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Exploring Heart Failure With Preserved Ejection Fraction
Key Points
"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.
Until the 1980s and 1990s, all congestive heart failure was lumped together based on signs and symptoms. Landmark clinical trials of the 1990s moved the field to divide patients into two distinctive groups based on readily available left ventricular ejection fraction (LVEF) measurements. It became clear that ejection fraction distinguished both response to treatments and prognosis.
After a stint as "diastolic heart failure," heart failure with preserved ejection fraction (HFpEF) now defines those with signs and symptoms of HF due to high LV filling pressure despite normal or near-normal LVEF of 50% or greater. (The definition used, however, has been variable in the research literature, with some studies including an EF as low at 40%; the guidelines, though, continue to use a percentage of >50%.)
The increased LV filling pressure is secondary to diastolic dysfunction, can be observed at rest or with exercise, and causes secondary pulmonary hypertension. It also dramatically limits systolic reserve capacity during stress but with little increase in ejection fraction.
"This syndrome was historically considered to be caused exclusively by left ventricular diastolic dysfunction, but research has identified several other contributory factors, including limitations in left ventricular systolic reserve, systemic and pulmonary vascular function, nitric oxide bioavailability, chronotropic reserve, right heart function, autonomic tone, left atrial function, and peripheral impairments," noted a review in Nature Reviews Cardiology.
Epidemiology
HFpEF accounts for about half of the approximately 6.5 million cases of heart failure in the U.S. Among four community-based cohorts, the incidence of HFpEF was 26.9 per 10,000 person-years.
While heart failure overall is decreasing in age-specific incidence, the trends diverge by ejection fraction. For example, in a study from the Minnesota county near the Mayo Clinic, age- and sex-adjusted incidence of HF declined significantly for both HF types from 2000 to 2010, but with a steeper slope for heart failure with reduced ejection fraction (HFrEF) than for HFpEF (down 45% vs 27.9%). In pooled data from the Framingham Heart Study and the Cardiovascular Health Study, the incidence of HFpEF rose from 4.7 to 6.8 per 1,000 from 1990-1999 to 2000-2009, whereas the rate dropped for HFrEF from 6.6 to 6.2 per 1,000 over that period.
Women have a higher incidence of HFpEF compared with HFrEF. "After adjusting for age and other risk factors, the risk of HFpEF is fairly similar in men and women, unlike the lower risk of HFrEF for women versus men," noted a 2017 review by Margaret Redfield, MD, of the Mayo Clinic in Rochester, Minnesota, and colleagues. In the Atherosclerosis Risk in Communities (ARIC) Community Surveillance study, HFpEF was most common in white females, who accounted for 59% of hospitalized HFpEF.
These numbers should be taken with the acknowledgment that challenges in the diagnosis of HFpEF, due to its multiple etiologies and lack of a single diagnostic test, make estimation of incidence and prevalence more difficult, noted a 2020 review by Nandini Nair, MD, of Texas Tech Health Sciences Center in Lubbock.
Pathogenesis
The heterogeneity continues in the pathophysiology and pathogenesis of HFpEF.
"Multiple individual mechanisms frequently coexist within the same patient to cause symptomatic heart failure, but between patients with HFpEF the extent to which each component is operative can differ widely," said the authors of a review in Nature Reviews Cardiology.
The variety of etiologies has contributed to challenges in finding effective treatments, as another review points out.
"Pathophysiology of HFpEF is multifaceted stemming from several disease-specific aspects of inflammation and endothelial function, cardiomyocyte hypertrophy and fibrosis, ventricular-vascular uncoupling, pulmonary hypertension, and chronotropic incompetence," those authors added. Peripheral impairments in endothelial function, body composition, and skeletal muscle function also play an important role in HFpEF.
Although development of animal models of HFpEF and other mechanistic research has lagged, some findings are emerging implicating nitric oxide synthase suppression and lipotoxicity as well as upregulation of reactive oxygen species.
Myocardial remodeling research has also shown that abnormal fibroblasts in HFpEF are "apoptosis resistant and initiate the development of an abnormal myocardial matrix resulting in initiation and progression of the disease," Nair noted in her paper. "Further investigation could provide new avenues to target therapeutics specifically to stop initiation and progression of fibrosis."
Older age is a big risk factor for HFpEF, but others are hypertension, obesity, and coronary artery disease.
Risk factors differ by HF subtype, according to AHA statistics for 2022. Large-scale, community-based studies have shown a greater impact of older age for incident HFpEF than for HFrEF, with a relative hazard ratio of 1.91 vs 1.69 per 10-year age increase, respectively. Male gender, prior myocardial infarction, left ventricular hypertrophy, and left bundle-branch block are all more strongly linked to HFrEF than HFpEF.
HFpEF is increasingly seen as a condition of multimorbidity -- i.E., the co-occurrence of two or more chronic conditions, such as cardiometabolic disorders including diabetes, obesity, sleep apnea, etc.
While both types of patients commonly face multimorbidity, it is slightly more severe in HFpEF, Redfield and co-authors noted. "A majority of deaths in patients with HFpEF are cardiovascular, but the proportion of noncardiovascular deaths is higher in HFpEF than HFrEF."
"Beyond classifications of EF and staging in HF, clinicians should seek the cause of HF because appropriate treatment may be determined by the cause," the 2022 heart failure guidelines state.
There is some evidence that lack of exercise may result in HFpEF, and that increased exercise may be a therapy for HFpEF.
Read Part 1 of this series: Heart Failure: A Look at Low Ejection Fraction
Up next: HFrEF Diagnosis and Evaluation
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What's The Difference Between Systolic And Diastolic Heart Failure?
In systolic heart failure, the heart cannot effectively contract with each heartbeat. In diastolic heart failure, your heart cannot relax between heartbeats. Both types can lead to right-sided heart failure.
Heart failure occurs when your heart is unable to pump the amount of blood your body needs to keep you healthy. It can occur on the left or right side of the heart or on both sides.
The left side is in charge of pumping oxygen-rich blood into your body, while the right side collects blood that's low in oxygen from your veins and sends it to your lungs to collect oxygen, after which it returns to the left side.
If you have left-sided heart failure, it means your heart is not pumping enough blood out to your body. Your heart may pump less efficiently when you're doing physical activity or feeling stressed.
Two types of heart failure can affect the left side of the heart: systolic and diastolic. The diagnosis depends on how well your heart can pump blood.
If you have systolic heart failure, it means your heart does not contract effectively with each heartbeat. If you have diastolic heart failure, it means your heart isn't able to relax normally between beats.
Both types of left-sided heart failure can lead to right-sided heart failure. Right-sided heart failure happens when the right ventricle functions poorly due to poor contraction or high pressure in the right side of the heart.
When it comes to diagnosing and managing these two types of heart failure, there are some similarities and some differences. Read on to find out what you need to know about systolic and diastolic heart failure.
If you have systolic or diastolic heart failure, you may experience symptoms such as shortness of breath after routine physical activity. Depending on the function of your heart, actions like climbing stairs or walking a short distance may cause these symptoms.
Symptoms of left-sided heart failure can include:
However, in the early stages of heart failure, you may not have any symptoms.
Doctors diagnose heart failure clinically at a patient's bedside. The diagnosis is confirmed based on the results from imaging tests, symptoms, and other lab tests, such as blood tests.
If doctors suspect you have heart failure, they may perform tests that can include:
Systolic heart failure happens when the left ventricle of your heart cannot contract completely. That means your heart will not pump forcefully enough to move your blood throughout your body in an efficient way.
It's also called heart failure with reduced ejection fraction (HFrEF).
Ejection fraction (EF) is a measurement of how much blood leaves a heart ventricle every time it pumps.
Doctors determine your EF as a percentage with an imaging test such as an echocardiogram. Between 50 and 70 percent EF is the typical range, according to the American Heart Association (AHA). It's still possible to have other types of heart failure, even if your EF is within that range.
If your EF is under 40 percent, you may have reduced ejection fraction or systolic heart failure.
Diastolic heart failure diagnosisDiastolic heart failure occurs when your left ventricle can no longer relax between heartbeats because the tissues have become stiff. When your heart cannot fully relax, it won't fill up again with blood before the next beat.
This type is also called heart failure with preserved ejection fraction (HFpEF).
For this type, your doctor may order an imaging test on your heart and determine that your EF looks fine.
Your doctor will then consider whether you have other symptoms of heart failure and if there's evidence from other tests that your heart is not functioning properly. If those criteria are met, you may be diagnosed with diastolic heart failure.
This type of heart failure most often affects older people and also affects more females than males. It typically occurs alongside other types of heart disease and other non-heart-related conditions such as cancer and lung disease.
Having high blood pressure, also called hypertension, is one of the most important risk factors. Another important risk factor is untreated sleep apnea.
There are different medications available to treat systolic heart failure. These can include:
Standard treatment can involve a combination of these medications, since each class of medication targets a different mechanism of heart failure.
A typical treatment regimen can include: ARNI, ARB, or ACE I along with a beta-blocker and an MRA. Diuretics may also be used for people who continue to have problems with urine retention despite other medical treatments and while following a low salt diet.
There is new evidence that SGLT2, originally a diabetes medication, can reduce the likelihood of death and re-hospitalization. It is now a standard part of heart failure treatment.
A review published in 2017 looked at 57 previous trials involving combination treatments. It found that people who took a combination of ACE inhibitors, BBs, and MRAs had a 56 percent reduced risk of death from systolic heart failure, compared with people who took a placebo.
People who took a combination of ARN inhibitors, BBs, and MRAs had a 63 percent reduced death rate compared with those who took a placebo.
Doctors may treat diastolic heart failure using many of the same medications that are options for systolic heart failure.
In general, the main approaches to treating diastolic heart failure with medication include:
Doctors may also recommend adopting a heart-healthy lifestyle as part of a cardiac rehabilitation program.
Recommendations can include:
For some people with left-sided heart failure, a device that is surgically implanted improves heart function. Types of devices can include:
In some cases, surgery may be recommended to treat left-sided heart failure. The two main types of surgery can include:
Systolic and diastolic heart failure both affect the left side of the heart. The left side of the heart is in charge of pumping oxygen-rich blood to the body. Having left-ventricle heart failure means that your heart is not able to efficiently pump all the blood that your body needs.
This can cause symptoms such as shortness of breath, fatigue, and weakness.
Doctors can diagnose left-ventricle heart failure as systolic, which means the heart is unable to contract well during heartbeats, or diastolic, which means the heart is unable to relax between heartbeats.
Both types of heart failure have treatment options, ranging from medication and adopting a heart-healthy lifestyle to implanted devices, surgery, and transplantation.
A primary care doctor provides overall healthcare and is your main point of contact for health concerns. They can refer you to a cardiologist, who specializes in heart disease.
A cardiologist may order tests to monitor your condition and recommend medication, certain procedures, surgery, or lifestyle changes. Both doctors often work with nurses and physician assistants.
A cardiac surgeon may perform coronary bypass surgery, heart valve repair, or other operations to treat underlying causes of heart failure. They may implant a device to help your heart work. Rarely, they may do a heart transplant. Their team may include nurses and physician assistants.
Cardiac rehabilitation includes lifestyle education, physical exercises, and psychosocial support. It can help strengthen your heart, improve your well-being, and reduce your risk of future heart problems. Your team may include nurses, occupational therapists, and physical therapists.
A balanced diet protects your heart and may help you lose weight. A registered dietitian can help you develop a sustainable, heart-healthy diet. You may need to adjust your intake of calories, saturated fat, sodium, or fluids.
Tobacco, alcohol, and other drugs can damage your heart and blood vessels. A smoking cessation or substance use counselor can help you stop using these substances if you find it hard to quit. They may prescribe medication and counseling.
Heart disease raises the risk of anxiety, depression, and post-traumatic stress disorder (PTSD), which can affect heart health.
A psychologist, clinical social worker, or licensed counselor may help treat mental health conditions with psychotherapy. A psychiatrist can prescribe medication if needed. Social workers can connect you with support services and assist with legal, financial, and insurance concerns.
Palliative care doctors and nurses provide care to ease heart failure symptoms and treatment side effects, such as fatigue and nausea. A palliative care social worker helps you and your family plan for the future. Palliative care may improve quality of life at any stage of heart failure.
It's common to have questions about medications, especially when they're first prescribed to you. Your pharmacist can help explain medication dosing and timing as well as check for interactions with other prescription drugs, foods, or supplements.
No-Implant Shunt For HF Looks Safe, Feasible In Early Snapshot
PHOENIX, AZ—A no-implant interatrial shunt (PAS-C; InterShunt Technologies) delivered percutaneously appears to reduce pulmonary capillary wedge pressure (PCWPs) and provide symptomatic relief for patients with heart failure with preserved ejection fraction (HFpEF), according to the results of EASE-HF.
The study was very small with just 10 patients, but Gil Vardi, MD (St. Louis Heart & Vascular, MO), who presented the results last week at TVT 2023, said postprocedure left-to-right atrial flow was observed in all patients and that there were no adverse events or complications observed. Vardi, who founded the company developing this shunt technology, said EASE-HF "demonstrates the safety and feasibility" of the procedure, noting the atrial shunt remained durable out to 6 months.
In a second presentation, Christopher Meduri, MD (Karolinska University Hospital, Stockholm, Sweden), provided an update on another no-implant shunt (Alleviant), one that is also being tested in patients with HF with midrange EF (HFmrEF).
Across four study programs, 38 patients have been treated so far, with the device safely and successfully establishing a shunt between the left and right atrium. In follow-up of 33 patients at 12 months, investigators observed improvements in NT-proBNP, functional capacity, and quality-of-life metrics. Additionally, peak exercise PCWP also declined in the shunted patients.
Interatrial shunts are designed to reduce left atrial pressure and volume overload, particularly in patients with HFpEF, although they are also being tested in those with HFmrEF or heart failure with reduced EF (HFrEF). In the REDUCE LAP-HF II trial, which is the only randomized, sham-controlled study to date, an atrial shunt didn't reduce HF events or improve health status in more than 600 patients with HFpEF. There was a signal of benefit in some subgroups, such as those without latent pulmonary vascular disease and those without pacemakers, which encouraged investigators.
As reported by TCTMD, excitement persists for the technology, partly on the basis of other single-arm studies showing that shunt creation can improve exercise capacity and quality of life, as well as reduce PCWP at rest or during exercise. But it's very early days.
In the EASE-HF study, peak PCWP declined from 32.4 mm Hg at baseline to 26.7 mm Hg at 30 days. At 6 months, all 10 patients had NYHA class II symptoms and there was a significant increase in 6-minute walk test distance, said Vardi. Quality of life also improved, with nine of 10 patients having a more than 15-point improvement in the Kansas City Cardiomyopathy Questionnaire score. NT-proBNP levels also significantly declined from baseline to 6 months.
With the Alleviant shunt, Meduri said investigators are currently embarking on an ambitious study, with anywhere from 400 to 700 patients expected to be enrolled in the ALLAY-HF trial led by James Udelson, MD (Tufts Medical Center, Boston, MA). That trial will include patients with symptomatic HFpEF or HFmrEF, which includes those with LVEF ≥ 40%.
Leaving Nothing but a Hole
Unlike other atrial shunts being tested, the PAS-C and Alleviant technologies (as well as a third, NoYa) leave no permanent implant as scaffold. Instead, PAS-C uses a mechanical cutting approach, first capturing and then excising tissue from the interatrial septum. The Alleviant shunt differs from PAS-C in that it uses radiofrequency (RF) energy to create the shunt.
To TCTMD, Meduri said the rationale for the no-implant approach is to avoid leaving something behind that might interfere with future left-sided procedures.
"The ability to navigate the septal space to do another intervention on the left side, if you have a device in the septum, is significantly more challenging," said Meduri. "It doesn't make it impossible, but it does make it harder to get over, and when it's harder you might not get an optimal transseptal puncture." As a result, it may be more difficult to achieve the best possible result for these left-sided procedures.
Even on its simplest level, "leaving behind something in the body leaves the patient at risk for something going wrong," said Meduri. "The ability to provide the same result with nothing left in the body is the optimal way. Most people, conceptually, can understand that pretty well."
There's also the possibility that leaving no rigid supporting structures against the septum might also be beneficial for hemodynamics.
During the TVT session, Samir Kapadia, MD (Cleveland Clinic, OH), one of the panel discussants, questioned what happens afterwards with no-implant shunts, noting that one of the concerns is that after the removal of the tissue, depending on the anatomy of the septum, the hole might either shrink, or worse, continue to enlarge. "This is an issue," Kapadia said. "Sometimes, when you create a hole, it can get bigger, especially with a flimsier septum."
Continuing follow-up in EASE-HF may help answer this question. According to Vardi, patients are being followed for 1 year, which will also give investigators an opportunity to look for any changes in the shunt's dimensions.
Meduri said there are animal data testing different approaches to creating a patent, implant-free shunt. With the RF approach, the tissue at the shunt's edges is almost sealed after healing, the goal being to keep the shunt's size consistent, he said, rather than shrinking over time.
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