Johns Hopkins Medicine

Johns Hopkins conducted studies to identify whether sex hormones are a significant factor in the problem and sought to identify potential solutions, tests and therapies

Heart failure affects an estimated 6 million Americans each year. Nearly half of cases requiring hospitalizations are caused by heart failure with preserved ejection fraction, also known as HFpEF. This occurs when the left ventricle can contract or pump normally but is unable to relax between heartbeats, which can lead to higher pressure within the muscle. Johns Hopkins used AHA funding to focus on HFpEF and why the condition is more common in older women, particularly African Americans. Despite the prevalence of HFpEF, there are no specific effective treatments. Much of the study focused on cyclic GMP (cGMP), a signaling molecule, or “second messenger,” vital to organ function, that produces its effect through the enzyme protein kinase G (PKG).

Center Research Overview

Pamela Ouyang, MBBS, MD, Center director for Johns Hopkins University
Pamela Ouyang, MBBS, MD

We were interested in the sex differences but also that the underlying mechanisms leading to HFpEF may be very heterogenous and maybe there are subgroups within that population, and, ultimately, therapy may need to be focused in different subgroups, as opposed to one-size-fits all — and maybe that’s why studies to-date have not shown particular therapies that have helped the overall population,” said Center Director Pamela Ouyang, MBBS, MD.

Patients were recruited from a heart failure pool for the clinical studies, and data was also analyzed from cohorts of participants that had already been studied for decades. The basic, clinical and population studies included biopsies, blood work, exercise tests and MRIs to look at muscle and fat distribution. A separate study in mice looked at the function of estrogen and ovaries when it came to heart pathway modulation.

Some findings have already been enlightening and, at times, surprising.

“What our team found was that many of the patients with HFpEF had a condition called amyloid,” said Wendy Post, MD, MS, “abnormal protein deposits in the wall of the heart — and that makes the heart stiff, makes the pressure go up and can cause HFpEF. So, with these biopsies, we saw a relatively high prevalence of amyloid in HFpEF. I think that’s leading to a greater awareness of the fact that, when we see older patients who are more likely to have amyloid who also have HFpEF and thick heart wall muscles, we should also do a complete work-up for amyloid, which is now treatable.”

"When it came to heart wall thickness relative to cGMP, studies concluded the opposite of what researchers had expected," Post said.

They had assumed lower levels of cGMP would be associated with thicker muscle — often a precursor or indicator of HFpEF. But it turned out that higher levels were a better predictor because the body was producing more as a “compensatory mechanism.”

“So, it appears that higher cGMP in the blood is a marker of future risk,” she said.

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