heart – Lightsources.org

Scientists visualise the paths controlling heart performance

2024/12/062024/12/10

Scientists have found the role of two proteins in the functioning of the heart. The results could help better design targeted strategies to treat certain cardiomyopathies. The results are out in PNAS.

The heart works using tiny muscle filaments, and two main steps control how they interact: first calcium signals cause changes in the thin filament (actin), allowing it to connect with myosin motors. Then myosin motors on the thick filament switch from “off” (inactive) to “on” (active), so they can pull on actin and create force and shortening. The thick filament can sense how much force is needed and adjust how many motors to turn on, but scientists are still figuring out exactly how this works.

Cardiomyopathies take place when these mechanisms regulating the contraction-relaxation cycle of the heart malfunction. This is due to mutations in the contractile proteins (myosin and actin) but also in accessory proteins (Myosin-binding protein-C and titin). Broadly, MyBP-C and titin ensure together that the heart contracts effectively while maintaining responsiveness to changes in demand.

A team from the University of Firenze (Italy) used small-angle X-ray diffraction at the ESRF’s ID02 beamline back in 2017 and showed that, during muscle contraction, myosin motors move outward from the thick filament, enabling interaction with actin based on the load, which in the cardiac ventricle is the arterial pressure against which blood must be pumped (Reconditi et al. PNAS 2017). Evidence from other laboratories also suggested that thick filament activation is modulated by regulatory domains in the myosin motor itself and by accessory proteins like MyBP-C and titin. However, their specific function in cardiac performance was not known in detail.

Now the same team has found the role that MyBP-C and titin play in the functioning of the heart, at beamline ID02. “The beamline ID02 is ideal thanks to its camera length, so we can have the detector closer or further to the samples in a range from 0.5 to 31 m. This lets us explore the contractile proteins as well as the sarcomere, the unit cell of muscle, which is crucial for our research”, says Massimo Reconditi, scientist at the University of Firenze and corresponding author of the paper. “With EBS, thanks to its low divergence, we can observe on the same diffraction pattern a high number of reflections together with their fine structure”, he adds.

Read more on ESRF website

Image: Theyencheri Narayanan, scientist in charge of ID02, on the beamline.

Credit: S. Candé.

A unique atlas of the human heart: from cells to the full organ

2024/07/172024/07/17

Scientists led by the University College London (UCL) and the European Synchrotron (ESRF), have, for the first time, imaged two whole human adult hearts, one healthy and one diseased, down to the cellular level in 3D, using an innovative X-ray technique called Hierarchical Phase-Contrast Tomography (HiP-CT). This new atlas of the heart can potentially lead to medical applications. The results are published in Radiology.

To study the human heart, researchers typically use clinical imaging techniques such as Ultrasound, Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). While these methods are effective for diagnosing cardiovascular disease, they do not provide detailed structural changes across the different scales within the heart. For higher resolution, histology is required, which involves slicing donor organs into sections. Although this method offers more detailed information, it significantly limits the field of view.

Now a new synchrotron X-ray imaging technique, called HiP-CT, overcomes these limitations by providing a comprehensive and detailed 3D view of the entire adult human heart. “HiP-CT provides a global view of whole donor organs at unprecedented resolution, bridging the gap between traditional imaging and histology,” says Professor Peter Lee of UCL, HiP-CT project lead.

A team led by UCL and the ESRF, in collaboration with the Wellcome Sanger Institute, Siemens Healthineers, Great Ormond Street Hospital, Hannover Medical School, the Aachen Medical University, the Helios University Clinic Wuppertal, the University Medical Center of the Johannes Gutenberg-University Mainz, and the Laboratoire d’Anatomie des Alpes Francaises (LADAF) has imaged two entire adult hearts, one healthy and one diseased, using the HiP-CT imaging technique on beamline BM18 at the ESRF. “BM18 is currently the only place in the world where complete human organs can be imaged with such a high level of contrast, and we are still quite far from the limits of the beamline capabilities. The main limiting factor is the processing of the very large data produced by HiP-CT”, explains Paul Tafforeau, ESRF scientist.

Read more on ESRF website

Image: Multidimensional Analysis of the Human Heart in Health and Disease using Hierarchical Phase-Contrast Tomography (HiP-CT).

Credit: Brunet et al. Radiology.

New Data sheds light on genesis of our body’s powerhouses

2021/02/192021/02/25

The mitochondria and its protein making “plants” – mitoribosomes

Scientists uncover for the first time how the body’s energy makers are made using Cryo-Electron Microscopy (cryo-EM) at eBIC within Diamond.

A new paper, published in Science on the 19th February, by an international team of researchers reports an insight into ‘the molecular mechanism of membrane-tethered protein synthesis in mitochondria’. This is a fundamental understanding of how the human mitoribosome functions and could explain how it is affected by mutations and deregulation that lead to disorders such as deafness and diseases including cancer development.

Mitochondria are intracellular organelles which serve as tiny but potent powerhouses in our body. They use oxygen which we inhale and derivatives from food we eat to produce more than 90% of our energy, and therefore effectively support our life. Mitochondria are particularly important in high-energy demanding organs such as heart, liver, muscles and brain. For example, almost 40% of each heart muscle cell is made up of mitochondria.

Read more on the Diamond website

Image: The mitoribosome is attached to its membrane adaptor as it synthesises a bioenergetic protein (glow yellow).

Credit: Dan W. Nowakowski and Alexey Amunts

Discovery shows men and women develop heart disease differently

2020/04/062020/04/08

Scientists from McGill University used the Canadian Light Source (CLS) at the University of Saskatchewan to uncover that different minerals block heart valves in men versus women. This discovery could impact how heart disease is diagnosed and treated for the different sexes. Heart disease is the leading cause of death throughout the world. Marta Cerruti, an Associate Professor with McGill University, and her team used the CMCF beamline at the CLS to analyze damaged heart valves from patients who needed transplants.

“What we showed, which was a surprise to us, is that the type of minerals in the heart valves is different between the sexes,” said Cerruti. The beamline allowed them to see that the buildup of minerals in the heart, and its progression to a more bone-like state, is slower in women than in men. There was also a type of mineral found almost exclusively in the female samples. “That finding was completely new, we did not expect it at all. There is no other technique that could have showed us this difference in mineral phase.”

The team hopes this finding could help to develop better diagnostics and therapies.

Image: Ophélie Gourgas, lead author of this research paper, holds a sample that was analyzed at the CLS in the study of vascular calcification that leads to what’s commonly called “the hardening of the arteries.”

Preventing heart attacks

2019/08/082019/08/13

Scientists have taken an important step towards finding a potential cure for the disease that causes strokes and heart attacks in seniors and increases the mortality rate of diabetic and chronic kidney disease patients.
Researchers from the University of McGill and SickKids Toronto in collaboration with Universite de Montreal developed a simplified laboratory model that mimics the formation of mineral deposits that harden arteries and leads to these devastating conditions.
They used the Canadian Light Source (CLS) at the University of Saskatchewan to understand the type of minerals that formed and how they develop on the arteries.
“The goal in developing our lab model is that it would help us understand the mineralization process. We can then mimic what happens, and use it to test hypotheses on why the minerals are forming and also test some drugs to find something that can stop it,” said lead researcher Dr. Marta Cerruti.
Her six-member team is focused on the poorly understood process of how minerals form and grow on elastin, a protein on artery walls that provides the elasticity needed for blood flow to the heart, said Cerruti, an associate professor in Materials Engineering at McGill.
The hypothesis is that calcium phosphate-containing minerals form inside the walls of arteries and then calcify into a bone-like substance that narrows arteries and causes them to lose elasticity crucial for blood flow.

Image: Marta Cerruti (left) and Ophelie Gourgas in a laboratory using a Raman machine.

Understanding the protein responsible for regulating heartbeats

2019/01/102019/01/10

A new research project uses the Canadian Light Source to help researchers understand the protein responsible for regulating heartbeats. Errors in this crucial protein’s structure can lead to potentially deadly arrhythmias, and understanding its structure should help researchers develop treatments. This protein, calmodulin (CaM), regulates the signals that cause the heart to contract and relax in almost all animals with a heartbeat.

“Usually you find some differences between versions of proteins from one species to another,” explains Filip Van Petegem, a professor in the University of British Columbia’s Department of Biochemistry and Molecular Biology. “For calmodulin that’s not the case—it’s so incredibly conserved.”

It also oversees hundreds of different proteins within the body, adjusting a broad array of cellular functions that are as crucial to our survival and health as a steady heartbeat.

Image: A surface representation of the disease mutant CaM (D95V, red) in complex with the piece of the voltage-gated calcium channel (blue).

Shining a new light on biological cells

2018/09/072018/09/12

Combined X-ray and fluorescence microscope reveals unseen molecular details

A research team from the University of Göttingen has commissioned at the X-ray source PETRA III at DESY a worldwide unique microscope combination to gain novel insights into biological cells. The team led by Tim Salditt and Sarah Köster describes the combined X-ray and optical fluorescence microscope in the journal Nature Communications. To test the performance of the device installed at DESY’s measuring station P10, the scientists investigated heart muscle cells with their new method.

Modern light microscopy provides with ever sharper images important new insights into the interior processes of biological cells, but highest resolution is obtained only for the fraction of biomolecules which emit fluorescence light. For this purpose, small fluorescent markers have to be first attached to the molecules of interest, for example proteins or DNA. The controlled switching of the fluorescent dye in the so-called STED (stimulated emission depletion) microscope then enables highest resolution down to a few billionth of a meter, according to principle of optical switching between on- and off-state introduced by Nobel prize winner Stefan Hell from Göttingen.

Image: STED image (left) and X-ray imaging (right) of the same cardiac tissue cell from a rat. For STED, the network of actin filaments in the cell, which is important for the cell’s mechanical properties, have been labeled with a fluorescent dye. Contrast in the X-ray image, on the other hand, is directly related to the total electron density, with contributions of labeled and unlabeled molecules. By having both contrasts at hand, the structure of the cell can be imaged in a more complete manner, with the two imaging modalities “informing each other”.
Credit: University of Göttingen, M. Bernhardt et al.

Scientist combines medicine and engineering to repair a damaged heart

2017/09/132017/10/16

Regenerating heart muscle tissue using a 3D printer – once the stuff of Star Trek science fiction – now appears to be firmly in the realm of the possible.

The combination of the Canadian Light Source synchrotron’s unique biomedical imaging and therapy (BMIT) beamline and the vision of a multi-discipline researcher from the University of Saskatchewan in confirming fiction as fact was published in the September issue of Tissue Engineering, one of the leading journals in this emerging global research field of tissue regeneration.

U of S researcher Mohammad Izadifar says he is combining medicine and engineering to develop ways to repair a damaged heart. “The problem is the heart cannot repair itself once it is damaged due to a heart attack.” he explained.

Izadifar has conducted his research out of three places on campus – the College of Engineering, the CLS and the College of Medicine where he has been certified in doing open heart surgery on rats, having trained in all the ethical protocols related to these research animals.

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