Javid Moslehi, MD and Justin M. Balko, Pharm.D., Ph.D. from Vanderbilt-Ingram Cancer Center discuss A genetic mouse model recapitulates immune checkpoint inhibitor-associated myocarditis and supports a mechanism-based therapeutic intervention.
Cancer therapy has been transformed by immune control point inhibitors (ICI) targeting CTLA-4 or PD-1/PD-L1 but is associated with immune-related adverse effects (irAEs), including myocarditis. A robust preclinical mouse model of ICI-associated myocarditis is reported here, in which mono-allelic loss of Ctla4 in the sense of complete genetic absence of Pdcd1 leads to premature death in about half of the mice. Premature death results from T cell and macrophage myocardial invasion and significant electrocardiographic defects, closely recapitulating the clinical and pathological characteristics of ICI-associated myocarditis found in patients. Using this model, we demonstrate that in a gene dosage-dependent way, Ctla4 and Pdcd1 interact functionally, providing a mechanism by which myocarditis occurs in the setting of combination ICI therapy with increased frequency. We show that CTLA-4-Ig (abatacept) intervention is appropriate to boost the progression of the disease and also include a case series of patients in whom abatacept mitigates the fulminant course of ICI-myocarditis.
C. Michael Gibson, MD, CEO non-profit Baim / PERFUSE Research Institute, Harvard Professor, Cardiologist BIDMC, Founder & Chairman WikiDoc.org speaks about ACC 2021 Abstract - 1063-07 - Association Of Cholesterol Efflux Capacity With Adverse Cardiovascular Outcomes - A Meta Analysis
Link to Article:
The principal process by which macrophages remove cholesterol from atherosclerotic plaque is reverse cholesterol transport. A systematic literature review and meta-analysis were done to investigate the relationship between cholesterol efflux capacity (CEC), a measure of high-density lipoprotein (HDL) function, and poor cardiovascular (CV) events.
A literature study was conducted to gather papers that looked at the link between CEC and CV outcomes. Adverse CV events, a composite of incident atherosclerotic CV disease (acute coronary syndrome, stroke/transient ischemic attack, revascularization, or new atherosclerotic plaque), or all-cause death, were the main outcomes.
The following are the outcomes:
Twenty investigations yielded a total of 25,132 individuals. High CEC levels were linked with a 37 percent decreased risk of the main outcome when compared to low CEC levels (RR=0.63; 95 percent CI, 0.52-0.76; P0.00001; Figure A). A 20 percent decreased risk of unfavorable CV events was related with every SD rise in CEC (HR=0.80; 95 percent CI, 0.66-0.97; P=0.02). After controlling for CV risk factors, medicines, and HDL concentration, the link remained significant (HR=0.76; 95 percent CI, 0.63-0.91; P=0.004). There was a 5% risk decrease in unfavorable CV events for every 0.1 unit rise in CEC (RR=0.95; 95 percent CI, 0.91-0.99; Figure B).
Higher CEC is linked to less negative CV outcomes. These findings call for more research on CEC as a possible therapeutic target in order to enhance clinical outcomes.
B. Daan Westenbrink, MD, Ph.D., Senior Author and Cardiologist at the University of Groningen, UMCG Cardiology speaks about Ketone Supplementation: A Novel Intervention for CVD?
Link to Article:
According to a recent study, regardless of the procedure used to increase ketone bodies' presence in the heart, they could have therapeutic benefits for patients with cardiovascular disease (CVD).
The authors examined the current body of experimental and clinical research on the potential function of ketone bodies in improving CVD and discovered that increasing circulating ketone levels can provide protective benefits in patients with the disease.
A ketogenic diet, which consists of a very low carbohydrate and high-fat intake, is a common way to induce ketosis; however, exogenous ketones could be a viable and superior alternative to the diet for increasing circulating ketone bodies, according to the researchers.
The study was published in the Journal of the American College of Cardiology on February 23.
This realization prompted Westenbrink and colleagues to conduct a clinical trial to examine the impact of exogenous ketones on exercise efficiency in patients with heart failure.
The aim of this review was to "summarize the existing literature from animal and human studies, in the hopes of facilitating more research into the benefits of ketones as therapeutic agents in CVD."
Beyond Fuel Efficiency
The authors have looked at the processes of ketone metabolism, such as ketogenesis and ketolysis, as well as cardiac metabolism in both healthy and diseased hearts.
The reactions that lead to the formation of the ketone bodies acetoacetate (AcAc), -hydroxybutyrate (OHB), and acetone are known as ketogenesis.
Fasting causes a reduction in the insulin-to-glucagon ratio, which mobilizes fatty acids, which the liver then converts into ketone bodies. They are then moved to peripheral tissues, where they go through a process known as "terminal oxidation."
The heart appears to "reprogram metabolism to increased dependence on ketone bodies as a fuel source" as heart failure progresses, according to the authors, with increased circulating ketone concentrations and cardiac ketone consumption.
Claudio de Lucia, MD, Ph.D. Center for Translational Medicine, Lewis Katz School of Medicine, Temple University speaks about G protein-coupled receptor kinase 5 (GRK5) contributes to impaired cardiac function and immune cell recruitment in post-ischemic heart failure.
Link to Article:
The most common cause of heart failure (HF) is myocardial infarction (MI). In animal models, the G protein-coupled receptor kinase 5 (GRK5) is upregulated in failing human myocardium and promotes maladaptive cardiac hypertrophy. The function of GRK5 in ischemic heart disease, on the other hand, is still unknown. In this research, we looked at whether myocardial GRK5 is essential after a heart attack in mice, as well as specific cardiac immune and inflammatory responses.
Methods and outcomes -
Cardiomyocyte-specific GRK5 overexpressing transgenic mice (TgGRK5) and non-transgenic littermate control (NLC) mice, as well as cardiomyocyte-specific GRK5 knockout mice (GRK5cKO) and wild type (WT) mice, were all given a MI and their functional and structural changes, as well as their outcomes, were investigated. When compared to NLC post-MI mice, TgGRK5 post-MI mice had a lower cardiac function, a larger left ventricular dimension, and a lower survival rate. TgGRK5 mice had more cardiac hypertrophy and fibrosis, as well as fetal gene expression, after MI than NLC mice. GRK5 elevation developed immuno-regulators in TgGRK5 mice, which led to increased and long-lasting leukocyte recruitment into the injured heart, and eventually to chronic cardiac inflammation. At 4-days and 8-weeks post-MI, we observed a rise in pro-inflammatory neutrophils and macrophages, as well as neutrophils, macrophages, and T-lymphocytes in TgGRK5 hearts. In contrast to WT post-MI mice, GRK5cKO mice were protected from ischemic injury and showed reduced early immune cell recruitment (primarily monocytes) to the heart, increased contractility, and lower mortality. Surprisingly, cardiomyocyte-specific GRK2 transgenic mice did not exhibit the same phenotype as TgGRK5 mice and did not exhibit increased cardiac leukocyte migration or cytokine or chemokine output after MI.
Final thoughts -
In a murine model of post-ischemic HF, our findings show that myocyte GRK5 plays a critical and GRK-selective role in the control of leucocyte infiltration into the heart, cardiac function, and survival, indicating that GRK5 inhibition may be a therapeutic target for HF.
Rohan Khera, MD, MS, Assistant Professor at Yale School of Medicine speaks about A phenomapping-derived tool to personalize the selection of anatomical vs. functional testing in evaluating chest pain (ASSIST).
Link to Lab's ASSIST:
Link to Article:
Coronary artery disease is often identified after anatomical or clinical examination is used to evaluate persistent chest pain. Personalized testing could be possible with a more detailed knowledge of patient phenotypes that benefit from either approach.
Methods and outcomes
We generated a topological representation of the sample population based on 57 pre-randomization variables using participant-level results from 9572 patients undergoing anatomical (n = 4734) vs. functional (n = 4838) research in the PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain) trial. Cox regression models presented individual patient-centered hazard ratios for significant adverse cardiovascular outcomes within each patient's 5% topological neighbourhood and showed marked heterogeneity around the phenomap [median 1.11 (10th to 90th percentile: 0.52–2.61]], suggesting distinct phenotypic neighbourhoods favoring anatomical or functional research. We used an intense gradient boosting algorithm in 80% of the PROMISE population to estimate the personalized value of anatomical vs. functional tests using 12 model-derived, regularly collected variables and generated a decision support method called ASSIST based on this vulnerability phenomap (Anatomical vs. Stress teSting decIsion Support Tool). The testing strategy recommended by ASSIST was associated with a significantly lower incidence of each study's primary endpoint in both the remaining 20% of PROMISE and an external validation set consisting of patients from SCOT-HEART (Scottish COmputed Tomography of the HEART Trial) undergoing anatomical-first vs. functional-first assessment (P = 0.0024 and P = 0.0321 for interaction, respectively) in both the remaining 20% of PROMISE and an external validation set consist
We suggest a new phenomapping-based decision support method to standardize the use of structural vs. functional research in the treatment of controlled chest pain, which has been tested in two broad and geographically disparate clinical trial populations.
Bart Meuris, prof. dr. from the University Hospitals Leuven Presentation on the HVS 2021 Abstract In-vivo Evaluation Of A Novel Surgical Heart Valve Prosthesis Designed To Be Durable, Anticoagulant-free And Silent.
Link to Abstract:
Reoperations of tissue valves or permanent anticoagulation of artificial valves are also drawbacks for heart valve prostheses. The Triflo valve, a tri-leaflet valve made of bio-inert materials with high resistance, was designed to overcome these limitations. In a chronic sheep model, we looked at protection and efficiency.
TECHNIQUES: The Triflo valve (size 21mm) was inserted in two models: in the aortic position for 90 days (n=7) and in the pulmonary position for 70 days (n=4). On-X valves (n=2) were used as a monitor in the pulmonary model. There was no more anticoagulant given after 7 days of low-molecular-weight heparin. Blood tests, echocardiography, acoustic measurements, fluoroscopy, and an autopsy were all performed.
The Triflo valve performed admirably during surgery. In the aortic analysis, there was one aborted surgery and one early death, all unrelated to the prosthesis. All of the other sheep (n=9) recovered well and continued in good clinical condition until they were slaughtered. We found low peak and mean gradients (8.1+/-2.7 and 4.8+/-1.9 mmHg, respectively), a large effective orifice area (2.3+/-0.2 cm2), no valvular regurgitation, and complete left ventricular activity in the aortic role. Both Triflo valves had a smooth surface at explantation, with no valve thrombosis. Thrombo-embolic (TE) damage was not found in any of the main organs. Both valve leaflet mobility was natural in the pulmonary role, and no TE-damage was observed in the lungs. Hematological parameters were stable, and no signs of hemolysis were present. In the pulmonary location, On-X valves performed well, but they produced slightly quieter acoustic signals (p0.05).
In both the aortic and pulmonary positions, the Triflo valve proved to be safe and reliable. These promising in-vivo effects, which include excellent hemodynamic activity and long-term operation even without anticoagulants, show that this valve is ready for human trials.
Paul W. Armstrong, MD Canadian VIGOUR Centre, University of Alberta, Edmonton, AB, Canada speaks about Merck Announces U.S. FDA Approval of VERQUVO® (vericiguat).
The primary efficacy objective of VICTORIA was to evaluate if VERQUVO, in conjunction with other heart failure therapies, is superior to placebo in reducing the risk of cardiovascular mortality or hospitalization for heart failure in adults with symptomatic recurrent heart failure and less than 45% of the ejection fraction following a worsening heart failure case. Based on a time-to-event study, VERQUVO reached the primary efficacy objective (hazard ratio [HR]: 0.90, 95 percent confidence interval [CI], 0.82-0.98; p=0.019). There was a 4.2 percent reduction in annualized absolute risk with VERQUVO compared to placebo over the course of the study. Therefore, to avoid one primary endpoint case, 24 patients will need to be monitored for an average of one year.
Information Supporting the Approval
VERQUVO approval was based on evidence from VICTORIA (NCT02861534), a randomized, concurrent, placebo-controlled, double-blind, event-driven, multi-center clinical trial comparing VERQUVO with placebo in 5,050 adult patients with New York Heart Association (NYHA) class II-IV symptomatic chronic heart failure and left ventricular ejection fraction (LVEF) less than 45% after a wound of symptomatic chronic heart failure (NYHA) class II-IV. A worsening case of heart failure was described as hospitalization for heart failure within six months or less prior to randomization or use for heart failure of outpatient IV diuretics within three months or less prior to randomization. In VICTORIA, the primary outcome was time-to-first cardiovascular death or heart failure hospitalization. The median follow-up time was 11 months for the primary endpoint. Based on a time-to-event analysis, VERQUVO was superior to placebo in reducing the risk of cardiovascular death or hospitalization for heart failure.
Patients were given VERQUVO 10 mg once daily or a matched placebo up to the target maintenance dose. Therapy started with VERQUVO 2.5 mg once daily and increased to 5 mg once daily and then 10 mg once daily, as tolerated, at roughly two-week intervals. The placebo doses were adjusted similarly. 90 percent of patients in both the VERQUVO and placebo arms were treated with the 10 mg target maintenance dose after approximately one year.
Participants in the study were: 76% male, 64% Caucasian, 22% Asian and 5% Black. The mean age was 67. 59 percent of patients were NYHA Class II at randomization, 40 percent were NYHA Class III and 1 percent were NYHA Class IV. The mean LVEF was 29 percent . Approximately half of all patients had an EF of less than 30%, and 14% of patients had an EF of between 40% and 45%. Sixty-seven percent of VICTORIA patients were enrolled within three months of a hospitalization index case for heart failure; 17 percent were enrolled within three to six months of hospitalization for heart failure; and 16 percent were enrolled within three months of outpatient care for worsening heart failure with IV diuretics. At randomization, the median NT-pro B-type natriuretic peptide (NT-proBNP) level was 2800 pg/mL.
Participants in the study were on quality of treatment. At baseline, 93 percent of patients received a beta-blocker, 73 percent received an angiotensin-converting enzyme (ACE) or angiotensin II receptor blocker (ARB) inhibitor, 70 percent received a mineralocorticoid receptor antagonist (MRA), 15 percent received an angiotensin receptor and neprilysin inhibitor (ARNI) combination, 28 percent had an implantable cardiac receptor antagonist (MRA), and 28 percent had an implantable cardiac inhibitor (ARNI). Ninety-one percent of patients were treated with two or more drugs for heart failure (beta-blocker, any receptor of the renin-angiotensin system [RAS], or MRA) and all three were treated in 60 percent of patients. At baseline, 6% of patients received an inhibitor of ivabradine and 3% of sodium glucose co-transporter 2 (SGLT2).
VERQUVO showed an adverse effect profile comparable to placebo in the VICTORIA trial. Hypotension (16% vs 15%) and anemia were the adverse drug reactions that occurred more frequently with VERQUVO than with placebo and in more than or equivalent to 5% of patients treated with VERQUVO in VICTORIA (10 percent vs 7 percent ). The VICTORIA trial included a total of 2,519 patients treated with VERQUVO (up to 10 mg once daily). The mean period of exposure to VERQUVO was one year, with a median duration of 2.6 years.
Robert D. Schaller, DO, MS, FHRS from Perelman School of Medicine at the University of Pennsylvania speaks about Magnetic Resonance Imaging in Patients With Cardiac Implantable Electronic Devices With Abandoned Leads.
Link to Article:
Question about the main points Is it safe to use magnetic resonance imaging (MRI) on patients who have had their cardiac implantable electronic system (CIED) leads removed?
There were no significant adverse effects recorded in this cohort study of 139 patients who had 200 MRIs of different anatomic regions, including the thorax. Transient decreases in lead sensing in 5 patients and subjective sternal heating in 1 patient with an abandoned subcutaneous array and sternal wires were among the CIED parameter changes.
In other words, The results of this analysis indicate that, regardless of the anatomic area being examined, the existence of abandoned CIED leads does not rule out MRI.
The meaning of for certain cases, magnetic resonance imaging (MRI) is the preferred method of diagnosis. Patients with legacy cardiac implantable electronic devices (CIEDs) now have more access to MRI thanks to conditional devices and innovative imaging protocols. The presence of abandoned leads, on the other hand, is an utter no-no.
The goal to see if performing an MRI in the presence of an abandoned CIED lead is safe and if there are any negative effects on active CIED leads nearby.
Participants, Design, and Setting Between January 2013 and June 2020, this cohort study included consecutive CIED recipients who underwent 1.5-T MRI with at least one abandoned lead. At the University of Pennsylvania Hospital, MRI scans were done. No patients were turned away.
CIEDs were reprogrammed to satisfy the pacing needs of individual patients. Electrocardiography telemetry and pulse oximetry were constantly tracked, and if possible, live visual and voice communication with the patient was maintained during the scan. The CIED assessment was replicated after the MRI, and the programming was reset to baseline or a clinically acceptable environment.
Measures and Key Outcomes
Variations of 50% or more in pre-and post-MRI capture thresholds, ventricular sensing of 40% or more, and lead impedance of 30% or more, as well as clinical sequelae including pain and sustained tachyarrhythmia, were considered important. If data on long-term follow-up leads was available, it was analyzed.
A total of 139 patients (110 men [79 percent]) with an average (SD) age of 65.6 (13.4) years had 200 MRIs of different anatomic regions, including the thorax, performed. Repeat examinations were normal, with one patient receiving up to 16 examinations. There were 243 discarded leads in total, with an average (SD) of 1.22 (0.45) per patient. The average (SD) number of active leads was 2.04 (0.78), with 64 patients (46%) requiring a pacemaker. In 41 patients (20.5%) who underwent MRI of the brain, a transmit-receive radiofrequency coil was used. There were no irregular vital signs or tachyarrhythmias that continued. There were no adjustments in battery voltage, power-on reset events, or pacing volume. There were transient CIED parameter shifts, including decreased right atrial sensing in four patients and decreased left ventricular R-wave amplitude in one patient. One patient who had a subcutaneous collection that had been discarded experienced sternal heating that went away when the analysis was stopped early.
Conclusions and Implications
In this large observational study, which included patients who had their thorax examined, the risk of MRI in patients with abandoned CIED leads was minimal. The growing body of evidence casts doubt on the utter contraindication of MRI in patients with CIED leads that have been abandoned.
Dino Mehic, MD from the Medical University of Vienna speaks about Elevated levels of tissue factor pathway inhibitor in patients with mild to moderate bleeding tendency.
Link to Abstract:
Points to Remember -
* TFPI levels are higher in patients with minor bleeding disorders, especially those that have BUC or PFDs.
* There were no genetic changes in the F5 gene that were related to increased TFPI levels.
High levels of tissue factor pathway inhibitor (TFPI) were recently discovered in two families with an unknown bleeding propensity, due to a longer TFPI half-life after binding to a factor V splice variant and variations in the F5 gene. The aim of this research was to look at the relationship between free TFPI and genetic alterations in the F5 gene in a well-characterized population of 620 patients with mild to moderate bleeding tendencies. Patients with leakage have higher TFPI values than stable controls (median [interquartile range], 8.2 [5.5-11.7] vs 7.8 [4.3-11.1]; P =.026). In comparison to stable samples, a higher percentage of patients had free TFPI ratios greater than or equal to the 95th percentile (odds ratio [OR] [95 percent confidence interval (CI)], 2.82 [0.98-8.13]). This was particularly noticeable in patients with no documented bleeding condition (bleeding of uncertain origin [BUC; n = 420]; OR [95 percent CI], 3.03 [1.02-8.98]) and platelet function defects (PFDs) (n = 121; OR [95 percent CI], 3.47 [1.09-11.08]). A rise in free TFPI was linked to a slight thrombin generation delay (longer lag time and time to peak), but not to changes in commonly used global clotting tests. In our patient cohort, we were unable to find any new or established genetic variants in the F5 gene that are linked to free TFPI levels, nor any effect of the single-nucleotide variant rs10800453 on free TFPI levels. Unexpected bleeding, which is more often multifactorial in the majority of patients, maybe caused or contributed by an excess of natural coagulation inhibitors such as TFPI.
Eric Y. Ding, Ms from the Division of Cardiology, Department of Medicine, University of Massachusetts Medical School speaks about the Survey of current perspectives on consumer-available digital health devices for detecting atrial fibrillation.
Link to Article:
Patients have direct access to a variety of digital health services that can detect atrial fibrillation (AF). Heart rhythm healthcare practitioners' (HCPs) adaptation into clinical practice, on the other hand, is uncertain.
The aim of this study was to look into the perspectives of HCPs on the use of commercial technologies for AF detection and management.
We developed an electronic survey for HCPs to determine practice demographics and attitudes toward digital devices for AF identification and management. The survey was sent to all members of three heart rhythm professional societies via email.
Out of 73,563 e-mails sent, we got 1601 responses, with 43.6 percent coming from cardiologists, 12.8 percent from fellows, and 11.6 percent from advanced practice practitioners. The majority of respondents (62.3 percent) said they had advised patients to use a digital system for AF detection. Many that didn't were worried about their accuracy (29.6%), the clinical usefulness of the findings (22.8%), and incorporation into electronic health records (22.8%). (19.8 percent ). For patients at high risk of stroke, the findings of a 30-second single-lead electrocardiogram were enough for 42.7 percent of HCPs to prescribe oral anticoagulation. More data comparing the accuracy of digital devices versus traditional devices for AF monitoring was requested by respondents (64.9 percent ). A quarter of HCPs (27.3%) had no concerns about recommending digital devices for AF detection, and the majority (53.4%) required guidelines from their professional societies about how to use them properly.
Many healthcare professionals have already begun to incorporate digital technologies into their clinical practice. However, when using digital technology for AF detection, HCPs identified difficulties, and professional society guidelines are required.
A. Michael Lincoff, MD, Professor of Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University speaks about Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) rationale and design.
Link to Article:
CVD is a leading cause of morbidity and mortality in the United States. While it is widely accepted that obesity is a major risk factor for CVD, successful, long-term weight loss therapies and the effects of weight loss on lowering cardiovascular risk have remained elusive. Instead, drugs for managing lipids, hyperglycemia, blood pressure, heart disease, inflammation, and/or thrombosis have made progress in lowering CVD risk. Obesity has been linked to many of these problems, implying that sustained, successful weight loss may have a separate cardiovascular gain. GLP-1 receptor agonists (RAs) help people with diabetes lose weight, boost their glycemia, and reduce cardiovascular events. They can also have other cardioprotective effects. At a dosage of 2.4 mg subcutaneously (s.c.) once weekly, the GLP-1 RA semaglutide is in phase 3 trials as an obesity treatment. SELECT (Semaglutide Impact on Cardiac Disease and Stroke in Patients with Overweight or Obesity) is a randomized, double-blind, parallel-group study to see whether semaglutide 2.4 mg subcutaneously once weekly is better than placebo at preventing significant adverse cardiovascular events in patients with proven CVD and overweight or obesity but no diabetes when added to standard of care. SELECT is the first cardiovascular outcomes study to measure an antiobesity medication's superiority in reducing significant adverse cardiovascular conditions in this population. As a result, SELECT has the ability to advance novel approaches to lowering CVD risk while also addressing obesity.
Design and care of the overall sample
SELECT (NCT03574597, www.clinicaltrials.gov) is a randomized, double-blind, parallel-group, placebo-controlled study that compares semaglutide to placebo as an alternative to the standard of care for the prevention of major adverse cardiovascular events (MACE) in patients with existing CVD who are overweight or obese. Novo Nordisk is the main sponsor of the trial. Every participating center's institutional review board and ethics committee approved the trial protocol. Before any trial-related operation, all patients gave written informed consent.
Figure 1 portrays a high-level overview of SELECT's core design elements. Once-weekly subcutaneous (sc) semaglutide 2.4 mg or placebo is given to patients in a 1:1 ratio. Patients are started on a once-weekly dose of 0.24 mg, which is increased every four weeks (to doses of 0.5, 1.0, 1.7, and 2.4 mg/wk) before they hit the target dose of 2.4 mg after 16 weeks. To minimize the possibility of side effects, the procedure is versatile, allowing for prolonged escalation and treatment pauses if appropriate. The investigators will receive ongoing support from a Global Exert Panel, which is made up of local experts with experience in CVOTs and GLP-1RA use, and there will be a strong emphasis on educating and encouraging them during the trial. Since the most common side effects are gastrointestinal (nausea, vomiting, diarrhea, and constipation), manuals for clinicians and patients have been established and distributed. Overall, trial behavior places a heavy emphasis on maximizing trial product exposure. The management of cardiovascular risk factors is emphasized in the SELECT trial to ensure that patients meet international recommendations for quality of care. Investigators are given guidelines in the form of a standard-of-care document that is revised on a regular basis.
The patient is in touch with the investigator every 13th week during the trial to ensure retention and compliance, as well as to optimize care. During the first months of the study, site visits are more frequent to help the patient during the dose-escalation phase. Detailed tracking and recording of treatment pauses, missed visits, and possible loss of follow-up is done during the study. To ensure a high retention rate and ongoing support for investigators and patients involved in Pick, a number of mitigation steps have been introduced.
Numbers of people
Around 17,500 volunteers will be enrolled in the study from over 750 locations around the world, including locations on all six continents (Africa, Asia, Oceania, Europe, and North and South America). The first patient was randomized in November 2018, and the trial is planned to last 5 years, despite being event-driven. Patients must be at least 45 years old, have a BMI of 27 kg/m2, and have a history of CVD. Prior myocardial infarction (MI), prior ischemic or hemorrhagic stroke, symptomatic peripheral arterial disease (PAD) with an ankle-brachial index of less than 0.85 at rest, prior peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease are all examples of proven CVD. Patients with hemoglobin A1c (HbA1c) ≥48 mmol/mol (6.5%); with a history of type 1 or type 2 diabetes; or who had suffered MI, stroke, hospitalization for unstable angina pectoris, or a transient ischemic attack within 60 days of screening are excluded. The full eligibility requirements can be found in Table I. Patients who acquire diabetes during the study are held in the study and given concomitant diabetes medication (excluding other GLP-1 RAs) at the investigator's discretion.
Johannes Mueller, MD, EMG, Ph.D. Co-founder and Chairman of Berlin Heals speaks about BERLIN HEALS Receives Breakthrough Device Designation from FDA for its C-MIC Heart Failure Device and Initiates Early Feasibility Study in the United States.
Link to C-MIC-II Study:
Link to Article:
BERLIN HEALS, a company designing new life-saving drugs for heart failure, revealed today that the US Food and Drug Administration (FDA) has given its patented Cardiac Microcurrent Therapy Device a Breakthrough Device Designation ("C-MIC"). The C-MIC is an implantable device that uses two electrodes to transmit a steady but low-current electrical DC current to the heart. The C-MIC technology has shown promise to become the first near-curative heart failure treatment, according to findings of first-in-human trials in 2019/20. Berlin Heals is about to file an Investigational Device Exemption (IDE) - Application with the FDA for an Early Feasibility Review (EFS) to begin later this year in the United States, after already launching a European-wide CE-study.
The FDA's Breakthrough Technologies initiative helps companies create medical devices that have the ability to cure or detect life-threatening or irreversibly disabling diseases. Heart failure, the most deadly condition on the planet, is a progressive inflammatory illness that affects millions of people worldwide. It accounts for 16% of all deaths and has seen the greatest growth among all deadly diseases since 2000, rising by more than 2 million to 8.9 million deaths in 2019. The FDA has designated the C-MIC technology as a revolutionary medicine because it has the potential to be the first medication to enable patients with cardiac failure to live a normal and mobile life.
As of today, no therapy, drug, or method has been developed and made available to reverse cardiac failure. Designation of the C-MIC as a breakthrough device by the FDA allows significant acceleration in the development and review of the technology, providing patients faster access. Marko Bagaric, CEO of Berlin Heals said, "Our completely novel therapeutic approach has the potential to almost cure heart failure rather than just delaying the progression of the disease. The FDA Breakthrough Designation is a tremendous turning point in the approval process for the US, enabling us to make our device available to patients with life-threatening heart disease much faster."
Berlin Heals has been designing cutting-edge technologies to cure heart disease since 2014. The patented C-MIC system was developed in response to the findings of pre-clinical trials conducted in close collaboration with the Medical University of Vienna, which verified that microcurrents have a highly beneficial effect on cardiac cells. The C-MIC is a small implantable device that causes cardiac muscle tissue to reverse remodel by supplying a steady but low-current electrical DC current to the heart. Extensive preclinical studies not only confirmed the effectiveness and protection of microcurrent application via C-MIC but also revealed a powerful anti-inflammatory impact as well as substantial improvements in cardiac function. Berlin Heals began the first implantations in patients under research conditions after verifying the distinctly beneficial effects of microcurrent in preclinical trials.
In April 2020, Berlin Heals successfully completed a pilot trial with ten patients. The electrical microcurrent was totally undetectable by the patients, had little effect on their heart rate, and resulted in dramatic changes in heart function in just a few days. The hearts of all of the patients, which are usually bloated in dilated cardiomyopathies, had narrowed, and all of the patients had dropped two NYHA classes. There were no device-specific side effects or follow-up procedures necessary.
With its C-MIC system, Berlin Heals has now initiated a European CE-multi-center analysis in Germany, Serbia, Austria, and Poland, which is scheduled to be completed by the end of 2022. In mid-2021, the organization will begin an Early Feasibility Study (EFS) in the United States with ten patients. The promising findings of the first human sample would then be confirmed in a significantly wider population of over 100 participants in a controlled two-arm multicenter experiment. The C-MIC technology will be available in Europe in 2022, the United States in 2025, and the rest of the world in 2025.
Khaled Ziada, MD from the Cleveland Clinic discusses Cangrelor in ST-Elevation Myocardial Infarction to Decrease Infarct Size.
Link to the Clinical Trial-
This research evaluates variations in the degree of myocardial necrosis observed by cardiac MRI in patients with randomized ST-elevated myocardial infarction who received cangrelor during the percutaneous coronary intervention and contrasts them with patients who did not receive cangrelor randomly.
Description in detail:
Cangrelor is a direct-acting and reversible intravenously administered platelet inhibitor approved as an alternative to percutaneous intervention (PCI) for reducing the risk of periprocedural myocardial infarction, repeat coronary revascularization, and stent thrombosis. Cangrelor is emerging as an important new choice for use in patients undergoing percutaneous intervention who have not been treated with oral platelet inhibitors, as it has a fast onset of action (2 minutes) compared with conventional oral platelet inhibitors.
In addition, several studies have shown that patients undergoing emergent PCI with ST-elevation myocardial infarction (STEMI) do not have adequate platelet inhibition even after a loading dose of conventional oral platelet inhibitors has been given. The clinical meaning of maximum platelet inhibition at the time of PCI, however, is not fully understood.
The primary objective is to characterize the efficacy of intravenous cangrelor immediate platelet inhibition in patients with acute STEMI by determining the degree of infarct size (either enzymatically or by imaging). If the results are positive, this could indicate that in this patient population, immediate platelet inhibition is an important part of treatment.
Professor Murray Esler from the Baker Heart & Diabetes Institute discusses the Editorial - Reflections on the past four decades of mental stress research in autonomic cardiology.
Link to Full Article -
This commentary, with some observations and a description of my experience in the field of mental stress science, is my contribution to the celebration of the thirtieth anniversary of Clinical Autonomic Research, a journal that has become the benchmark publication for all those interested in the autonomic nervous system in recent years, regardless of their primary medical specialty, which in my case is the automobile.
In 1977, I returned to the Baker Medical Research Institute and the Alfred Hospital in Melbourne, Australia, after 4 years of postgraduate research and clinical training with Prof. Stevo Julius in the Hypertension Division of the University of Michigan Medical Center, where I worked as a clinical cardiologist and founded a laboratory for cardiovascular neuroscience.
I recall being struck by how the involvement of patients with myocardial infarction or ventricular arrhythmias was often precipitated by emotional turmoil in my early clinical practice in Melbourne. "I saw patients in whom armed robbery, robberies, and even an owner's racehorse winning by a "nose" had induced a heart attack. I was delighted to accept, in 1985, an invitation to participate in what I expected would be an influential national panel to discuss the relationship between mental stress and heart disease with this clinical exposure. However, I was not ready for the meeting chair's opening remark (whose name I will not say): "There is no proof that stress causes heart disease, nor will there ever be." I was saddened, but not discouraged, as this could not be true, of course. Where was his crystal ball? Even if the comment captured the pessimism that was prevalent in that era's cardiology.
Faced with this setback, by researching cardiac sympathetic responses to mental stress, I applied my newly developed noradrenaline spillover methodology to the stress-heart issue, tapping into research possibilities that are open to a cardiologist. I performed this study in a cardiac catheterization facility, using a tritiated noradrenaline infusion to measure the isotope dilution release of this catecholamine from sympathetic nerves, with sampling from the heart's coronary sinus. This was to make these measurements of noradrenaline release unique to the cardiac sympathetic nerves, all achieved during the study participants' exposure to laboratory mental stress (Fig. 1a). The applied stressor, as accepted by my institutional ethics committee, was 10 minutes of challenging mental arithmetic, only to surpass the arithmetic competence of the volunteer, and paced by a metronome. For the mathematically talented, an additional tweak was made by informing the individual that they were incorrect... when they were actually correct! In a standard experiment, we measured the secretion of adrenaline by the adrenal medulla, the release of noradrenaline from the sympathetic nerves and sympathetic nerves of the whole body, the concentrations of noradrenaline and adrenaline plasma sampled from the antecubital vein, and the firing of sympathetic outflow using microneurography in the innervation of the vasculature of the skeletal muscle in the leg.
Carol Chiung-Hui Peng, MD and Kashif Munir, MD, Medical Director Of The University Of Maryland Center For Diabetes And Endrocrinology, University of Maryland Medical Center Midtown Campus, University of Maryland School of Medicine speaks about Fracture Risks in Patients Treated With Different Oral Anticoagulants: A Systematic Review and Meta‐Analysis.
Link To Abstract:
To evaluate the fracture risk associated with NOACs and warfarin, we performed a systematic review and meta-analysis.
Methods and Results:
From inception to May 19, 2020, we searched PubMed, Embase, Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov. We included studies that recorded measurements for any fracture in NOAC and warfarin users (regardless of major, secondary, tertiary, or safety outcomes). Two or more reviewers worked together to screen relevant papers, extract data, and evaluate accuracy. To synthesize the pooled relative risk (RR) of fractures associated with NOACs versus warfarin, data were retrieved. For data synthesis, random-effects models were used. There were 388 209 patients in 29 studies (5 cohort studies and 24 randomized controlled trials). Patients taking NOACs had a lower risk of fracture than those taking warfarin (pooled RR, 0.84; 95 percent CI, 0.77–0.91; P0.001), and there was little variability (I2=38.9%). NOACs were also linked to a lower risk of hip fracture than warfarin (pooled risk ratio, 0.89; 95 percent confidence interval, 0.81–0.98; P=0.023). There was also a nonsignificant trend of NOAC users having a lower risk of vertebral fracture (pooled RR, 0.74; 95 percent CI, 0.54–1.01; P=0.061). Specific NOACs dabigatran, rivaroxaban, and apixaban were found to be significantly associated with lower fracture risks in subgroup analyses. Furthermore, the data synthesis results from randomized controlled trials and real-world cohort studies were remarkably consistent, suggesting the validity of our findings.
NOACs are associated with a lower risk of bone fracture as compared to warfarin.
Todd Chapin, PharmD, BCPS from Sanford Health speaks about Apixaban Versus Warfarin for the Management of Post-operative Atrial Fibrillation.
Link to Study:
Patients who experience atrial fibrillation after isolated coronary artery bypass grafting surgery will be identified in this open-label, prospective, randomized pilot study. Patients with chronic prolonged atrial fibrillation (>2 episodes of atrial fibrillation lasting longer than 30 minutes) or persistent atrial fibrillation (>12 hours) would be qualified. Patients will be randomized to either the standard of care (warfarin per protocol) or the apixaban arms of the trial after meeting research inclusion and exclusion requirements and giving informed consent. Both groups will receive routine postoperative treatment after CABG. The anticoagulation clinic will treat anticoagulation in both classes after discharge. After surgery, patients will be monitored for 30 days.
Naveen L. Pereira, MD, Consultant for the Department of Cardiovascular Diseases and Professor of Medicine and Associate Professor of Pharmacology, Mayo Clinic College of Medicine speaks about ACC 2021 - Late-Breaking Clinic Science - Effect of CYP2C19 Genotype on Ischemic Outcomes During Oral P2Y12 Inhibitor Therapy: A Meta-Analysis.
Link to Abstract:
The aim of this research was to compare the effects of ticagrelor or prasugrel versus clopidogrel treatment on clinical results in patients with coronary artery disease (CAD) who were primarily treated with percutaneous coronary intervention (PCI).
Background: The impact of CYP2C19 genotype on ticagrelor or prasugrel patient results relative to clopidogrel is unknown.
Methods: Experiments comparing the effects of CYP2C19 genotype on ischemic results during ticagrelor or prasugrel versus clopidogrel therapy were scanned through February 19, 2020. Results for CYP2C19 genotype status, clopidogrel, and alternative P2Y12 inhibitors in patients with CAD with at least 50% undergoing PCI are expected for study eligibility. The main focus of the study was on randomized controlled trials (RCTs). Non-RCTs are added to the main analysis as a supplementary analysis. Cardiovascular mortality, myocardial infarction, stroke, stent thrombosis, and extreme chronic ischemia were the main outcomes. To analyze the two-drug regimens and assess the relationship with the CYP2C19 genotype, a meta-analysis was performed.
Seven RCTs were found among the 1,335 studies found (15,949 patients, mean age 62 years; 77 percent had PCI, 98 percent had acute coronary syndromes). The probability of prejudice was poor, and statistical variability was small. When ticagrelor and prasugrel were linked to clopidogrel, there was a substantial decrease in ischemic incidents (relative risk: 0.70; 95 percent confidence interval: 0.59 to 0.83) in CYP2C19 loss-of-function carriers but not in noncarriers (relative risk: 0.70; 95 percent confidence interval: 0.59 to 0.83). (relative risk: 1.0; 95 percent confidence interval: 0.80 to 1.25). The association test on the basis of CYP2C19 genotype status was statistically significant (p = 0.013), implying that the genotype of CYP2C19 altered the effect. Four further observational experiments were discovered, and when they were used in the study, the results were the same (p-value of the interaction test 0.001).
Conclusions: The role of ticagrelor or prasugrel in minimizing ischemic events in patients with CAD who specifically experience PCI is dependent on the existence of CYP2C19 loss-of-function carrier status when opposed to clopidogrel. These findings back up genetic tests before administering P2Y12 inhibitors.
Mehmet Asim Bilen, MD from Winship Cancer Institute of Emory University discusses the Evaluation of a novel blood pressure scoring method and its association with clinical response in cancer patients treated with anti-vascular endothelial growth factor therapy.
Link to Study -
Background: In advanced cancer patients treated with anti-vascular endothelial growth factor (VEGF) therapies, the aim of this study was to develop a novel blood pressure (BP) scoring method and correlate it with clinical response.
Methods: We retrospectively evaluated data from 23 clinical trials involving at least one anti-VEGF agent for 368 patients. Using the standard Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and our latest system, BP scores were measured using both BP readings and the amount of anti-hypertensive drugs obtained by the patient. BP ratings at baseline and four months have been classified. Elevated scores were correlated with the clinical response through logistic regression analysis. An agreement was assessed between the CTCAE and the new system.
Results: Under the latest BP scoring system, partial response rates were 20 percent for four-month elevated patients versus 6 percent for non-elevated patients (P < 0.001). When adjusted for tumor type, age, sex, history of anti-VEGF treatment, and the number of anti-VEGF treatments, the odds ratio was 3.8 (95% confidence interval [CI]: 1.8, 8.2; P < 0.001) for elevated BP under the new scoring system. The kappa statistics were 0.57 (95 percent CI: 0.47, 0.67; P < 0.001) for agreement between the CTCAE and current scoring methods, suggesting substantial concordance.
Conclusion: The rise in BP scores was a proxy for favorable clinical response in patients receiving anti-VEGF therapy using the novel scoring system. Ultimately, this new approach offers details about the clinical tumor response over and above that given by the scoring method of CTCAE.
Professor David A. Kass, MD, Department of Medicine, Division of Cardiology, Department of Biomedical Engineering, Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine speaks about Review: Cellular and molecular pathobiology of heart failure with preserved ejection fraction.
Link to Review Article:
Heart failure with retained ejection fraction (HFpEF) affects half of all heart failure patients worldwide, is becoming more common, is associated with significant morbidity and mortality, and has few successful therapies. The largest unmet medical need in cardiovascular disease is probably HFpEF. While HFpEF was once thought to be a haemodynamic disorder characterized by hypertension, cardiac hypertrophy, and diastolic dysfunction, the pandemics of obesity and diabetes mellitus have changed the HFpEF syndrome, which is now recognized as a multisystem disorder involving the heart, lungs, kidneys, skeletal muscle, adipose tissue, vascular system, immune and inflammatory systems. Since the disorder is more than just cardiac hypertrophy and hypertension with abnormal myocardial relaxation, HFpEF is difficult to model in laboratory animals. New animal models of haemodynamic and metabolic disease, as well as increased efforts to investigate human pathophysiology, are revealing new signaling mechanisms and possible therapeutic targets. We address the cellular and molecular pathobiology of HFpEF in this Study, with a specific emphasis on mechanisms related to the heart, as most research has been done on this organ. Other critical organ systems, such as the lungs, kidneys, and skeletal muscle, are also involved, as are attempts to characterize patients using systemic biomarkers and ongoing therapeutic efforts. Our aim is to build a map of the signaling pathways and mechanisms of HFpEF that are currently being studied, with the intention of creating more patient-specific therapies and enhancing clinical outcomes.
Points to remember:
* Historically, diastolic dysfunction, cardiac hypertrophy, and myocardial fibrosis have been the subject of research into the pathophysiology of heart failure with preserved ejection fraction (HFpEF).
* Moreover, HFpEF is made up of a variety of factors that affect both systolic and diastolic heart function, as well as other organs and systems such as the lungs, kidneys, vasculature, adipose tissue, and skeletal muscle.
* Preclinical studies, especially those that combine obesity and metabolic defects with haemodynamic and cardiac disease, as most patients with HFpEF do, are revealing novel molecular mechanisms and therapeutic targets.
* Metabolic defects in fuel utilization and performance, inflammatory responses, lipotoxicity, pathological growth of myocytes, and lack of cytoprotective signaling are all proposed molecular and cellular abnormalities in HFpEF and those seen in diabetes mellitus and obesity.
*New therapies are targeting pleiotropic signaling cascades to reverse improvements in metabolic, inflammatory, and pathological stress pathways, in addition to developing innovative haemodynamic treatments with drugs and devices.
Carol Chiung-Hui Peng, MD from the University of Maryland Medical Center Midtown Campus, and Kashif Munir, MD from the University of Maryland School of Medicine, associate professor, and Medical Director of the University of Maryland Center for Diabetes and Endocrinology speak about Non‐vitamin K antagonist oral anticoagulants vs. warfarin for AFib patients: What the latest research tells us.
@UMMC @umms @UMmedschool
Link to Abstract:
Comparison of the risk of developing diabetes in patients with non-vitamin K antagonist oral anticoagulants (NOACs) treated with atrial fibrillation (AF) and warfarin.
Materials and Methods
Using Taiwan's National Health Insurance Research Database, we carried out a nationwide retrospective cohort analysis. Adult new-onset AF patients treated with NOACs or warfarin between 2012 and 2016 have been included. The NOAC cohort was further categorized into classes of dabigatran, rivaroxaban, and apixaban. Incident diabetes requiring treatment with antidiabetic medications was the primary outcome. Subdistribution hazard models of Fine and Gray were used to estimate the adjusted hazard ratio (aHR). For each head-to-head analysis, propensity score matching was conducted.
Our analysis included a total of 10,746 new-onset AF patients. NOACs were associated with a lower risk of developing diabetes than warfarin during the mean 2.4-year follow-up (aHR = 0.80, 95 percent confidence interval [CI]: 0.68-0.94, P = .007). Analyses of the subgroup indicated that dabigatran, rivaroxaban, and apixaban each had a decreased risk of diabetes. Stratified studies found that the lower risk of NOAC-related diabetes was specific for patients 65 years of age or older (aHR = 0.74, 95% CI: 0.62-0.89, P = .002) and those with strong adherence to medication (aHR = 0.70, 95% CI: 0.58-0.84, P < .001).
In patients with AF, taking NOAC was associated with a lower risk of developing diabetes compared to taking warfarin.