Accelerated Pacing and Cardiac Filling Pressures During Exercise in Patients With Heart Failure With Preserved Ejection Fraction

First, we will review patient records to identify eligible participants, who will then be contacted during their regular check-up visit. If they are interested in participating, they will be invited for an additional screening visit if needed.

Patients who meet the eligibility criteria will be invited for an invasive exercise test. At this visit, two small tubes (catheters) will be placed, one in a neck vein and one in a wrist artery, to measure heart pressures and blood oxygen levels. The patient then sits on a reclined stationary bike, wearing a breathing mask to monitor oxygen uptake. Throughout the visit, ultrasound measurements of the heart will also be performed.

First, heart pressures are measured at rest while the pacemaker rate is gradually increased in three steps (+20, +40, +60 beats per minute). Second, the patient cycles gently while the same measurements are repeated, with the pacemaker rate increased in three steps (+10, +30, +50 beats per minute). In a final step of both the rest and exercise protocol, the heart rate will return to the level associated with the lowest heart pressure, and blood oxygen levels will be checked, allowing the research team to calculate how many liters of blood the heart pumps per minute. Afterward, the catheters are safely removed and the pacemaker settings are restored to their original values. This visit is expected to last about three hours, after which study participation ends.

The full study is expected to be completed once 20 patients have finished all study tests.

Participants eligible for inclusion in this study must meet all of the following criteria:

• Voluntary written informed consent of the participant has been obtained prior to any screening procedures
• At least 18 years of age at the time of signing the Informed Consent Form (ICF)
• Heart failure with preserved ejection fraction, defined as one of the below criteria:

• EF >= 45% and HFA-PEFF score >= 5 (Heart Failure Association-Pre-test assessment, Echocardiography and natriuretic peptide, Functional testing, Final etiology; heart failure association of the European Society of Cardiology and the Heart Failure Association (34))
• EF >= 45% and H2FPEF score >= 6 (Heavy, Hypertensive, Atrial fibrillation, Pulmonary hypertension, Elder, Filling pressure; Mayo Clinic group (35)))
• EF >= 45% and

i. History of heart failure hospitalization after pacemaker implantation or ii.On loop-diuretics at time of inclusion

• Having a DDD-pacemaker with LBB area pacing, implanted at least 12 weeks before iCPET
• >=6 weeks on optimal HFpEF therapy (MRA and SGLT2i) at time of iCPET, unless contraindicated or not tolerated
• Sinus rhythm at time of screening and iCPET

Participants eligible for this Study must not meet any of the following criteria:

• Participant has a history of:

• Evidence of significant pulmonary comorbidity based on abnormal pulmonary function tests (FEV1 <60%) or aberrant lung parenchyma more than mild on radiological imaging
• Severe/symptomatic valvular diseases
• Severe pulmonary hypertension (PASP > 55mmHg estimated by Doppler Echo)
• Unstable arrhythmias (VT, VF)
• Recurrent syncopes after pacemaker implantation
• Permanent atrial fibrillation
• Amyloid cardiomyopathy
• Physical inability to perform exercise
• More than 1 hospitalization for heart failure in the last year
• Resting heart rate> 100bpm
• At time of iCPET or inclusion: decompensated heart failure, unstable coronary syndrome
• Contraindication to central venous access

• Severe coagulopathy (e.g., spontaneous INR > 2, thrombocytopenia < 50,000/µL)
• Local infection or skin infection at the insertion site
• Thrombosis or anatomical abnormalities of the right jugular vein
• Pneumothorax or contralateral lung pathology
• Inability to properly position the patient
• Contraindication to arterial access

• Thrombosis or occlusion of the target artery
• Raynaud's phenomenon or other vasospastic disorders
• Active infection at the intended insertion site
• Severe coagulopathy (e.g., spontaneous INR > 2, thrombocytopenia < 50,000/µL)
• Insufficient collateral circulation (e.g., inadequate perfusion in an Allen test)
• Contraindications to CPET

• ECG signifying myocardial injury
• ECG signifying current or potentially lethal arrhythmias
• Systemic hypotension (e.g. systolic blood pressure < 90 mmHg)
• Extreme hypertension (e.g. systolic blood pressure > 220 mmHg)
• Syncope, presyncope, or lightheadedness
• SaO2 < 88%
• Severely elevated PCWP (> 40 mmHg) during exercise