How endocannabinoids regulate the heart’s electrical wave
Eureka Science published a lay article discussing research that claims cannabis increases the risk of cardiac arrest. Meanwhile, a few days prior, The Lancet released a study that covers an atypical endocannabinoid and its role in regular heart function. Endocannabinoids are biological transmitters that respond to cannabis, diet, and exercise, and are employed to perform various biological tasks. Arachidonic-serine (ARA-s), for example, is a special negatively charged endocannabinoid that regulates our heart’s electrical wave.
The heart is just a muscle, but its structure and function are unique. It’s comprised of three cell types in a family of cardiocytes, which are muscle cells found exclusively in the heart. Cardiocytes support a symphony of gates orchestrated by electrical signals. The heart’s electrical activity is measured as a sharp wave on an electrocardiogram (ECG) monitor. (Fig 1.) Intervals occur across the wave, such as the QT segment when the heart contracts and relaxes.
Smaller segments of the QT interval appear on an ECG, including the contraction phase, known as the QRS complex. The heart then refills when it relaxes during the ST segment and the T wave. A prolonged QT interval means the heart takes longer to relax after contraction. A team of Canadian, Swedish, and Danish researchers authored the recent Lancet study. They found a special endocannabinoid that shortens the duration of this electric impulse, which might help to regulate the heart.
Cellular depolarization and repolarization cause the heart to contract and relax, respectively. The potassium in bananas helps to drive energy and cellular function, in part, because potassium is an electrically charged molecule, also known as an ion. Heart cell depolarization happens as soon as potassium ions (K+) enter a cell, which repolarizes after those ions leave the party.
Depolarization and repolarization are on respective ends of the wave that comprises a regular heartbeat. The contraction phase occurs during the depolarization process, but to understand that, we have to first look at repolarization. Polarity means there is an electrical charge on both ‘poles’ — and in the cases of cells, the poles are simply on each side of a cellular membrane.
Once positively charged potassium moves into a cell, depolarization — the loss of polarity — occurs, and the heart contracts. Those potassium ions then move out of the cell, repolarizing the heart, which allows it to relax and fill back up with blood. And an ECG can measure this particular polarity shift.
A moment of hyperpolarization also occurs just before the T wave that further drops the heart’s voltage. Overall, a prolonged QT interval negatively impacts heart health. But at this point, we have to ask — how does potassium move around? And why are different types of endocannabinoids important for the heart’s electrical wave?
Lipids: Heads and tails
Several channels in the body help transport electrically charged ions, including potassium (K+). 2-AG and anandamide (AE interact with at least two potassium ion channels, including Kv1.5 and Kv4.1. The researchers noted that endocannabinoids are polyunsaturated fats, likewise to linoleic acid, which shortens the QT interval by activating the potassium channel, Kv7.1. Therefore, they tested various endocannabinoids for activity at this particular channel.
Lipids, such as PUFAs, are comprised of two main sections — the head and tail. Unlike linoleic acid, for example, 2-AG and AEA have positively charged heads comprised of either glycerol or ethanolamide. This means that they cannot bind to Kv7.1, according to the new Lancet study on heart function. Only negatively charged endocannabinoids can enter through a pore in this particular potassium current. To prove this, the researchers tested an endocannabinoid comprised of regular with either negatively charged serine or carboxyl heads.
Negative fats, heart health, and cannabis
They concluded that the lipid with a negative serine head, ARA-s, activated the potassium channel 7.1. And ARA-s shortened the QT interval, more potently than a lipid with a carboxylic head. Whereas lipids with much more positive heads, such as 2-AG or AEA, had no effect. 2-AG and AEA instead inhibit potassium channels Kv1.5 and Kv4.5, which facilitate a different mechanism in the heart. Overall, endocannabinoids perform various tasks in the heart’s electrical symphony, helping to regulate its rhythm.
The study published recently by The Lancet noted that FAAH, an enzyme in the body, breaks down ARA-s. And CBD, a phytocannabinoid in cannabis, inhibits FAAH. But the researchers only tested endogenous compounds and did not conclude any impacts on heart health caused by cannabis ingredients. The American College of Cardiology recently presented their unpublished study that implies cannabis can increase the risk for cardiac arrest at the Annual Scientific Session Together With the World Congress of Cardiology.
Uprooted Concepts reached out to the American College of Cardiology and will report if we receive a copy of their presentation.
Dr. Sergei Yu Noskov from the University of Calgary’s Centre for Molecular Simulation and Department of Biological Sciences, who co-authored the study on endocannabinoids that regulate heart function via Kv7.1 potassium channels, passed away during the manuscript’s completion.
Lead author and Associate Professor, Sarah Liin from Linköping University’s Department of Biomedical and Clinical Sciences declared an interest conflict regarding patent # 62/032,739, which covers the “interaction of charged lipophilic compounds with the Kv7.1 channel”.
Human Kv7.1 channels were transfected in avian ovarian cells (Xenopus oocytes) and endocannabinoids were further tested in vitro on Guinea Pigs
Kv7 channels contain six transmembranes (TMs) and ARA-S binds to two active sites.
Lipids with a negative head, including LIN-S and ARA-S potently activate Kv7.1 by binding to the amino acid, lysine, on transmembrane 6 in the lipid pore.
The negative serine and carboxylic heads both form hydrogen bonds with an active site comprised of the amino acid, arginine, located on transmembrane 4 in the voltage-gated potassium channel.
This writing author is not an expert in cardiology and is summarizing published research.
Hiniesto-Iñigo I, Castro-Gonzalez LM, Corradi V, et al. Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT interval. eBioMedicine. 2023;89:104459