectively confirmed and classified at any time prior to the enrollment in the study, with monoclonal protein AL amyloidosis ruled out, according to American Heart Association (AHA) 2020 criteria

Inclusion criteria in Control Subjects

• No diagnosis of HF or cardiomyopathy according to the universal definition of Heart Failure
• No diagnosis of Transthyretin amyloid cardiomyopathy (ATTR-CM) or Amyloid light-chain (AL) amyloidosis

Exclusion Criteria

Exclusion criteria common to the three arms:

• Pregnant OR pre-menopausal woman
• Vulnerable patients
• Acute Coronary Syndrome within 30 days
• Heart rate greater than 130 beats/minute at the time of the measurements
• Atrial fibrillation or flutter at the time of SWV measurement (history of AF is authorized provided they patient is in sinus rhythm at the time of the measurements)
• Any clinically significant cardiac arrhythmia at the time of SWV measurement
• Poor echogenicity preventing accurate ultrasound measurements
• Patients with segmental wall motion abnormalities thought to be due to myocardial infarction.
• Severe mitral or aortic valve disease (regurgitation or stenosis) excluded if the cause is other than ATTR (e.g., prolapse, endocarditis, prosthetic valve.)
• Severe tricuspid valve disease (regurgitation or stenosis) excluded if the causes are other than ATTR.
• Distance from skin to IVS ≥ 8 cm
• Any prosthetic mechanical valve
• Patients with mechanical cardiac assist devices other than pacemakers or defibrillators
• Heart, lung, liver or kidney transplant history or expected in the next year
• Severe renal impairment with eGFR \< 15 mL/min/1.73m² or end-stage renal disease or patient on dialysis.
• Presence of any competing life-threatening risk over the next 12 months
• Complicated uncontrolled diabetes mellitus HbA1c ≥9% with target organ damage.
• Uncontrolled and persistent high-blood pressure with diastolic pressure > 100 mmHg or systolic pressure > 160 mmHg at the time of the measurement.
• Acute decompensated state such as volume overload, etc. in the opinion of the study investigator
• Skin abnormalities, infections, or open wounds at the site of the SVW measurement
• Liver disease, at least moderate

Exclusion criteria in both the HF with non-reduced LVEF with or without ATTR-CM Arms:

• Known inherited cardiomyopathy, infiltrative cardiomyopathy (other than ATTR-CM for the study arm for ATTR-CM), cardiomyopathy from muscular dystrophies, cardiomyopathy with reversible causes (e.g., stress cardiomyopathy), hypertrophic cardiomyopathy or known pericardial constriction
• History of treatment for ATTR-CM with Transthyretin (TTR) depleters

Exclusion criteria Specific to Control Subjects:

• Any diagnosis of cardiomyopathy or HF, whatever the cause46
• LVH based on LV mass index female >95 g/m², in male ≥115 g/m² OR IVS thickness ≥12 mm unless thought to be due to athlete's heart