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HFpEF in women: A growing public health issue that requires more attention
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HF with preserved ejection fraction, or HFpEF, is a disease of aging. Experts today are discovering that more HF cases are presenting with preserved ejection fraction than in the past decade, especially in women. HFpEF also is a disease without established therapy, and recent studies have not demonstrated significant benefits of potential new treatments under investigation. Clinicians rely on consensus, professional guidelines and individualization of therapy.
“We need more research in women and in HF with preserved ejection fraction,” said C. Noel Bairey Merz, MD, a member of the Cardiology Today Editorial Board. Bairey Merz is also the Women’s Guild endowed chair in women’s health; director of the Barbra Streisand Women’s Heart Center; director of the Preventive Cardiac Center; and professor of medicine at Cedars-Sinai Medical Center.
Although the incidence of HF in general has remained relatively flat during the past 10 years in the United States, the case allocation may be changing.
Véronique L. Roger, MD, discussed the
growing number of HF cases presenting
with preserved ejection fraction.
Source: Mayo Clinic; reprinted with permission
“The incidence of HF has remained stable, but a greater proportion of cases are presenting with preserved ejection fraction over time,” said Véronique L. Roger, MD, professor of medicine and professor of epidemiology at Mayo Clinic in Rochester, Minn.
It is estimated that more than 1 million patients are hospitalized for HF each year, 50% of whom have HFpEF.
“HFpEF is a disease of older women,” Lee R. Goldberg, MD, associate professor of medicine, University of Pennsylvania, said in an interview.
Women outnumber men by a 2:1 ratio, according to a 2011 report by Dawn C. Scantlebury, MD, and Barry A. Borlaug, MD. “Sex-specific maladaptations to hypertensive aging in women may underlie greater risk of HFpEF,” Scantlebury and Borlaug wrote in Current Opinion in Cardiology.
Experts expect the numbers to continue to rise.
“Better understanding of HFpEF is critical because it is growing relative to HF with reduced ejection fraction by 1% per year, and we have no treatment. With the epidemic of childhood obesity in the United States, I would expect that this problem will only get worse as the next generation reaches their 60s,” Borlaug, director of circulatory failure research and associate professor of medicine at Mayo Clinic, told Cardiology Today.
Increased awareness
Mariell Jessup
“There is increasing recognition of HFpEF in the medical community,” said Mariell Jessup, MD, American Heart Association president and professor of medicine at University of Pennsylvania Heart and Vascular Center.
“Many true HFpEF patients were formerly told, ‘you’re just getting old’ or ‘you’re too overweight’ because the gross measure of heart function that we obtain routinely [the ejection fraction on echocardiography] was normal,” Borlaug said. “This led physicians to erroneously exclude HF as a diagnosis. There is now much better, though still incomplete, appreciation of the magnitude of this problem, which is substantial.”
Management of HFpEF
Despite the rising incidence, research and established therapies for HFpEF are lacking.
Barry A. Borlaug
“In contrast to HF with reduced EF [systolic HF], there is no proven effective treatment for HFpEF. We rely on consensus guidelines and individualization of therapy,” Borlaug said.
In Jessup’s practice, “women who complain of fatigue and breathlessness are taken seriously and the possibility of HF is explored,” she said. “The use of biomarkers and more sophisticated imaging techniques have facilitated clinicians in making the diagnosis.
“Comorbidities in these women are highly prevalent, including CAD, diabetes, atrial fibrillation and hypertension; these conditions must be addressed. Many of these patients also have sleep apnea as well. Exercise training seems to help symptoms in many patients for unclear reasons,” she said.
Now may be the time to emphasize prevention of HFpEF.
“We have to place a more vigorous focus on prevention, with efforts directed toward better control of hypertension and avoidance of obesity and diabetes,” Jessup said.
Available evidence
Few clinical trials have focused exclusively on HFpEF, even fewer on HFpEF in women.
“We don’t have the blockbuster trials that we have had in systolic HF. For HFpEF, it is much more expert consensus as opposed to clinical trials results,” Goldberg said.
Jessup said the lack of clinical evidence is discouraging, “There are no positive trials showing the efficacy of medications in HFpEF. The latest trial from the HF-Network (RELAX) was likewise negative.”
RELAX was a randomized trial that tested the effect of the phosphodiesterase-5 inhibitor sildenafil (Revatio, Viagra; Pfizer) vs. placebo on exercise capacity and clinical status. “The trial unfortunately failed to show a benefit,” Borlaug said.
“Recent trials are focused on aldosteone antagonists,” Goldberg said.
Anticipated results from the large, international TOPCAT trial presented at the AHA Scientific Sessions in November demonstrated that spironolactone treatment did not yield significant reductions in the primary outcome of CV mortality, aborted cardiac arrest or HF hospitalization when compared with placebo in patients with HFpEF.
The drug was, however, associated with reductions in hospitalizations for HF.
An earlier trial, Aldo-DHF, also investigated spironolactone in this patient population. “This study showed that spironolactone improved measures of heart function but failed to improve symptoms or exercise capacity,” Borlaug said.
Aldo-DHF researchers concluded that long-term aldosterone receptor blockade improved LV diastolic function, but further research is needed to determine whether this improvement is clinically significant.
In the Japanese Diastolic Heart Failure Study (J-DHF), researchers tested carvedilol (Coreg, GlaxoSmithKline) in patients with HFpEF. Results of the multicenter, prospective, randomized trial demonstrated that low-dose carvedilol did not improve prognosis. Researchers called for additional research on the effectiveness of the standard dose.
Lee R. Goldberg
Metalloproteinase inhibitors are also under investigation. These compounds are thought to make the heart more flexible, less stiff and less thickened, according to Goldberg.
Borlaug discussed why trials might be exhibiting negative results.
“While the ‘party line’ is that diastolic dysfunction explains most or all of HFpEF, our group and others have recently shown that there are significant limitations in heart and blood vessel reserve capacity with stress. The most common stress encountered in everyday life is exercise, and patients with HFpEF cannot increase their forward pumping function, increase their heart rate, utilize oxygen in the muscles, or relax the blood vessels as well as normal people. This multifaceted aspect of the disease likely explains why many of the previous trials have been negative — if you test a drug that improves only one component of heart or blood vessel function, it may not be adequate to improve the overall system in such a complex and highly integrated ‘systems disease,’” Borlaug said.
Future directions
Supporting research to better understand HFpEF is imperative, Roger said.
A diagnosis of HFpEF should “be a wake-up call for patients to focus their energy on controlling the underlying diseases that are affecting their heart,” Goldberg said.
C. Noel Bairey
Merz
“Understanding the role and treating vascular stiffness and compliance to improve ventricular function are important areas of focus for future strategies in treating HFpEF,” Bairey Merz said. “We are exploring microvascular coronary dysfunction related ischemia as a mechanistic pathway for HFpEF.”
Borlaug discussed hope for treatments.
“There is hope for spironolactone,” he said. “Drugs and interventions that increase the production of [cyclic guanosine monophosphate] are believed by many to hold great promise, since this can decrease the stiffness of heart cells and prevent or reverse the heart remodeling seen with aging and high blood pressure. Many patients with HFpEF have an inadequate increase in heart rate during exercise, and it may be that pacemakers could improve symptoms in HFpEF. There is also some evidence that energy reserves in heart cells are inadequate, and this may explain the ‘reserve dysfunction.’ New drugs that improve these energy reserves might also hold promise. Exercise training needs no further testing and should already be encouraged, but a major barrier is patient compliance. Many patients start the training, but it is difficult to keep it up to have sustained improvements.”
In the meantime, “HFpEF remains a disease that we don’t understand well. What is important on the clinical side, in addition to the research agenda, is to do everything we can to control the risk factors for HFpEF. This is an issue of preventing HFpEF, and addressing and controlling CVD risk factors is critical,” Roger said. – by Suzanne Bryla
Disclosure: Borlaug reports consulting or serving on advisory boards regarding HFpEF for Amgen, GlaxoSmithKline and Medscape; he does not report any personal interest. Bairey Merz is a Gilead-sponsored investigator. Goldberg, Jessup and Roger report no relevant financial disclosures.