Newly discovered pathway may have potential for treating heart failure - Presentation MP140
Researchers have found an important and previously undiscovered pathway with therapeutic potential for treating heart failure.
Heart failure occurs when there is a loss of the heart's ability to pump blood to the rest of the body. One of the reasons this happens is when the cells are inefficient in managing calcium. This can lead to a decrease in the ability of cells to contract and push blood out of the heart. This dysfunction occurs in the part of the cell called the endoplasmic reticulum/sarcoplasmic reticulum and is linked to an intracellular membraned called SERCA (Sarco/Endoplasmic Reticulum Calcium-ATPase). SERCA is important and helps to keep the heart contracting and in proper balance. There currently is no treatment (medications, procedures, etc.) that can impact SERCA.
In this study, researchers found a substance called Inc-SYNPO in the heart tissue of the left ventricle. Inc-SYNPO has the potential to change SERCA. Finding this new pathway is important because if Inc-SNYPO can be altered to change SERCA, thus improving the strength and vigor of the heart's ability to pump blood out, this may lead to an improvement in heart failure.
Min Yi You, M.S., National Taiwan University
New research model helps predict heart muscle cells' impact on heart function after injury - Presentation MP160
Researchers have developed a powerful model that can be used to identify what is happening in heart muscle cells under stressful conditions, which can be useful to learn about the impact of those cells on heart function after injury.
Most adult heart cells cannot divide and regenerate after injury, unlike most other cell types. In the rare event that a heart cell does start to cycle, it usually only creates extra genetic material (endoreplicate) and does not complete cytokinesis to divide (proliferate). It is generally assumed the few cells that reenter the cell cycle do not contribute to improved function, regardless of whether they endoreplicate or proliferate. This reaction presents a significant problem in the search to find therapies to repair heart tissue after injury, such as a heart attack due to blockage and lack of blood flow.
Researchers used a combination of techniques to develop a visual and genetic assay to distinguish the changes a heart cell undergoes during the rare event it naturally enters the cell cycle. Using special, genetically engineered mice, researchers tagged a green fluorescent protein (GFP) to express in heart cells entering the cell cycle and endoreplicate (one cell visible) or proliferate (two neighboring cells visible). The researchers activated the gene program then "stressed" the cells with an ischemic heart attack. After the injury, they observed cell cycle activity in the edges of the blockage, with more endoreplication than proliferation. This will allow researchers to count the number of green cells and compare the effectiveness of different types of treatments after a heart attack.
Once researchers locate, identify and isolate this small population of green heart cells, their goal is to study the genes that enable them to endoreplicate vs. proliferate. They can then manipulate these genes that are specifically targeted only to these naturally dividing heart cells to help improve heart function after injury.
This is a powerful model that offers a unique and less invasive approach that researchers can use to identify therapies that could potentially improve heart function after disease or injury.
Matthew Wolf, M.D., Ph.D. University of Virginia
New mass spectrometry approach generates libraries of glycans in human heart tissue - Presentation MP143
Researchers used a new mass spectrometry approach to generate libraries of glycans in human heart tissue, heart muscle cells enriched from heart tissue and heart muscle cells derived from human-induced pluripotent stem cells.
This study offers new knowledge about glycans and informs cell surface glycoproteins. These large molecules are composed of oligosaccharide chains (glycans) attached to amino acid chains and can undergo reactions that modify their function. Knowledge is emerging that glycoproteins are important in the heart's ability to maintain structure through protein structure and signaling. The differences in the glycan libraries show that there are differences in the way these molecules appear in different types of heart cells and add to existing information about glycoproteins.
Rebekah L. Gundry, Ph.D., University of Nebraska Medical Center
Understanding heart damage after heart attack and treatment may provide clues for prevention - Presentation MP124
New research in a mouse model brings us a little closer to understanding why the stop and start of blood flow to heart tissue during a heart attack and then after treatment causes tissue damage and provides clues as to how it might be prevented.
The mitochondrion, the powerhouse of a cell, has received more attention over the past few years as its role in heart regulation has emerged, in addition to Adenosine Triphosphate (ATP) generation. ATP provides energy to drive many processes in living cells, e.g. muscle contraction, nerve impulse propagation, condensate dissolution and chemical synthesis. The mitochondria also have other roles in heart function, particularly through the activity of the permeability transition pore (PTP) during a heart attack. Regulation of PTP in ischemia reperfusion, which is what happens when blood flow to the heart muscle stops during a heart attack then restarts again when the person gets treatment in the hospital, has been known to happen through a protein called cyclophilin-D (CypD) for some time; however, the exact mechanism was unknown.
This study found that during ischemia in mouse hearts the increase in mitochondrial calcium concentration causes an amino acid on CypD (cysteine 202) to undergo a post-translational modification (de-palmitoylation), which promotes PTP-opening, which leads to the tissue damage.
These results suggest that the mitochondria may add to heart tissue damage during a heart attack through regulation of PTP by mitochondrial calcium concentration and post-translational modifications on cysteine 202 of CypD. More studies are needed to discover how this might lead to a treatment to reduce or repair damaged tissue after a heart attack.
Georgios Amanakis, M.D., National Institutes of Health
Understanding atrial fibrillation's effects on heart cells may help find treatments - Presentation 304
In this study, researchers made strides in understanding what happens in heart muscle cells during atrial fibrillation, and this new information may help with finding an effective treatment.
Although it's more common with advancing age, in the patients with chronic heart conditions, often post-surgically, there is still a lot unknown about the cellular mechanisms that initiate or sustain atrial fibrillation, especially in the early stages before there's been time for extensive tissue fibrosis (scarring). So far, a lot of research attention has focused on intracellular calcium cycling and alterations in the membrane ion channel functions, including modification of proteins and changes in cellular metabolism.
This study used atrial muscle cells from patients with atrial fibrillation without valve disease or systolic heart failure, which could confound the results, and compared them to cells from healthy hearts in normal sinus rhythm. These muscle cells contract due to a lattice structure of molecular motors inside each cell, and researchers compared the ability of these motors to develop force.
Researchers were surprised to discover that the atrial fibrillation cells contracted more strongly, in fact they had the capacity to develop nearly double the maximum force. Further, the atrial fibrillation myocytes switched their molecular motors from primarily alpha myosin heavy chain that healthy atrial cells use, to the more efficient beta myosin heavy chain. While their heart cells are nearly twice as strong, the atria contract weakly in people with atrial fibrillation, this means there is more happening that is not yet known especially at the level of the molecular motors that drive contraction. Additional research is needed to understand the cell changes that happen due to atrial fibrillation and how it can be treated.
Parth V. Desai, M.D., Loyola University Medical Center
New research may lead to therapy for heart failure caused by ICI cancer medication - Presentation 350
Cardio-oncology is a rapidly emerging area of research and physician interest. In this study, researchers analyzed the impact of a class of cancer treatment medications - Immune Checkpoint Inhibitors (ICI) - used to improve patient survival.
Even with the benefits to patients in cancer treatment, ICI medications can lead to side effects including fulminant myocarditis, which causes severe, rapid onset of cardiac inflammation, and heart failure, and both can be fatal. The cellular mechanisms that happen during this immune response are unknown. In this study, researchers sought to understand the mechanism of the inflammatory response induced by ICIs.
Researchers used a mouse model of myocarditis, or heart inflammation, as well as blood samples from ICI patients to look at the mechanisms of antigen-mediated T-immune cell response. The results show that an expansion of the immune CD8+ T-cells occurs in the blood and heart of patients receiving ICI therapy.
Researchers say the next steps are to identify the auto-antigens that may cause the CD8+ expansion. This research has the potential to lead to therapies to help stop fulminant myocarditis and heart failure death in cancer patients undergoing ICI treatment.
Han Zhu, M.D., Stanford University
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