Why the Most Common Form of Heart Failure Is Also the Hardest to Treat

If you ask someone to picture heart failure, they will usually imagine a weakened heart that has lost the ability to pump blood effectively.

That image fits a significant portion of cases. But it describes an increasingly smaller share of the disease overall.

Heart failure with preserved ejection fraction (also known as HFpEF) now represents more than half of all heart failure cases, and its share is growing across every region where the data has been tracked. In this form of the disease, the heart’s pumping function is largely intact, but the problem is stiffness. The heart muscle cannot relax and fill properly between beats, so pressure builds, fluid backs up and the patient experiences breathlessness, fatigue, and fluid retention. These are the same symptoms as other forms of heart failure, produced by a different underlying process.

The clinical consequences of that difference are severe. According to the American College of Cardiology, HFpEF is associated with one-year mortality of 20% to 29% and a 30-day all-cause readmission rate of 21%. It will affect nearly one in 10 people by the age of 45. In Canada, it is one of the leading causes of hospitalization for people over 65.

The burden is substantial and growing, and yet the treatment options have not kept pace.

Why Existing Therapies Have Not Translated

The treatments that transformed outcomes in heart failure with reduced ejection fraction were built around the specific mechanisms driving that condition. When tested in HFpEF populations, most delivered weaker signals, narrower benefits or no significant effect. This reflects a mismatch between what existing therapies are designed to do and what HFpEF actually requires, rather than a failure of scientific effort.

The complexity of HFpEF goes well beyond its cardiac presentation. The Heart Failure Society of America’s HF Stats 2025 report documents a pattern central to understanding why the disease has resisted treatment. The proportion of heart failure patients living with three or more cardiovascular-kidney-metabolic conditions (obesity, diabetes, hypertension, chronic kidney disease) has more than doubled when comparing 1999–2002 data against 2015–2020. In HFpEF patients, these comorbidities are not peripheral to the diagnosis. They interact with one another and with cardiac function in ways that actively shape how the disease develops and progresses. A therapy targeting any one of them in isolation addresses one thread of a problem woven from many.

The Experience for Patients and Clinicians

For clinicians, this creates a difficult treatment environment. The evidence base for HFpEF is thinner than for other forms of heart failure. The toolkit developed over decades of cardiovascular medicine provides partial answers at best. Managing these patients often means navigating a complex interaction of conditions, adjusting medications and targets in a space where the guidance is less definitive than the field has been accustomed to.

For patients, the experience is frequently one of severe symptoms, treatments that help only partially, and a diagnosis that is hard to articulate, in part because HFpEF does not match the dominant cultural image of a failing heart. The breathlessness and fatigue are real and often debilitating. The path forward is less clear than most patients are told at the outset.

Where the Research Is Turning

Rather than asking which existing therapeutic class can be adapted to fit HFpEF, researchers are increasingly asking what is driving the disease upstream and whether addressing those processes directly might be more productive than adapting treatments designed for a different condition.

Inflammation is one of the mechanisms drawing significant attention in that context. Research suggests that chronic systemic inflammation contributes to the stiffening of cardiac tissue that defines HFpEF and may help explain the variability in how patients progress and respond to treatment. If that hypothesis holds, the implication is significant: the most productive path forward in HFpEF is not a better version of what has already failed, but a fundamentally different category of intervention: one that targets the biology driving disease rather than the damage it leaves behind.

That is the scientific logic increasingly shaping how researchers approach HFpEF, and it is the premise we at Cardiol Therapeutics have built our research program around.

Related reading

Heart Failure Is Getting Worse. Understanding Why Is the First Step.