Cold hands, warm heart: some arrhythmias are related to body temperature

If you think that the popular saying 'cold hands, warm heart' only indicates a person who is apparently gruff in manner but strongly generous, you should know that science has a surprise in store for you. Because there would be a biological parallel to this metaphor, linked to mutations in the TRPM4 ion channel, encoded by the gene of the same name. These are related to cardiac pathologies such as rhythm disorders and defects in the heart's electrical conduction system, such as Brugada syndrome or other genetically based alterations, and also to rare dermatological pictures, such as symmetrical progressive erythrokeratodermia, with reddened and thickened patches that tend to enlarge. Generally, however, when the alterations are present there are no signs of other skin conditions and vice versa.

The reason? It lies in the relative 'coldness' of the skin compared to the warmth of the internal organs. Temperature, in fact, would act on the activation of gene mutations, resulting in one or the other tissue being affected. Clarifying this scientific 'mystery' by attributing to the relative warmth what happens to the heart and not to the skin and vice versa is research coordinated byJie Zheng, of the University of California Davis, which appeared in Proceedings of the National Academy of Sciences - PNAS (first name Yuhua Tian).

The experts looked at mutations in the TRPM4 ion channel and observed that one of them is only active in the cooler skin, while another exerts its effects only at the higher body temperature of the heart. Not only that: in addition to the thermal aspect, cell type and local chemical signals also play an important role. But let's go in order. The TRPM4 gene is located on chromosome 19 and provides instructions for the production of a protein that acts as a kind of 'gate' in the cell membrane. When calcium levels within the cell increase, the gate opens, altering the electrical state of the cell and causing abnormal signals to appear. The process is crucial for many organs, first and foremost the heart, as it helps regulate heart rhythm. In the skin and immune system, this gate-regulated activity helps control inflammation and cell migration. Beware, however, that patients with similar mutations never develop the different diseases together, even if TRPM4 activity increases.

According to the models of classical genetics, if the same channel works excessively, theoretically the influence on all tissues should be the same. But in the human body this is not the case. And this is the major breakthrough of the study: by measuring ion channel activity and cellular behaviour under temperature conditions similar to those in the skin and heart, the scientists discovered how heat and cold determine where these mutations cause disease. "The research clearly shows how 'warming the heart', a phrase that helps us define how much better we feel, in these cases is not useful but even negative," comments Giulio Molon, Director of Cardiology at Irccs Sacro Cuore in Negrar, near Verona.

Thermal values, in particular, would act on a membrane lipid, characterised by the initials PIP2, which with the calcium levels in the cells would regulate the activity of TRPM4. But while mutations linked to skin diseases disrupt the control of TRPM4 by PIP2 itself at around 25-30 degrees Celsius (i.e. at values that can be recorded for the skin of the hands and feet), mutations that cause heart disease increase the number of TRPM4 channels in heart cells and enhance electrical signalling, but only at core body temperature, i.e. around 37 degrees Celsius. So the mutations that cause heart disease are largely inactive in skin tissue, which is colder. Conclusion: 'This explains why skin mutations only cause damage to the skin, while heart mutations only affect the heart,' Zheng comments in a note. The channel reacts to its environment -'.