Phenotyping Could Be Useful Tool in Diagnosing HFpEF

The proper diagnosis of heart failure with preserved ejection fraction (HFpEF) can be crucial in prolonging the life of the patient and giving them the best prognosis possible. A panel held during the CHEST 2025 Annual Meeting focused on just that: highlighting the importance of identifying the different types of heart failure and the use of phenotyping in clinical settings.

Lisa Mielniczuk, MD, a cardiologist and senior associate consultant at Mayo Clinic in Rochester, Minnesota, went over not just phenotyping in HFpEF but also diagnosing the heart condition and tailoring therapies around the condition to best suit the patient. The prevalence of heart failure has been increasing for years, according to Mielniczuk, which makes this topic more prevalent than ever.

Phenotyping could be the key in getting accurate treatments to patients with HFpEF, as their specific diagnosis could tell which treatment is likely to work best. | Image credit: lovelyday12 - stock.adobe.com

“It’s estimated that between 2012 and 2030, the prevalence of heart failure is going to increase by about 46%, and about half of all of that heart failure is HFpEF,” she explained. “Similar to our patients with heart failure with reduced ejection fraction, mortality for a patient with HFpEF is significantly reduced at all age cohorts.”

Hospitalization has become a key clinical end point in heart failure due to its association with mortality, according to Mielniczuk, which makes phenotyping in HFpEF interesting because it may help to target particular phenotypes with treatment to address the condition and all comorbidities surrounding it.

To demonstrate this, Mielniczuk shared the results of the TOPCAT trial (NCT00094302),1 which was focused on testing spironolactone vs placebo in patients who have hepatitis. Clinical features, arterial resistance, and echocardiographic features were identified through machine learning, and the participants were split into a first phenotype of a younger cohort with fewer symptoms, a second phenotype of older participants with more atrial fibrillation and more calcification along with chronic kidney disease, and a third phenotype of patients who were likely to have obesity and diabetes. Although all-cause mortality was similar in the latter 2 groups, spironolactone was only significant in the third group, demonstrating that phenotyping these patients has immense benefit in understanding which treatments to use.

Artificial intelligence could be a means of coming up with a proper diagnosis, with Mielniczuk presenting data from a study that found that a machine learning model was able to utilize echocardiograms with a 4-chain chamber clip to estimate the probability of HFpEF. The model performed very well, with HFpEF predicted in 74% of the cases, and was able to predict mortality.2

Ultimately, however, all of this is in service to treating the patient with proper medications. According to Mielniczuk, the Canadian Cardiovascular guidelines released on October 18 recommend that those with HFpEF and heart failure with nonreduced ejection fraction should be treated with sodium-glucose transport 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs).3

“And beyond that, we should now be starting to phenotype. We should be phenotyping to body size, perhaps phenotyping to blood pressure,” she said.

SGLT2s have previously shown the ability to reduce heart failure, hospitalization, and cardiovascular mortality. “We know that these drugs have a profound effect on vascular, cardiac, neurohormonal, and inflammatory functions directly involved in the pathophysiology of habit. SGLT2 inhibitor use should be standard of care for all of our patients with HFpEF,” she concluded.

Other treatments primarily known for their use in heart failure with reduced ejection fraction, such as MRAs and glucagon-like peptide-1 inhibitors, have also shown promise in HFpEF, including tirzepatide in the SUMMIT study (NCT04847557).4 These, said Mielniczuk, should be taken alongside exercise training for chronic HFpEF. Clinical trials for pharmacologic therapies are also in effect, including an interatrial stent that would offload left atrial pressures.

Mielniczuk reiterated that HFpEF is here to stay, with prevalence only increasing and mortality still being significant. “Just like the way our HFpEF patients present with so much heterogeneity, I think we’re moving to an era of management where management is going to be heterogeneous as well. There is no longer a one-size-fits-all for our HFpEF patients, and this is where phenotyping is going to be very important,” she concluded.

References

1. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383-1392. doi:10.1056/NEJMoa1313731

2. Akerman AP, Porumb M, Scott CG, et al. Automated echocardiographic detection of heart failure with preserved ejection fraction using artificial intelligence. JACC Adv. 2023;2(6):100452. doi:10.1016/j.jacadv.2023.100452

3. Virani S, Zieroth S, Aleksova N, et al. Canadian Cardiovascular Society/Canadian Heart Failure Society 2025 guideline update for pharmacologic management of heart failure with nonreduced ejection fraction (LVEF > 40%). Can J Cardiol. Published online October 18, 2025. doi:10.1016/j.cjca.2025.07.027

4. Packer M, Zile MR, Kramer CM, et al. Tirzepatide for heart failure with preserved ejection fraction and obesity. N Engl J Med. 2025;392(5):427-437. doi:10.1056/NEJMoa2410027