Category: Cardiovascular Disease

Categories : Cardiovascular DiseaseTags :

Cardiac Arrest Survivors have Better Outcomes if Cerebrovascular Regulation Kicks in

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A study of out-of-hospital cardiac arrest patients has shown that they have better neurological outcomes if a protective cerebrovascular regulation system reasserts itself. The research, published in the Journal of Cerebral Blood Flow and Metabolism, shows that this information can be used to assign more intensive rehabilitation, and also can be used to develop new interventions to improve cerebral perfusion.

Despite advances in treatment for out-of-hospital cardiopulmonary arrest and efforts to improve outcomes, many patients still suffer neurological sequelae (hypoxic-ischaemic brain injury, HIBI) even after return of spontaneous circulation. It is known that if brain function is maintained normally, there is a mechanism, cerebrovascular autoregulation (CVAR), that tries to maintain cerebral blood flow at a constant level even with changes in systemic blood pressure, but until now, it was unclear whether such a reaction occurs in the brain after resuscitation. Cerebral regional oxygen saturation (crSO2), a measure of oxygen supply and demand balance in the brain, is affected by blood pressure, and we focused on a method to evaluate the presence or absence of CVAR using this correlation. The researchers used this correlation to evaluate the presence or absence of CVAR in the post-resuscitated brain and assessed its relationship to life expectancy.

In this study, the research group analysed 100 patients with out-of-hospital cardiac arrest who were transported to the trauma and acute critical care centre of the Osaka University Graduate School of Medicine. CVAR was determined by calculating the moving Pearson correlation coefficient and by continuously monitoring crSO2 and mean blood pressure for 96 hours after return of spontaneous circulation. Assuming undetected CVAR time as a bad exposure for the organism (time-dependent covariate), the researchers evaluated the association of life prognosis using Cox proportional hazards model. CVAR was detected in all 24 patients with good neuroprognosis (Cerebral Performance Scale5: CPC 1-2) out of 100 analysed subjects and in 65 (88%) of 76 patients with poor neuroprognosis (CPC 3-5). The analysis using the Cox proportional hazards model showed that the survival rate decreased significantly as the undetected time of CVAR increased.

The results of this study have two major implications. First, the ability to identify subgroups with high mortality from early post-resuscitation clinical data can help identify populations that should receive enhanced therapeutic intervention. In addition, it may help to avoid early withdrawal of treatment from those who may recover. Secondly, we believe that intensive therapeutic management that maintains proper cerebral perfusion suggests improved life outcomes, and that developing a systemic management approach based on cerebral perfusion may be a breakthrough in reducing post-resuscitation neurological sequelae.

Source: EurekAlert!

Categories : Cardiovascular Disease Surgeries & ProceduresTags :

Do not Automatically Bar Stroke Patients on Warfarin from EVT, Study Suggests

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Most ischaemic stroke patients taking the anticoagulant warfarin were no more likely than those not on the medication to experience a brain bleed when undergoing endovascular thrombectomy (EVT), UT Southwestern Medical Center researchers report in a new study. The findings, published in JAMA, could help doctors better gauge the risk of EVT, widening the pool of patients for this intervention.

“Although not very common, patients taking warfarin may still experience a stroke. In clinical practice, it’s very possible that some physicians may withhold an endovascular thrombectomy because patients have been treated with warfarin before their strokes. Our study could increase the number of patients for whom this lifesaving and function-saving surgery would be appropriate,” said study leader Ying Xian, MD, PhD, Associate Professor of Neurology at UT Southwestern.

EVT – a surgery that removes the clot by threading instruments through the blood vessels – is the most common treatment for acute ischaemic stroke. EVTs can sometimes cause potentially fatal symptomatic intracranial haemorrhage (sICH), Dr Xian explained. Although warfarin is a known risk factor for bleeding, it’s been unknown whether the risk of sICH following EVT is higher for stroke patients who have been on the blood thinner.

To help answer this question, Dr Xian worked with Eric Peterson, MD, MPH, Professor of Internal Medicine at UTSW, along with colleagues from other medical institutions across the country. Together, they gathered data on 32 715 stroke patients who underwent EVT within six hours of stroke symptom onset between 2015 and 2020. Data came from the American Heart Association’s Get with the Guidelines-Stroke registry – the world’s largest registry of stroke patients.

The researchers compared a variety of outcomes for the 3087 patients who took warfarin prior to stroke and the 29 628 patients who did not take any blood thinner. They evaluated whether patients experienced sICH within 36 hours of their EVT procedure, whether they had a serious systemic haemorrhage, or whether they had other complications that required additional medical intervention or an extended hospital stay. Researchers also tracked complications from additional therapies that reintroduced blood flow in the brain, in-hospital deaths, and discharges to hospice care.

After adjusting for differences inherent to patients taking or not taking warfarin, the researchers found no difference in overall risk of sICH or other adverse outcomes in patients in these two groups. However, patients with an international normalised ratio (INR) greater than 1.7 – a measure of clotting tendency of blood in patients taking warfarin – the risk of experiencing sICH increased by about 4%.

Whether this effect translates into worse outcomes for patients is unclear, Dr Peterson said. Except for higher risk of bleeding, these patients with INRs greater than 1.7 were no more likely than those not taking warfarin to die or have worse functional outcomes at discharge.

“Physicians must evaluate stroke patients on a case-by-case basis to determine whether EVT is appropriate, but our study suggests that taking warfarin alone should not necessarily be a limiting factor,” he added.

Drs Xian and Peterson said they are planning to study whether other anticoagulants frequently taken by patients at risk of stroke might increase the risk of sICH or other serious complications following EVT for ischaemic stroke.

Source: UT Southwestern Medical Center

Categories : Cardiovascular Disease TransplantsTags :

Lessons Learnt From First Human Transplant of Genetically Modified Pig Heart

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A new study published in The Lancet has revealed the most extensive analysis to date on what led to the eventual heart failure in the world’s first successful transplant of a genetically modified pig heart into a human patient. This groundbreaking procedure was conducted by University of Maryland School of Medicine (UMSOM) physician-scientists in January 2022.

The patient, 57-year-old David Bennett, was treated at the University of Maryland Medical Center. He experienced strong cardiac function with no obvious signs of acute rejection for nearly seven weeks after the surgery. A sudden onset of heart failure led to his death two months after the transplant. Since then, the transplant team has been extensively studying the physiologic processes that led to the heart failure to identify what needs to be prevented in future transplants to improve the odds of success.

“Our paper provides crucial insight into how a multitude of factors likely played a role in the functional decline of the transplanted heart,” said study lead author Muhammad M. Mohiuddin, MD, Professor of Surgery and Scientific/Program Director of the Cardiac Xenotransplantation Program at UMSOM. “Our goal is to continue moving this field forward as we prepare for clinical trials of xenotransplants involving pig organs.”

Mr. Bennett, who was in end-stage heart failure and nearing the end of his life, did not qualify for a traditional heart transplant, but the experimental procedure was authorised by the US Food and Drug Administration under compassionate use.

“We were determined to shed light on what led to the heart transplant dysfunction in Mr. Bennett, who performed a heroic act by volunteering to be the first in the world,” said study co-author Bartley Griffith, MD, Professor of Surgery and The Thomas E. and Alice Marie Hales Distinguished Professor in Transplantation at UMSOM. “We want our next patient to not only survive longer with a xenotransplant but to return to normal life and thrive for months or even years.”

To better understand the processes that led to dysfunction of the pig heart transplant, the research team performed extensive testing on the limited available tissues in the patient. They carefully mapped out the sequence of events that led to the heart failure demonstrating that the heart functioned well on imaging tests like echocardiography until day 47 after surgery.

The new study confirms that no signs of acute rejection occurred during the first several weeks after the transplant. Likely, several overlapping factors led to heart failure in Mr. Bennett, including his poor state of health prior to the transplant that led him to become severely immunocompromised. This limited the use of an effective anti-rejection regimen used in preclinical studies for xenotransplantation. As a result, the researchers found, the patient was likely more vulnerable to rejection of the organ from antibodies made by the immune system. The researchers found indirect evidence of antibody-mediated rejection based on histology, immunohistochemical staining and single cell RNA analysis.

The use of an intravenous immunoglobulin, IVIG, a drug that contains antibodies, may also have contributed to damage to the heart muscle cells. It was given to the patient twice during the second month after the transplant to help prevent infection, likely also triggering an anti-pig immune response. The research team found evidence of immunoglobulin antibodies targeting the pig vascular endothelium layer of the heart.

Lastly, the new study investigated the presence of a latent virus, called porcine cytomegalovirus (PCMV), in the pig heart, which may have contributed to the dysfunction of the transplant. Activation of the virus may have occurred after the patient’s anti-viral treatment regimen was reduced to address other health issues. This may have initiated an inflammatory response causing cell damage. However, there is no evidence that the virus infected the patient or spread to organs beyond the heart. Improved PCMV testing protocols have been developed for sensitive detection and exclusion of latent viruses for future xenotransplants.

“Valuable lessons can be learned from this groundbreaking surgery and the courageous first patient, Mr. Bennett, that will better inform us for future xenotransplants,” said UMSOM Dean Mark T. Gladwin, MD, Vice President for Medical Affairs, University of Maryland, Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor. “In the future, our team of surgeon-scientists will utilise newly designed immune cell assays to monitor the patient more precisely in the days, weeks, and months following the xenotransplant. This will provide stricter control of the earliest signs of rejection and the promise of a truly lifesaving innovation.”

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Categories : Cardiovascular Disease Diet and NutritionTags :

Five Years of High-dose Vitamin D Reduced Atrial Fibrillation Risk

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Taking higher-than-recommended doses of vitamin D for five years reduced the risk of atrial fibrillation in older adults, according to a randomised controlled study conducted in Finland and published in the American Heart Journal.

Atrial fibrillation is the most common arrhythmia, the risk of which increases with age, and which is associated with an increased risk of stroke, heart failure and mortality. Vitamin D has been shown to have an effect, for example, on the atrial structure and the electrical function of the heart, suggesting that vitamin D might prevent atrial fibrillation.

Conducted at the University of Eastern Finland in 2012–2018, the main objective of the Finnish Vitamin D Trial (FIND) was to explore the associations of vitamin D supplementation with the incidence of cardiovascular diseases and cancers. The five-year study involved 2 495 participants, men aged 60 and older, and women aged 65 and older, who were randomised into three groups: one placebo group and two vitamin D3 supplementation groups, with one of the groups taking a supplement of 40µg (1600 IU) per day, and the other a supplement of 80µg (3200 IU) per day. All participants were also allowed to take their personal vitamin D supplement, up to 20µg (800 IU) per day, which at the beginning of the study was the recommended dose for this age group. Participants had no diagnoses of cardiovascular disease or cancer at baseline, and they completed comprehensive health-related questionnaires, both at the beginning. Data on the occurrence of diseases and deaths were also obtained from Finnish nationwide health registers. Approximately 20% of participants were randomly selected for more detailed examinations and blood samples.

During the five-year study, 190 participants were diagnosed with atrial fibrillation: 76 in the placebo group, 59 in the 40µg group, and 55 in the 80 micrograms group. The risk of atrial fibrillation was 27% lower in the 40µg group, and 32% lower in the 80 micrograms group, when compared to the placebo group. In the sub-cohort selected for more detailed examinations, the mean baseline serum calcidiol concentration, which is a marker of the body’s vitamin D concentration, was relatively high, 75nmol/l. After one year, the mean calcidiol concentration was 100nmol/L in the 40µg group, and 120nmol/l in the 80µg group. No significant change in the calcidiol concentration was observed in the placebo group.

Only two randomised trials tried to test whether vitamin D supplementation reduces AF risk in healthy adults, and they did not observe an effect when using doses of 10µg (400 IU) or 50µg (2000 IU) per day. Further confirmation of the present results from the FIND study is therefore needed before doses of vitamin D that significantly exceed current recommendations can be recommended for preventing atrial fibrillation. The FIND study has previously published findings showing no association with the incidence of other cardiovascular events or cancers.

Source: University of Eastern Finland

Categories : Cardiovascular DiseaseTags :

Treatment-resistant Hypertension Affects 1 in 10 Hypertensive Patients

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In apparent resistant hypertension (aRH), more medication and medical management is needed than for normal hypertension. Novel research published in Hypertension found that aRH prevalence was lower in a real-world sample than previously reported, but still relatively frequent – affecting nearly 1 in 10 hypertensive patients. The researchers stressed the need for clinicians to be on the lookout for the condition.

In their analysis, the Cedars-Sinai investigators also learned that patients with well-managed aRH were more likely to be treated with mineralocorticoid receptor antagonist (MRA). These MRA treatments were used in 34% of patients with controlled aRH, but only 11% of patients with uncontrolled aRH.

“Apparent resistant hypertension is more common than many would anticipate,” said Joseph Ebinger, MD, assistant professor of Cardiology in the Smidt Heart Institute and corresponding author of the study. “We also learned that within this high-risk population, there are large differences in how providers treat high blood pressure, exemplifying a need to standardise care.”

Study findings were based on a unique design, which used clinically generated data from the electronic health records of three large, geographically diverse healthcare organisations. Of the 2 420 468 patients analysed in the study, 55% were hypertensive. Of these hypertension patients, 8.5%, or 113 992 individuals, met criteria for aRH.

According to Ebinger, treating aRH can be just as tricky as diagnosing it.

In fact, the “apparent” in apparent resistant hypertension stems from the fact that before diagnosis, medical professionals must first rule out other potential reasons for a patient’s blood pressure to be high.

These reasons might include medication non-adherence, inappropriate medication selection, or white coat hypertension from measurement in the doctor’s office.

“Large amounts of data tell us that patients with aRH, compared to those with non-resistant forms of hypertension, are at greatest risk for adverse cardiovascular events,” said Ebinger, director of Clinical Analytics in the Smidt Heart Institute. “Identifying these patients and possible causes for their elevated blood pressure is increasingly important.”

The takeaway, Ebinger says, is awareness – for both medical professionals and patients. He says providers should be mindful that if it’s taking four or more antihypertensive medications to control a patient’s blood pressure, they should consider evaluation for alternative causes of hypertension, or refer patients to a specialist.

Similarly, patients should press their healthcare providers to help them navigate the complex disease, including talking about strategies for remembering to take their medication and addressing possible treatment side effects.

Source: Cedars-Sinai Medical Center

Categories : Cardiovascular Disease Mental HealthTags :

Depressed Patients with ICDs More Likely to Stop Taking their Cardiac Medications

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Patients with implanted cardiac devices are more likely to stop taking their heart medications if they are feeling depressed or anxious, according to research presented at ACNAP 2023, a scientific congress of the European Society of Cardiology (ESC).

The study author, psychologist Ole Skov at the University of Southern Denmark, said: “Medications help to control symptoms and prevent further heart problems so adherence is important. Patients with an implantable cardioverter defibrillator (ICD) who feel depressed or anxious should be encouraged to express their concerns, thoughts, and feelings and contact a health care professional who can screen them for distress to explore the best course of action. This could be referral to a psychologist or other measures.”

An ICD implantation is recommended for people at high risk of a life-threatening arrhythmia and for those who have had a sudden cardiac arrest. It is estimated that one in five patients with an ICD are affected by depression or anxiety, something which has been linked to increased mortality risk for those patients. Most patients with an ICD are prescribed medication to manage their heart disease. It is therefore crucial to identify patients at risk of stopping their medication so that support measures can be initiated.

This study examined whether anxiety and depression at the time of ICD implantation are associated with medication adherence one year after receiving the device. The study was a secondary analysis of the ACQUIRE-ICD randomised controlled trial of an eHealth intervention. Of 478 patients in the trial with an ICD or an ICD with cardiac resynchronisation therapy (CRT-D), 433 (91%) were taking at least one heart medication when their device was implanted. These included beta-blockers, ACE inhibitors, statins and diuretics. Of the 433 patients, 322 patients (74%) completed assessments of medication adherence at both baseline (implantation) and 12 months after implantation and were included in the current analyses.

Medication adherence was measured by self-report using the Morisky Medication Adherence Scale (MMAS) which is scored from 0 to 8. Low, medium and high adherence were defined as scores below 6, 6 to <8, and 8, respectively. Depression and anxiety were assessed at baseline with the Patient Health Questionnaire 9 (PHQ-9; scores 0–27) and the Generalised Anxiety Disorder (GAD-7; scores 0–21) scale, with higher scores indicating more symptoms. Both were used as continuous measures, and patients were not categorized as depressed/not depressed or anxious/not anxious.

The average age of participants was 60 years and 84% were men. Medication adherence was generally medium to high at baseline (6.8% low adherence, 40.1% medium adherence, 53.1% high adherence; average MMAS score 7.31) and at 12 months (8.1% low adherence, 37.3% medium adherence, 54.6% high adherence; average MMAS score 7.33).

The researchers analysed the association between mental health scores and medication adherence after adjusting for baseline MMAS score, sex, trial intervention group, heart failure severity and implantation centre. Depression scores at baseline were negatively associated with medication adherence at 12 months (p=0.02). The association with anxiety was not statistically significant.

Mr. Skov said: “Patients with higher levels of depressive symptoms at the time of ICD implantation were less likely to be taking their heart medications one year later. The effect of depression was statistically significant but small, which is not surprising given the complexity and multitude of factors involved in medication adherence.”

He concluded: “These results highlight the importance of considering the psychological status of people receiving an ICD. Those with symptoms of depression at the time of implantation could be at risk of discontinuing their heart medications, even if they are taking them initially, and may need extra support.”

Source: European Society of Cardiology

Categories : Cardiovascular Disease COVIDTags :

European COVID Lockdowns Cost Heart Attack Patients up to Two Years of Life

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Patients who had heart attacks during the first COVID lockdown in the UK and Spain are predicted to live 1.5 and 2 years less, respectively, than their pre-COVID counterparts. That’s the finding of a study just published in European Heart Journal – Quality of Care and Clinical Outcomes.

“Restrictions to treatment of life-threatening conditions have immediate and long-term negative consequences for individuals and society as a whole,” said study author Professor William Wijns of the Lambe Institute for Translational Medicine, University of Galway, Ireland. “Back-up plans must be in place so that emergency services can be retained even during natural or health catastrophes.”

Research has shown that during the first wave of the pandemic, about 40% fewer heart attack patients went to hospital as governments told people to stay at home, fear of catching the virus, and the stopping of some routine emergency care. Compared to receiving timely treatment, heart attack patients who stayed at home were more than twice as likely to die, while those who delayed going to the hospital were nearly twice as likely to have serious complications that could have been avoided.

Heart attacks require urgent treatment with stents (called percutaneous coronary intervention or PCI) to open the blocked artery and restore blood flow. Delays, and the resulting lack of oxygen, lead to irreversible damage of the heart muscle and can cause heart failure or other complications. When a large amount of heart tissue is damaged, potentially fatal cardiac arrest results.

This study estimated the long-term clinical and economic implications of reduced heart attack treatment during the pandemic in the UK and Spain. The researchers compared the predicted life expectancy of patients who had a heart attack during the first lockdown with those who had a heart attack at the same time in the previous year. The study focused on ST-elevation myocardial infarction (STEMI), where a coronary artery is completely blocked. The researchers also compared the cost of STEMIs during lockdown with the equivalent period the year before.

A model was developed to estimate long-term survival, quality of life and costs related to STEMI. The UK analysis compared the period 23 March (when lockdown began) to 22 April 2020 with the equivalent time in 2019. The Spanish analysis compared March 2019 with March 2020 (lockdown began on 14 March 2020). Survival projections considered age, hospitalisation status and time to treatment using published data for each country. For example, using published data, it was estimated that 77% of STEMI patients in the UK were hospitalised prior to the pandemic compared with 44% during lockdown. The equivalent rates for Spain were 74% and 57%. The researchers also compared how many years in perfect health were lost for patients with a STEMI before versus during the pandemic.

The analysis predicted that patients who had a STEMI during the first UK lockdown would lose an average of 1.55 years of life compared to patients presenting with a STEMI before the pandemic. In addition, while alive, those with a STEMI during lockdown were predicted to lose approximately one year and two months of life in perfect health. The equivalent figures for Spain were 2.03 years of life lost and around one year and seven months of life in perfect health lost.

The cost analysis focused on initial hospitalisation and treatment, follow-up treatment, management of heart failure and productivity loss in patients unable to return to work. For example, the cost applied to a STEMI admission with PCI was £2837 in the UK and €8780 in Spain. Heart failure costs were estimated at £6086 in year one and £3882 in all subsequent years for the UK. The equivalent figures for Spain were €3815 (year one) and €2930 (each subsequent year).

Professor Wijns said: “The findings illustrate the repercussions of delayed or missed care. Patients and societies will pay the price of reduced heart attack treatment during just one month of lockdown for years to come. Health services need a list of lifesaving therapies that should always be delivered, and resilient healthcare systems must be established that can switch to emergency plans without delay. Public awareness campaigns should emphasise the benefits of timely care, even during a pandemic or other crisis.”

Source: European Society of Cardiology

Categories : Cardiovascular DiseaseTags :

Can We Use Light Instead of Shocks to Treat Atrial Fibrillation?

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New research published in the Journal of Internal Medicine demonstrates that optogenetics, a technique which uses light-sensitive proteins to control the activity of targeted cells. is a promising shock-free approach to treating atrial fibrillation (AF), or an irregular, often rapid heart rate, for immediate restoration of regular rhythm.

Current treatments for AF, which include medications and shocks to restore a regular heart rhythm, come with low success rates and/or serious side effects. In this new study, rats’ hearts were optogenetically modified to express light-gated ion channels. After AF was induced, the animals’ chests were illuminated resulting in acute restoration of regulation rhythm. This shows that sufficient light penetrated the chest wall, which suggests that full penetration of the human atrial wall may be feasible as well, if deemed necessary for clinical translation.

“Shock-free cardioversion of AF would allow restoration of regular rhythm at any place and time, which may improve the prognosis and quality of life of patients suffering from AF. We hope that our paper will contribute to the realization of this much desired option in clinical practice,” said corresponding author Daniël A. Pijnappels, PhD, of Leiden University Medical Center, in The Netherlands.

Source: Wiley

Categories : Cardiovascular Disease Diseases, Syndromes and ConditionsTags :

Even Modest Drop in Kidney Function is Linked to Greater Health Risks

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A Canadian study of more than 8 million adults suggests that even a modest loss of kidney function is associated with increased health risks. The study, published in The BMJ, could lead to better approaches to prevent chronic kidney disease and related conditions, particularly in younger adults.

“The dogma is that healthy, young adults don’t need to worry about kidney function unless it drops to around 50% of the normal level, but our research suggests that even a more modest 20–30% drop may have consequences and we may want to have earlier conversations about prevention and monitoring,” explained senior author Dr Manish Sood at the University of Ottawa.

The research team used health records from 2008 to 2021 for every Ontario, Canada adult aged 18–65 who had at least one blood test for kidney function, but no history of kidney disease. They found that 18% of those in the 18–39 age group had kidney function that was modestly below normal levels, but not low enough to be diagnosed with chronic kidney disease. Individuals in this ‘grey zone’ faced a modestly increased risk of kidney failure, death and cardiovascular events.

For example, in young adults (age 18–39), a 20–30% loss in kidney function was associated with a 1.4-fold increase in death, 1.3-fold increase in a cardiac event and a 6-fold increase in the risk of kidney failure. The absolute risk of any of these events was still low at less than 2 per 1000.

“Thankfully, the absolute risk for any one individual with kidney function in this grey zone is low, but when we look at the whole population, the impact could be quite significant,” said co-senior author Dr Greg Knoll, senior scientist, nephrologist and Head of the Department of Medicine at The Ottawa Hospital and the University of Ottawa. “We need further research to confirm these findings and then see if we can reduce the risk through lifestyle modification.”

While the blood creatine test for kidney function is relatively inexpensive and readily available, the researchers are not suggesting routine testing for all individuals at this time. However, if an individual has had a kidney test that shows a modest reduction in function, it could prompt consulting health care provider. All individuals can also reduce their risk of kidney disease by eating a healthy diet with lower salt, exercising regularly and limiting alcohol intake.

Dr. Sood and his colleagues previously developed the Project BigLife Chronic Kidney Disease calculator to help individuals calculate their kidney disease risk and see the impact of lifestyle changes. The calculator will continue to be refined as new research arises.  

Source: EurekAlert!

Categories : Cardiovascular DiseaseTags :

Repurposed Cancer Drug Might Treat Cardiac Arrhythmias

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Ruxolitinib, a drug that is already approved by the U.S. Food and Drug Administration (FDA) for treating certain cancers and skin conditions, is effective at inhibiting CaMKII, a protein kinase linked to cardiac arrhythmias.

In a new study published in Science Translational Medicine, researchers invented a new reporting technique to monitor activity of CaMKII while screening the effects of nearly 5000 FDA-approved drugs on human cells that expressed the enzyme. The screen identified five previously unknown CaMKII inhibitors; ruxolitinib, which is used to treat cancers of the blood and bone marrow, along with skin conditions like atopic dermatitis and vitiligo, was the most effective.

CaMKII, or Calcium and calmodulin-dependent protein kinase II, is critical to cardiomyocytes, the muscle cells of the heart, where it maintains the balance of calcium. Activation of CaMKII helps facilitate rapid changes in heart activity, such as initiating a fight-or-flight response in the body. Overactivation can lead to impaired heart function and cell death, which can in turn lead to poor heart health outcomes like arrhythmia.

CaMKII is perhaps best known, however, for its role in the brain, where it is believed to play key roles in learning and memory. This has slowed the development of CaMKII inhibitors to treat arrythmia, for fear they could impact cognitive function.

“Finding an FDA approved drug means that millions of people have been taking CaMKII inhibitors, and in the case of ruxolitinib, there are no reported major problems with the brain,” said Mark Anderson, MD, PhD, a senior author of the paper. “That should give pharma and biotech companies confidence that they could carry out development of a CaMKII inhibitor program, because the biggest obstacle seems to be surmountable.”

The research began in Anderson’s lab at Johns Hopkins University Oscar Reyes Gaido, the study’s first author and an MD-PhD student in the lab, developed a new tool to measure activity of CaMKII in living cells. He started with a protein called green fluorescent protein (GFP), originally derived from jellyfish, that emits green light. He then engineered the GFP tag to detect CaMKII activation, making a new reporter called CaMKAR (CaMKII Activity Reporter). When this reporter was inserted into human heart cells, it helpfully glowed bright green whenever CaMKII became active, allowing researchers to monitor enzyme activity.

“This biosensor will be very useful for studying how CaMKII activity changes in both healthy and pathological contexts. Existing methods can measure CaMKII activity, but they lack the versatility and resolution to track in real time and with high sensitivity,” Reyes Gaido said. “This has been a real obstacle for studying enzyme biology in general, so this gives the field an important new tool.”

Using this tool, the researchers conducted a drug repurposing screen to test the effects of 4,475 approved compounds on cultured human cardiomyocytes. This identified five previously unknown CaMKII inhibitors: ruxolitinib, baricitinib, silmitasertib, crenolanib, and abemaciclib. Of the five, ruxolitinib was the most effective at inhibiting CaMKII activity in cell and mouse models of CaMKII-driven arrhythmias. A 10-minute application of the drug was enough to prevent catecholaminergic polymorphic ventricular tachycardia (CPVT), a congenital source of pediatric cardiac arrest, and rescue atrial fibrillation, the most common clinical arrhythmia. Crucially, the mice treated with ruxolitinib did not show any adverse cognitive effects when they were tested with memory and learning tasks.

Anderson said that new drugs based on ruxolitinib could be used in several ways to treat heart conditions. One would be what he called the “pill in a pocket” scenario. In the early stages of atrial fibrillation, people could take the medication occasionally as symptoms arise. Patients with CPVT are often resistant to standard treatments, and a ruxolitinib-based treatment could provide another option. Finally, there is evidence that inhibiting CaMKII during a heart attack can prevent heart muscle from dying, so emergency responders could potentially administer such a drug as part of standard practice.

“There’s been a long search for fundamental pathways that could be targets for therapeutics in arrhythmias,” Anderson said. “This could be a finding that will translate relatively rapidly into people now since it’s already been proven to be safe in humans.”

Source: University of Chicago