6.3 Strategies for HFpEF: Mavacamten, SESAME, PIMSRA, or More Shunts?

Problem Presenter: Adam Greenbaum

These proceedings summarize the educational activity of the 18th Biennial Meeting of the International Andreas Gruentzig Society held January 27 to 30, 2026, in Puerto Ayora, Santa Cruz, Ecuador.

Faculty Disclosures     Sponsors

2026 IAGS Summary Document

Statement of problem or issue

Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for approximately one-half of all heart failure cases, and its prevalence is increasing.[1] No drug has yet been proven to reduce mortality in HFpEF patients; therefore, medical therapies are focused on relief of symptoms and reduction in comorbidities. While some comorbidities are modifiable, like hypertension, obesity, sleep apnea, and metabolic syndrome, others are not, like age and female sex. An overview of current approaches in HFpEF is shown below:

• SGLT2 inhibitors (empagliflozin, dapagliflozin)
  • Reduce hospitalization and cardiovascular death
• MRA (mineralocorticoid) inhibitors (finerenone, spironolactone)
  • Reduce hospitalization and cardiovascular death
• ARN inhibitors (sacubitril/valsartan)
• Beta blockers/Calcium channel blockers for atrial fibrillation
• Diet/weight loss (GLP-1 antagonists)
  • Improve 6-minute walk test; KCCQ (semaglutide)
  • Reduce HF hospitalizations (tirzepatide)
• Exercise

Gaps in current knowledge

How to combine and adjust medical therapies to reduce HF hospitalizations, improve quality-of-life, and ultimately reduce mortality, is a knowledge gap area that requires additional research studies. In addition, various devices have been proposed as therapies in HFpEF. However, one aggressive approach, inter-atrial shunting, was found to benefit only patients with HFrEF, but was harmful in patients with HFpEF.[2] The reasons for this are unknown and constitute a knowledge gap.

Another large knowledge-gap area are physiologic parameters and endpoints. We do not yet know which parameters are most useful for assessing clinical status and response to therapy. Some candidates are listed below:

• Hemodynamics (which?)
• Measures of diastolic function (which?)
• Hospital admissions for heart failure
• Quality-of-Life scores
• Mortality

Possible solutions or future directions

There are two avenues for future approaches: novel drugs and novel devices.

Novel drugs

• Cardiac myosin inhibitors (mavacamten, aficamten, RLC-1)
  • Reduce NT-proBNP, troponin
  • Improve diastolic dysfunction and NYHA class in some phase 2 studies
• Soluble guanylate cyclase (sGC) stimulators (riociguat, vericiguat, cinaciguat)
  • Increase cGMP, enhance nitric oxide (NO)
  • Vasodilatation, increase cardiac output
  • Improve hemodynamics in HFpEF
• Anti-inflammatory drugs (IL-1 antagonists)
  • Decrease CMP, increase peak VO2 (Anikinra)
• Anti-fibrotic drugs (VS-041)
  • MMP and endotroponin inhibition – improves diastolic dysfunction

Novel devices and transcatheter therapies

• Alternative inter-atrial shunt concepts
  • Concentrate on specific patient subsets
  • Examine shunt size and/or shunt characteristics
• Cardiac contractility modulation (CCM)
  • Approved for HFrEF
  • Device delivers signals during diastole (5 hours/day, 1-hour intervals, recharge 40-60min/week)
  • Improves calcium cycling, enhances contractility

• Renal denervation
  • Reduces sympathetic drive, lowers blood pressure, may decrease inflammation
  • Preclinical and pilot studies show –
    - Increased VO2, E/e’ ratio, NT-pro-BNP, NYHA class
  • Improves cardiac function, increases exercise capacity, fewer hospitalizations
  • The UNLOAD-HFpEF sham-controlled trial (NCT05030987) is currently underway
• Splanchnic nerve ablation

• Targets the right greater splanchnic nerve (access via the azygous vein)
• Reduces filling pressures in response to exercise

• Pericardial resection
  • The PeriCut company makes a small device to perform percutaneous pericardiotomy via the subxiphoid approach

The CCM approach in patients with HFpEF was studied in a small pilot trial.[3] The results showed improvements in NYHA class and exercise tolerance, concomitant reductions in hospitalizations, and an 18-point increase in KCCQ scores.[3] A larger, sham-controlled clinical trial, the AIM-HIGHer trial (NCT05064709), is currently enrolling, and planned for 1500 patients.

Splanchnic nerve ablation was examined in a sham-controlled randomized trial, the REBALANCE-HF trial. [4] Results showed that the procedure was safe and technically feasible, but did not reduce exercise PCWP at 1 month (the primary endpoint) or improve clinical outcomes at 12 months in a broad population of patients with HFpEF. It is now being targeted at patients with higher filling pressures and less severe diastolic dysfunction.

Pericardial resection was studied in a small pilot trial (REIMAGINE-HFpEF, NCT06702501).[5, 6] Preliminary results found no change in baseline PCWP but less increase in exercise PCWP, lower PA pressures, and increased peak VO2 and KCCQ scores.

The larger question for the future is whether any device therapy will make sense, or be found useful, either alone or in combination with drug therapy.

References

1. WRITING COMMITTEE MEMBERS. HF STATS 2025: Heart Failure Epidemiology and Outcomes Statistics An Updated 2025 Report from the Heart Failure Society of America. J Card Fail. 2026 Feb;32(2):439-498. doi: 10.1016/j.cardfail.2025.07.007. Epub 2025 Sep 22. PMID: 40987671.
2. Stone GW, et al; RELIEVE-HF Investigators. Interatrial Shunt Treatment for Heart Failure: The Randomized RELIEVE-HF Trial. Circulation. 2024 Dec 10;150(24):1931-1943. doi: 10.1161/CIRCULATIONAHA.124.070870. Epub 2024 Sep 23. PMID: 39308371
3. Linde C, et al. Cardiac contractility modulation therapy improves health status in patients with heart failure with preserved ejection fraction: a pilot study (CCM-HFpEF). Eur J Heart Fail. 2022 Dec;24(12):2275-2284. doi: 10.1002/ejhf.2619. Epub 2022 Aug 11. PMID: 35855646.
4. Fudim M, et al. Endovascular Ablation of the Greater Splanchnic Nerve in Heart Failure With Preserved Ejection Fraction: The REBALANCE-HF Randomized Clinical Trial. JAMA Cardiol. 2024;9(12):1143–1153. doi:10.1001/jamacardio.2024.2612
5. Borlaug, B, Strong, M. Heart Failure Solutions: The PeriCut Device as a Treatment for HFpEF. J Am Coll Cardiol Basic Trans Science. 2024 Apr, 9 (4) 448–450. doi:10.1016/j.jacbts.2024.02.010.
6. Killiu A. Percutaneous Pericardiotomy: Preliminary findings from the PeriCut Catheter System Early Feasibility Stud (REIMAGINE-HFpEF). Presented at THT-2026, Boston, MA. Available at: www.thtmeeting.com. Accessed April 20, 2026.