Background:

Heart failure with reduced ejection fraction (HFrEF) is a heterogeneous condition with variable potential for left ventricular ejection fraction (LVEF) recovery. While LVEF improvement and reverse remodeling predict better outcomes, the determinants that predict left ventricular recovery remain poorly understood. An expert panel of the Journal of American College of Cardiology highlighted the need for improved HFrEF phenotyping to clarify recovery patterns and support personalized management and risk stratification.

Methods:

PRIMA-HF is a prospective prediction study designed to determine whether baseline cardiac multimodality imaging can predict LVEF recovery in patients with de novo HFrEF (n=180). The imaging protocol includes cardiac magnetic resonance (CMR), coronary computed tomography and [¹⁵O]H₂O positron emission tomography ([¹⁵O]H₂O-PET) and echocardiography. Patients will also undergo a six-minute walk test, blood volume measurement, and blood sampling. The primary outcome is the change in LVEF from baseline to approx. after 3-12 months (or after full optitration in GDMT), assessed by CMR.

In 60 patients from the PRIMA-HF cohort, the randomized, double-blind study High Dose Adenosine During Perfusion Imaging in Heart Failure (HAI-HF) will be conducted. HAI-HF evaluates whether high-dose adenosine (210 µg/kg/min) versus standard-dose (140 µg/kg/min) during [¹⁵O]H₂O-PET changes the stress myocardial blood flow, which is the primary endpoint.

Aim:

The PRIMA-HF study comprehensively characterizes patients with newly diagnosed HFrEF through multimodality imaging and systematically assesses change in LVEF using CMR. The study's deep phenotyping approach integrates clinical, imaging, biomarker, and functional data to capture disease heterogeneity, rather than relying on traditional measures such as LVEF or symptom class. This enables the identification of distinct patient subgroups with shared pathophysiological mechanisms.

The HAI-HF trial examines whether higher adenosine doses improve [¹⁵O]H₂O-PET perfusion imaging in HFrEF.

Together, the studies will advance understanding of myocardial recovery, improve perfusion assessment, and support development of a predictive model for HFrEF prognosis.

Inclusion Criteria:

• Age ≥ 18 years
• Capable and has provided written informed consent
• LVEF ≤ 40% by echocardiography in connection with hospitalization for heart failure or in connection with outpatient evaluation for heart failure

Exclusion Criteria:

• Previous diagnosis of heart failure
• Unable to understand the patient information
• Pregnancy, as the study involves ionizing radiation.
• Current severe valvular disease (as defined by the Danish national treatment guidelines on cardio.dk)
• Atrial fibrillation with a heart rate > 130 beats per minute during the inclusion echocardiography
• Cardiac surgery within 6 months prior to inclusion
• Acute exacerbation of existing chronic obstructive pulmonary disease
• Severe asthma or chronic obstructive pulmonary disease with FEV1 < 1L
• any contraindication for adenosine stress testing
• Severe renal failure < 15 mL/min/1.73m² or dialysis
• Advanced liver disease (Child-Pugh class C)
• Endocarditis at inclusion/baseline
• Isolated right-sided heart failure
• Malignant disease treated with chemotherapy or radiotherapy, or expected life expectancy under 1 year

The study will adhere to all applicable regulations and guidelines governing the transfer of individual participantdata (IPD), which will be biological material (blood samples), abroad, ensuring that all data are handled confidentially and in full compliance with relevant legislation.

Data sharing is planned after the enrollment of 200 patients in PRIMA-HF, which is anticipated to be achieved by the end of 2027. Approximately two months thereafter, we expect to have completed the necessary analyses, at which point the availability of individual participant data will cease.

Upon completion of the project, collaborating partners will destroy all data in accordance with our agreements and applicable requirements.

We plan to send biological material for proteomics measurements for further analysis to either deCODE, Reykjavik, Iceland, or Olink, Uppsala, Sweden. This will only take place after legal approval has been obtained in the Central Denmark Region.