The purpose of this research study is to evaluate the safety and effectiveness of tirzepatide compared to placebo (an inactive substance) in the treatment of individuals with Heart Failure with Preserved Ejection Fraction (HFpEF) and obesity.

Participants will undergo a screening visit where they will have a physical exam to asses health and blood will be drawn. If the blood tests show that a participant qualifies to continue, then they will be randomly assigned to either tirzepatide or placebo. Each participant will have a 50:50 chance of being on tirzepatide (like the flip of a coin.) Both tirzepatide and placebo will be supplied as a single dose in an injectable pen device. Subjects will inject the study drug under the skin (or subcutaneous) once a week with the injectable pen. Participation will last at least 52 weeks and may last up to 120 weeks.

Tirzepatide has been proven to provide significant body weight loss and improvement of fat and sugar metabolism in patients with type 2 diabetes. Body weight percent reduction in this study is estimated to be 15% to 16%.

This study will include volunteers diagnosed with a form of heart failure that is characterized by a weakened heart muscle that appears to be pumping in a normal manner. This condition is called "heart failure with preserved ejection fraction" or HFpEF. For these individuals, it has been determined that the health problems and symptoms experienced may be due to a significant increase in the pressure of one of the chambers of the heart. This pressure build-up causes a variety of symptoms, including tiredness, difficulty breathing, and reduced ability to exercise/walk.

This study is to help evaluate a new device (the "Axon System") designed to reduce the build-up of pressure described above. The Axon system is a catheter used to ablate or destroy the splanchnic nerve on one side of the body. The Sponsor believes by destroying this nerve there may be some reduction in the symptoms caused by HFpEF. The procedure using the Axon System will be performed in the catheterization lab and does not involve surgery. Participants will stay overnight in the hospital following the procedure for observation.

The length of subject participation in the study will be approximately 12 -14 months and includes 7 office visits, 2 phone calls and 3 procedures. Participants in this research study will be randomized to either the treatment group or the control group and have a 50:50 chance of receiving the research treatment with the Axon System at the time of randomization.

This study will help us learn more about how safe and effective the Axon System is in treating the symptoms of patients with HFpEF.

Volunteers are being asked to participate in a clinical research study to find out if the drug mavacamten is safe and effective in treating elevated biomarker levels that occur in patients who have Heart Failure with Preserved Ejection Fraction (HFpEF). HFpEF is a syndrome that leads to stiffening in the left bottom chamber of the heart. This stiffening makes it difficult for the chamber to relax enough to fill up with blood, leading to increased pressure inside of the heart. MyoKardia is doing this research to find out if the new medication called mavacamten will work and be safe for the treatment of heart failure patients with the elevated levels the biomarkers NT-proBNP (a marker of wall stress inside the heart) and/or cardiac troponin (a marker of heart muscle injury). Biomarkers are biological molecules found in bodily fluids that can indicate abnormal conditions within the body. The study is planned to go on for about 2 years and include 35 patients from about 30 different study sites.