Paul W. Armstrong, MD from the Canadian VIGOUR Centre, University of Alberta, Edmonton, AB, Canada and the Merck speaks about the ACC 2021 Abstract - Coronary Artery Disease and Cardiovascular Outcomes in Heart Failure: Insights from the VerICiguaT Global Study in Patients With Heart Failure and Reduced Ejection Fraction (VICTORIA).

Link to Study:
https://www.acc.org/latest-in-cardiology/clinical-trials/2020/03/26/19/43/victoria#references-for-article

Detailed description:

The trial's purpose was to compare vericiguat to placebo in individuals with chronic heart failure (CHF) caused by a low ejection fraction (EF). Vericiguat boosts the activity of soluble guanylate cyclase. This may assist to enhance cardiac and vascular function by increasing the generation of cyclic guanosine monophosphate.

Design of the Research

* This is a randomized sample.

* Double-blind study

* Concurrent

Vericiguat (n = 2,526) versus placebo (n = 2,524) were given to CHF patients. Vericiguat was begun at 2.5 mg per day, then raised to 5 mg, then 10 mg per day.


* The total number of students enrolled is 5,050.

* Follow-up period: 12 months

* The average patient is 68 years old.

* Females account for 24% of the total.



Criteria for inclusion:

* CHF; New York Heart Association class II-IV, left ventricular EF 45%, and heart failure treatment based on guidelines.

* A recent hospitalization for heart failure or the administration of an intravenous diuretic

* Natriuretic peptides elevated; N-terminal pro–B-type natriuretic peptide (NT-proBNP) 1000 pg/ml (1600 pg/ml if atrial fibrillation) or BNP 300 pg/ml (500 pg/ml if atrial fibrillation).

* Clinically stable (systolic blood pressure 100 mm Hg for 24 hours and no IV diuretics)



Criteria for exclusion:

* Nitrates with a lengthy half-life, phosphodiesterase type 5 inhibitors, and riociguat

* Awaiting a heart transplant, using continuous intravenous diuretics, or using a ventricular assist device now or in the future.

* Dialysis or chronic renal disease (evaluated glomerular filtration rate of 15 ml/min/1.73 m2)

* Severe pulmonary illness that necessitates the use of oxygen on a continual basis

* Hepatic insufficiency (severe)

* Cardiovascular comorbidities that can be treated

Other noteworthy features/characteristics include:

* The average EF is 29%.

* In 89 percent of cases, the target dosage of vericiguat was met.

The Most Important Findings:

Cardiovascular mortality or heart failure hospitalization occurred in 35.5 percent of the vericiguat group compared to 38.5 percent of the placebo group (hazard ratio [HR] 0.90, p = 0.019). The major outcome risk for vericiguat vs. placebo was 0.84% for those aged 75 years and 1.04% for those aged 75 years (p for interaction = 0.030).

Secondary effects include:

* Cardiovascular death: 16.4% in the vericiguat group vs. 17.5 percent in the placebo group (p = 0.27)

* Death from any cause: 20.3 percent in the vericiguat group vs. 21.2 percent in the placebo group (p = 0.38)

* Hospitalization for heart failure: 27.4 percent of the vericiguat group vs. 29.6 percent of the placebo group (p = 0.048).

* Serious adverse event: 32.8 percent of the vericiguat group versus 34.8 percent of the placebo group had a serious adverse event.

Contextualization:

A new technique of boosting soluble guanylate cyclase activity with vericiguat proved successful in individuals with CHF who had recently decompensated. Vericiguat was shown to be more efficacious than placebo in lowering cardiovascular mortality and hospitalization for heart failure. There was a possibility of a greater advantage for those above the age of 75. Vericiguat did not appear to reduce all-cause mortality when compared to placebo. Vericiguat was well tolerated and did not need renal function or electrolyte monitoring. Vericiguat might be a potential therapy option for individuals who have recently had heart failure decompensation.

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:
https://academic.oup.com/cardiovascres/advance-article/doi/10.1093/cvr/cvab044/6131786

Synopsis:

Objectives -

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.

Joan E. Briller, MD Division of Cardiology, Department of Medicine, University of Illinois at Chicago speaks about Pregnancy Associated Heart Failure With Preserved Ejection Fraction: Risk Factors and Maternal Morbidity.

Link to Article:
https://www.sciencedirect.com/science/article/pii/S107191642031592X#!

Highlights


• Pregnancy-related heart loss with retained ejection fraction (HFpEF) hospitalizations have risen by more than 19 percent per year.


• HFpEF admissions are driven by chronic hypertension and hypertensive pregnancy conditions.

• Women who were black, older, or weaker had a higher percentage of HFpEF hospitalizations.

• Pregnancy-related HFpEF is often linked with negative pregnancy outcomes.

Synopsis:

Background information -

Cardiovascular disease is one of the main causes of maternal morbidity and mortality. The majority of HF admissions in women are due to heart failure with retained ejection fraction (HFpEF), but its effect on pregnancy is unclear. During pregnancy-related hospitalizations in the United States, we looked at the prevalence rates, risk factors, and unfavorable pregnancy effects in women with HFpEF.

Results and Methods -

Using the National Inpatient Sample, we performed a cross-sectional study of pregnancy-related hospitalizations from 2002 to 2014. The 428.3 International Classification of Diseases, 9th edition, Clinical Modification code was used to identify HFpEF cases. For national projections, weighting variables were used, and unconditional survey logistic regression was used to derive odds ratios and 95 percent confidence intervals (CI) reflecting modified correlations with adverse pregnancy outcomes, as well as Joinpoint regression to predict temporal patterns. There were 3840 HFpEF cases out of 58,732,977 hospitalizations, with a prevalence of 7 cases per 100,000 pregnancy-related hospitalizations; 56 percent occurred postpartum, 27 percent during birth, and 17 percent occurred antepartum. The hospitalization rate rose by 19.4 percent (95 percent confidence interval 13.9–25.1) over time. Hospitalizations due to HFpEF were more frequent in Black, elderly, and disadvantaged women. Hypertension (chronic hypertension and pregnancy-related hypertension), anemia, obesity, asthma, kidney dysfunction, and coronary atherosclerosis were all identified as risk factors for HFpEF. Women with HFpEF had a 2.61–6.47 times higher chance of having a bad pregnancy.

Final thoughts -

The rate of HFpEF hospitalization during pregnancy has increased, and it is linked to poor pregnancy outcomes. The risk factors are similar to those found outside of pregnancy, highlighting the importance of screening and tracking women with risk factors for HFpEF during pregnancy.

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:
https://clinicaltrials.gov/ct2/show/NCT04662034

Link to Article:
https://www.globenewswire.com/news-release/2021/03/11/2191572/0/en/BERLIN-HEALS-Receive-Breakthrough-Device-Designation-from-FDA-for-its-C-MIC-Heart-Failure-Device-and-Initiates-Early-Feasibility-Study-in-the-United-States.html

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.

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:
https://www.nature.com/articles/s41569-020-00480-6

Synopsis:

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.

Frank Gommans, MD, PhD from the Radboud University Medical Centre speaks about Soluble Neprilysin and Corin Concentrations in Relation to Clinical Outcome in Chronic Heart Failure.


Link to Study -
https://www.jacc.org/doi/10.1016/j.jchf.2020.08.015

Summary -

Aims and goals

This research looked at whether soluble neprilysin and corin concentrations can be used to stratify patients with chronic heart failure (HF) and whether this is related to clinical outcomes.

Foreground

Corin and neprilysin, two enzymes that process natriuretic peptides, play a key role in the conversion of pro–natriuretic peptides to active natriuretic peptides as well as their degradation

Methodologies

A prospective cohort of 1,009 patients with chronic HF was divided into four equal classes based on their neprilysin/corin concentration relative to the median: 1) low neprilysin/low corin; 2) low neprilysin/high corin; 3) high neprilysin/low corin, and 4) high neprilysin/high corin. The composite primary outcome of cardiovascular mortality and HF hospitalization was subjected to a Cox regression survival study.

Conclusions

The median concentrations of neprilysin and corin were not associated (rho:0.04; p = 0.21). While there was no correlation with outcome in univariate research, after accounting for baseline variations in age and sex, a substantial association with survival was observed, with the highest survival in group 1 (low neprilysin/low corin) and the lowest in group 4 (high neprilysin/high corin) (adjusted hazard ratio: 1.56; p = 0.003) (adjusted hazard ratio: 1.56; p =

Final Thoughts

Clinical results are related to the stratification of patients with chronic HF based on circulating neprilysin and corin concentrations. These findings indicate that the control of these enzymes is important in chronic HF, and they may provide an intriguing mechanism for classifying patients with HF as the first step toward individualized HF patient care.

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