Tag: heart failure

A Surprising Benefit of Dapagliflozin in Patients with Heart Failure

Photo by Artem Podrez from Pexels

Dapagliflozin, widely used to treat type 2 diabetes, was shown to improve symptoms and physical limitations in patients with heart failure with preserved ejection fraction, according to clinical trial results reported in Nature Medicine.

Heart failure with preserved ejection fraction (HFpEF) occurs when the heart’s lower left chamber is unable to fill with blood properly. The condition accounts for approximately half of all heart failure cases and disproportionally affects older individuals. Patients with HFpEF can experience a host of debilitating symptoms linked to cardiometabolic abnormalities, including physical limitations, impaired cognition and poor quality of life. Life expectancy is also reduced for patients with this diagnosis, with 50% of patients with the diagnosis not expected to survive more than five years.

Finding ways to improve patients’ health and developing or identifying therapeutic interventions that not only reduce hospitalisation but also improve patient survival is key, the researchers said, but at present there are no available treatments that improve patient survival for patients with HFpEF.

Previous studies have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors – which inhibit SGLT2 receptor proteins produced by the kidneys and are used to treat type 2 diabetes – reduces risk of cardiovascular death and heart failure-related hospitalisation in patients with HFpEF.

For this trial, the researchers measured patient-reported symptoms, physical limitations and function in patients with HFpEF who were taking dapagliflozin, an SGLT2 inhibitor drug.

A total of 324 patients with HFpEF, 56.8% women, were randomised to receive either dapagliflozin or placebo for 12 weeks and at the end of the trial were evaluated using the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, a measure of heart failure-related health status.
“It’s important to note the percentage of women that were enrolled in this study because usually women are under-enrolled in clinical trials,” pointed out study co-author Professor Sadiya Khan.

Compared to the placebo group, an overall improvement in patient-reported symptoms, physical limitations and exercise function was seen in the dapagliflozin group. Adverse events were also similar between both groups, the authors reported.

“It was definitely surprising and very exciting to see such a stark difference between the treatment group and the placebo group, that there was this clear separation that happened even over a short period of time,” Prof Khan said, adding that next steps will be to investigate dapagliflozin’s precise molecular mechanisms that enable its effectiveness.

Source: Northwestern University

Heart Failure Risk Further Increased by Aspirin Use

Aspirin may increase heart failure risk in at-risk people
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Aspirin use is associated with a 26% higher risk of heart failure in people with at least one risk factor for it, according to a study published today in ESC Heart FailureRisk factors included smoking, obesity, hypertension, high cholesterol, diabetes, and cardiovascular disease.

“This is the first study to report that among individuals with a least one risk factor for heart failure, those taking aspirin were more likely to subsequently develop the condition than those not using the medication,” said study author Dr. Blerim Mujaj of the University of Freiburg, Germany. “While the findings require confirmation, they do indicate that the potential link between aspirin and heart failure needs to be clarified.”

The influence of aspirin on heart failure is controversial, and so the study sought to investigate its association with heart failure incidence in people with and without heart disease and assess whether it is related to a new heart failure diagnosis in at-risk individuals.

The analysis included 30 827 individuals at risk for developing heart failure who were enrolled from Western Europe and the US into the HOMAGE study. The definition of “at risk” included one or more of the following: smoking, obesity, hypertension, high cholesterol, diabetes and cardiovascular disease. Participants were aged 40 years and older and were free of heart failure at baseline. Aspirin use was recorded at enrolment and participants were classified as users or non-users. Participants were followed-up for the first incidence of fatal or non-fatal heart failure requiring hospitalisation.

Average participant age was 67, 34% were women, and at baseline, a total of 7,698 participants (25%) were taking aspirin. During the 5.3-year follow-up, 1330 participants developed heart failure.

The investigators assessed the association between aspirin use and incident heart failure after adjusting for factors including demographic variables, medical history and medication. Taking aspirin was independently associated with a 26% raised risk of a new heart failure diagnosis.

For consistency, the researchers repeated the analysis after matching aspirin users and non-users for heart failure risk factors. In this matched analysis, aspirin was associated with a 26% raised risk of a new heart failure diagnosis. After excluding patients with a history of cardiovascular disease, in 22 690 participants (74%) without cardiovascular disease, aspirin use was still associated with a 27% increased risk of incident heart failure.

Dr Mujaj noted that “this was the first large study to investigate the relationship between aspirin use and incident heart failure in individuals with and without heart disease and at least one risk factor. Aspirin is commonly used – in our study one in four participants were taking the medication. In this population, aspirin use was associated with incident heart failure, independent of other risk factors.”

He concluded that “large multinational randomised trials in adults at risk for heart failure are needed to verify these results. Until then, our observations suggest that aspirin should be prescribed with caution in those with heart failure or with risk factors for the condition.”

Source: European Society of Cardiology

A Year of Exercise Reverses Heart Failure Signs

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In a small study, a year of exercise training helped to maintain or increase the youthful elasticity of the heart muscle among people in late middle age showing early signs of heart failure.

Published in Circulation, the research reinforces the notion that “exercise is medicine,” an important shift in approach, according to the researchers.

The study focused on heart failure with preserved ejection fraction, which is characterised by stiffening of the heart muscle and high pressures inside the heart during exercise. Once established, the condition is largely untreatable and causes fatigue, excess fluid in the lungs and legs, and shortness of breath.

“It is considered by some to be one of the most important virtually untreatable diseases in cardiovascular medicine,” said senior author Dr Benjamin Levine,  professor of internal medicine at UT Southwestern and director of the Institute for Exercise and Environmental Medicine at Texas Health Presbyterian Dallas. “So, of course, if there are no therapies, then the most important thing to do is to figure out how to prevent it from happening in the first place.”

In previous studies, prolonged exercise training was shown to improve heart elasticity in younger people, but was ineffective for heart stiffness in people 65 and older. The researchers decided to see if committed exercise could improve heart stiffness in healthy, sedentary men and women ages 45 to 64.

The study recruited 31 participants who showed some thickening of the heart muscle and an increase in blood biomarkers associated with heart failure, even though they had no other symptoms such as shortness of breath.

Eleven were randomly assigned to a control group and prescribed a program of yoga, balance and strength training three times a week. The rest were assigned to an individually tailored exercise regimen that gradually ramped up until the participants were doing intensive aerobic interval training for at least 30 minutes at least twice a week, plus two to three moderate-intensity training sessions and one to two strength training sessions each week. 

After one year, the group assigned vigorous exercise training showed a physiologically and statistically significant improvement in measures of cardiac stiffness and cardiorespiratory fitness, compared to no change in the control group.

The results suggest late middle age may be a “sweet spot” for using exercise to prevent heart failure with preserved ejection fraction, before the heart gets too stiff, Prof Levine said. He compared the heart muscle to an elastic band: a new one stretches easily and snaps right back.

“That’s a youthful cardiovascular system,” he said. “Now, stick it in a drawer and come back 30 years later—it doesn’t stretch, and it doesn’t snap back. And that’s one of the things that happens to the circulation, both the heart and the blood vessels as we age, particularly with sedentary aging.”

However, the study cannot determine if the participants will still go on to develop heart failure. This question will have to be addressed by larger studies. Furthermore, it is difficult for people to adhere to an exercise program, and the intensive intervention studied may be difficult and expensive to replicate on a large scale.

Source: American Heart Association

New Approach to Address Cardiac Disease in Rheumatoid Arthritis

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A new approach to address cardiac disease in rheumatoid arthritis (RA) patients has been developed.

Currently patients suffering from RA are also particularly susceptible to diastolic dysfunction, a type of cardiac deficiency which may lead to heart failure, resulting in a higher mortality rate among such patients.
To address this unmet clinical need, researchers from Queen Mary’s William Harvey Research Institute (WHRI) responded by developing an experimental model of cardiomyopathy in inflammatory arthritis.

After several attempts, the researchers finally hit upon the right model by characterising experimental animals with arthritis. The animals developed cardiac diastolic dysfunction, recapitulating the symptoms presented by RA patients. Diastolic dysfunction means the heart is able to contract as normal but unable to dilate properly, ultimately leading to heart failure over time.

Professor Mauro Perretti, lead study author and Professor of Immunopharmacology at Queen Mary University of London said, “As is often the case, the description of a valid model of disease can open new vistas on pathogenic mechanisms as well as on novel therapeutic approaches. At present, the cardiomyopathy of patients affected by rheumatoid arthritis is not treated, and on top of this, current anti-rheumatic drugs (eg biologics or steroids) may even worsen it. As such there is an urgent therapeutic need to intervene and treat, if not cure, the cardiomyopathy of patients affected by rheumatoid arthritis.”

“The broad area of cardiac inflammation is largely unexplored. At the WHRI we have several groups addressing experimental and translational work on several syndromes of the heart. Thus, there is work on myocarditis, on diabetes-induced cardiomyopathy and now with this study, the cardiomyopathy of inflammatory arthritis. The WHRI at Queen Mary University of London is a place of excellence to study cardiac inflammation in all its multiple faces, thanks also to our partnership with the Barts Heart Centre at Barts Health NHS Trust.”

The study was published in PNAS.

Source: EurekAlert!

Unexpected Cognitive Effect of ARNI Therapy in Heart Failure

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Despite fears about cognitive decline in heart failure patients taking angiotensin receptor-neprilysin inhibition (ARNI), an observational study found that the drug instead had a protective effect.

Adults with systolic heart failure taking sacubitril/valsartan (Entresto) starting from 2015–2019 had fewer neurocognitive diagnoses up to 5 years later compared with a those staying on angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) alone.

  • Alzheimer’s disease: 1.11% on ARNI vs 1.24% on ACE inhibitors/ARBs
  • Dementia: 4.18% vs 6.49%
  • Cognitive decline: 11.82% vs 14.53%

On the basis of the PARAGON-HF trial,  sacubitril/valsartan won a broad heart failure indication, reaching into the normal ejection fraction range, for prevention of cardiovascular death and hospitalisation.

“Experimental studies with sacubitril/valsartan have fueled theoretical concerns about neurocognitive side effects, but long-term clinical data are scarce,” noted Prabhjot Grewal, MD, of Stony Brook University Hospital in New York, who reported the findings for the Heart Failure Society of America annual virtual meeting.

She explained that neprilysin inhibition by sacubitril could theoretically inadvertently interfere with the degradation of beta amyloid in the central nervous system, where neprilysin is expressed, in addition to the kidneys where it is most abundant.

However there are many factors in cognitive decline in heart failure, such as the circulatory deficit itself; vascular dementia resulting from comorbidities such as hypertension and vascular disease; and Alzheimer’s disease or Lewy body dementia. By ameliorating heart failure and improving blood pressure, drugs such as ACE inhibitors and sacubitril/valsartan could protect cognition, according to Mandeep Mehra, MBBS, MSc, of Brigham and Women’s Hospital and Harvard Medical School in Boston.

“Thus, even if a drug like sacubitril may cause worsening of one type of cognitive decline, it may be counterbalanced by positive effects on other domains since the reasons for cognitive decline in such patients are almost always multi-factorial and the signals may therefore be obfuscated in general analyses,” explained Mehra, who was not involved in the study.

The authors acknowledged that the observational study lacked systematic characterisation, and also leaves room for residual confounding despite propensity matching.

“This is why we require a prospective study that includes mechanistic end points (degree of beta amyloid protein deposition) in concert with functional outcomes (sensitive measures of cognitive decline) while ensuring that sufficient time is allowed to be evaluated since these are slow and subtle effects,” Mehra said, adding that the PERSPECTIVE trial will likely publish findings in 2022.

Source: MedPage Today

Study Evaluates Efficacy and Tolerability of Ultrafiltration

A new study evaluates the efficacy and renal tolerability of ultrafiltration in acute decompensated heart failure.

Acute decompensated heart failure (ADHF) is a life-threatening and costly disease. Controversy remains regarding the efficacy and renal tolerability of ultrafiltration for treating ADHF. This article by Yajie Liu and Xin Yuan from the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China, and published in Cardiovascular Innovations and Applications, evaluated this clinical issue.

After searching databases for relevant trials, their quality and outcomes were evaluated with the use of the risk of the bias assessment tool and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, respectively. Risk ratio and the standardised or weighted mean differences were computed and pooled with fixed-effects or random-effects models.

The 19-study meta-analysis, involving 1281 patients, found that ultrafiltration was superior to control for weight loss (1.24kg) and fluid removal (1.55L) and was associated with a significant increase in serum creatinine level compared with the control treatments (0.15 mg/dL).
No significant effects were found for serum N-terminal prohormone of brain natriuretic peptide level, length of hospital stay, all-cause mortality, or all-cause rehospitalisation in the ultrafiltration group.

Overall, the meta-analysis found that use of ultrafiltration in patients with ADHF is superior to control treatments for weight loss and fluid removal but has adverse renal effects and lacks significant effects on long-term prognosis.

Source: News-Medical.Net

Lung Fibrosis Drug Pirfenidone Shines in Heart Failure Trial

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Pirfenidone, a drug to treat lung fibrosis, has shown in early trial phases that it could also help patients who suffer from a common form of heart failure.

Trialed by University of Manchester and Manchester University NHS Foundation Trust doctors and scientists, in conjunction with Liverpool Clinical Trials Centre, pirfenidone could offer a much-needed viable treatment for heart failure with preserved ejection fraction (HFpEF). The study was published in Nature Medicine.

Just under a third of 55-year-olds will develop heart failure, and 2 to 3 of every 10 people diagnosed die within a year. In about half of patients with heart failure, the forward pumping function of the heart is normal, referred to as heart failure with preserved ejection fraction (HFpEF).

While a number of processes lead to heart failure, fibrosis of the heart muscle is thought to be an important mechanism in around half to two-thirds of patients with HFpEF and is associated with adverse outcomes.

Study leader Dr Chris Miller, National Institute for Health Research Clinician Scientist at The University of Manchester, said: “Heart failure is as devastating an illness as some of the most common cancers, however its profile is much lower and treatment options for HFpEF are very limited.

“Using cardiac MRI, we were able to select patients in whom heart scarring is important. Pirfenidone then reduced that scarring.”

Pirfenidone inhibits the biological processes involved in scar formation.

The study enrolled 94 patients with heart failure, normal forward pumping function of the heart and evidence of fluid retention, randomising half to a pirfenidone treatment group and half to placebo.

Eligible patients had cardiac MRI scanning, and those who had evidence of heart scarring, as indicated by a measurement called ‘extracellular volume’. 

A second cardiac MRI was conducted a year later to measure change in heart scarring, and researchers found that extracellular volume fell by 1.21% on average in patients who took pirfenidone compared with those receiving placebo.

“Based on data from previous studies, this amount of reduction in heart scarring could translate into a substantial reduction in rates of death and admission to hospital for heart failure, however larger trials are needed to determine this,” said Dr Miller.

Additionally, fluid retention also improved in patients taking pirfenidone compared to those receiving placebo, measured using a blood test called NT-proBNP.

Dr Miller added: “Though further investigation is required, the associated improvement in fluid retention provides support for heart scarring having a causal role in heart failure and being an effective treatment target”.

The most common side effects were nausea, insomnia and rash, which are similar to that which lung patients can experience taking the drug. The results are “exciting”, Dr Miller said, but added that further trials are needed.

Source: University of Manchester

Ventricular Assist Device Pulled from Market due to Failures

Photo from Olivier Collett on Unsplash
Photo from Olivier Collett on Unsplash

The HeartWare system, a left ventricular assist device (LVAD) for advanced heart failure patients, is being discontinued immediately, according to the Food and Drug Administration.

The manufacturer, Medtronic, is halting global distribution and sale of its HeartWare system in the wake of observational evidence of increased neurological adverse events and mortality for its LVAD compared with similar mechanical circulatory support (MCS) devices.

Last December, some HeartWare LVADs were recalled because of complaints that the pump may delay or fail to start. So far 100 of these complaints have been received, including 14 patient deaths and 13 cases where an explant was necessary, the FDA noted.

“We have been carefully monitoring the adverse events associated with this device and support its removal from the marketplace,” said Bram Zuckerman, MD, director of the Office of Cardiovascular Devices at the FDA’s Center for Devices and Radiological Health, in a statement.

Medtronic now advises physicians to immediately stop new implants of the HeartWare device, but does not recommend explants.

The company is working on a plan for ongoing support of the some 4000 patients around the world who currently have this LVAD. It received commercial approval for use in the US in November 2012.

The FDA named Abbott’s HeartMate 3 as one alternative LVAD for patients with end-stage heart failure. This device features a magnetic levitation system that keeps the rotor separate without mechanical contact.

“The FDA is working closely with both Medtronic and Abbott to ensure patient care is optimised during this transition period and that there is an adequate supply of devices available to provide this patient population with options for end-stage heart failure treatment,” said Dr Zuckerman.

In a separate press release, Abbott reassured the public that it has the ability to meet increased demand for MCS devices as a result of HeartWare withdrawal from clinical use.

Source: MedPage Today

Averting Heart Failure by Shutting Down a Heart Protein

Photo from Olivier Collett on Unsplash
Photo from Olivier Collett on Unsplash

Shutting down a protein found in cardiac muscle could be a new mechanism to treat post-heart attack heart failure, according to research led by the University of Cambridge.

New drugs are needed to improve the heart’s pumping ability after damage from a heart attack. Drugs that strengthen the contraction of failing heart muscle have been deemed unsafe, leaving a gap in the heart attack and heart failure armamentarium.

Researchers now believe that they might have identified a new drug target—a protein called MARK4.

In research funded by the British Heart Foundation (BHF), Cambridge scientists found levels of MARK4 were elevated in mouse hearts after a heart attack. When they compared mice with and without MARK4 in the heart, they found hearts lacking the protein pumped blood 57% more efficiently. This protective effect was seen 24 hours after a heart attack and persisted over the entire follow-up period of four weeks.

The team was first in identifying that MARK4 fine-tunes a structural network within the heart muscle cell—called the microtubule network—that attaches to the machinery governing heart muscle cells contraction and relaxation. When MARK4 levels were increased after a heart attack, microtubules were tightly anchored onto the contractile machinery in the heart, increasing resistance and hindering normal function. When MARK4 levels were reduced, microtubules were loosely anchored, making contraction and relaxation easier.

Following a heart attack the speed of contraction in MARK4-lacking muscle cells increased by 42 percent and the speed of relaxation increased by 47 percent, compared to muscle cells from mice that had the MARK4 protein. They were also almost on par with healthy heart muscle performance, attesting to the power of reducing MARK4.

Based on these findings, the researchers suggested that drugs to switch off MARK4 could be a new way to improve recovery and help the heart to pump blood more efficiently in people with failing hearts.

Dr Xuan Li, BHF Intermediate Research Fellow at University of Cambridge BHF Centre of Research Excellence, said: “After years of research we’ve revealed an entirely new and promising way that could help the recovery of failing hearts.

“It’s early days, and we now need to test the longer-term effects of switching off MARK4. But if drugs to do that prove successful, the life-changing benefits could be seen in people with other types of heart disease as well as those who’ve had a heart attack and developed heart failure.”

Professor Metin Avkiran, Associate Medical Director at the British Heart Foundation, said: “Heart attacks are a major cause of disability worldwide—people who’ve had a major heart attack are at much greater risk of developing chronic heart failure. There are around 920 000 people living with heart failure in the UK, and we desperately need drugs to drastically improve the heart’s function in these patients.

“These findings are a positive step forward. Further research is needed to refine and test drugs that can target MARK4 before we’ll see them given to people who’ve had a heart attack and develop heart failure.”

Source: University of Cambridge

Tailored Heart Failure Rehabilitation Improves Outcomes

An innovative early cardiac rehabilitation intervention customised for the individual improved physical function, frailty, quality of life, and depression in hospitalised heart failure patients. 

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These findings were published  in the New England Journal of Medicine and also presented at the American College of Cardiology’s 70th Annual Scientific Session.  

“Designing earlier and more personalised individual-specific approaches to heart failure rehab shows great promise for improving outcomes for this common but complex condition that is one of the leading causes of hospitalisation for older adults,” said National Institute on Aging (NIA) Director Richard J Hodes, MD. “These results mark encouraging progress on a path to better overall quality of life and physical function for the millions of older Americans who develop heart failure each year.”

The study team was led by Dalane W Kitzman, MD, professor of cardiovascular medicine and geriatrics/gerontology at Wake Forest School of Medicine, Winston-Salem, North Carolina, and they followed 349 clinical trial participants with heart failure enrolled in “A Trial of Rehabilitation Therapy in Older Acute Heart Failure Patients” (REHAB-HF). On average, participants had five comorbidities that reduced of function — diabetes, obesity, high blood pressure, lung disease or kidney disease.

In an earlier pilot study, Kitzman and colleagues found striking deficits in strength, mobility and balance, along with the expected loss of endurance in older patients with acute heart failure, who were mostly fail or pre-fail. The team decided to focus on improving patients’ physical function, weakened already by chronic heart failure and age, and which was worsened by the traditional cardiac hospital experience involving lots of bedrest and resulting in loss of functions often persisting after discharge.

To address this. The REHAB-HF team designed earlier and more customised exercise programs focusing on improving balance, strength, mobility and endurance. They also began REHAB-HF during a patient’s hospital stay when possible rather than the usual six weeks post-discharge. After discharge, participants shifted to outpatient sessions three times per week for three months.

Compared to a control group getting usual cardiac rehab care, REHAB-HF participants showed significant gains in measures of physical functioning and overall quality of life, including tests for lower extremity function and mobility, and a six-minute walk test. Self-perception of their health status and depression improved in surveys compared to pre-trial baselines. Over 80% of REHAB-HF participants reported they were still doing their exercises six months after study completion.

“These findings will inform choices of heart failure rehabilitation strategies that could lead to better physical and emotional outcomes,” said Evan Hadley, M.D., director of NIA’s Division of Geriatrics and Clinical Gerontology. “Tailored interventions like REHAB-HF that target heart failure’s related decline in physical abilities can result in real overall benefits for patients.”

The study did not show significant differences in related clinical events including rates of hospital readmission for any reason or for heart-failure related rehospitalizations. The research team plans to further explore that and other issues through future expansions of REHAB-HF into larger and longer-term trials with broader participant subgroups.

Source: National Institute on Aging

Journal information: Kitzman et al. Rehabilitation Intervention in Older Patients with Acute Heart Failure with Preserved versus Reduced Ejection Fraction. New England Journal of Medicine. 2021 May 16 doi: 10.1056/NEJMoa2026141.