High Altitude‐Induced Pulmonary Hypertension: Our Scientific Journey to Prove Cold Exposure Is Also an Important Cause

From the earliest days of human existence, people have inhabited some of the most challenging environments on Earth, including high-altitude regions. It is well established that chronic hypoxia, the defining environmental feature of mountainous areas, leads to high altitude-induced pulmonary hypertension (HAPH) in individuals who are not adequately adapted. Yet, despite the apparent presence of another environmental stressor, such as cold, its role in development remained overlooked for decades. My personal connection to this question began in childhood, when I spent holidays with my grandparents in a mountain village. Even before I understood the science of hypoxia, my mother always reminded me to “dress well because it's a mountain and it's colder there.” For me, the mountains were synonymous with cold. This early association stayed with me, and years later, as I embarked on a research career in pulmonary vascular diseases, I was struck by how little attention had been paid to the effects of cold exposure on pulmonary circulation in the context of HAPH. While working at Justus-Liebig University in Giessen, Germany, I decided to address the childhood experience and address the many remaining gaps in our understanding of the effect of high altitude. The scientific literature offered only a few notable studies conducted in cattle: one by the Grover group and another by Busch et al. [1, 2]. These investigations demonstrated that cold and high altitudes significantly impact the pulmonary vasculature in cattle. However, there was a glaring lack of data on how cold affects humans living at high altitudes. Kyrgyzstan, a country renowned for its mountains and high-altitude communities, provided the ideal setting for our research. I was fortunate to have both professional and personal connections there, including Prof. Dr Akpay S. Sarybaev from the National Center of Cardiology and Internal Medicine in Bishkek, who shared my scientific interests. After months of planning, discussion, and successful grant applications, we organized two research expeditions to Kyrgyzstan in 2017. The leadership team included myself, Prof. Dr Ralph Theo Schermuly, Prof. Dr Hossein Ardeschir Ghofrani from Giessen, and Prof. Dr Sarybaev from Bishkek. We selected the village of Sary Mogol, situated at approximately 3,000 meters above sea level, known for its long, harsh winters and extremely low temperatures. This location was ideal for investigating the effects of cold on high-altitude residents (Figure 1). I am deeply grateful to the villagers of Sary Mogol, who participated enthusiastically and generously gave their time. Special thanks go to Dr. Abdygany Toktorbaev, the local physician and a kind of village sage and leader, whose support was indispensable to our success. Sadly, he passed away a few years after our expeditions. Our scientific adventure was documented in the film _Spending Life at High Altitude_, which premiered at the Bansko Mountain Film Fest in Bulgaria in 2023 [3]. The expeditions were conducted during the late winter (February/March) and late summer (September/October) to capture the seasonal effects of cold on pulmonary circulation in Kyrgyz highlanders using echocardiography. For comparison, we also studied lowland residents in Bishkek (approximately 760 m above sea level) during both seasons. Additionally, we performed controlled experiments exposing participants to cold and warm room conditions to analyze the acute effects of cold on the pulmonary vasculature. Beyond the scientific rigor, the expeditions provided unforgettable experiences: the breathtaking mountain landscapes, the warmth of Kyrgyz hospitality, the nomadic Kyrgyz music, and the taste of traditional dairy products like ayran, kaymak, and kumis, and even a close encounter with the yak, a high-altitude animal perfectly adapted to these extreme conditions. Our research yielded a wealth of data, resulting in three published scientific papers over the following years [4-6]. Most importantly, we confirmed our hypothesis: environmental cold is a significant factor affecting the pulmonary circulation of people living at high altitudes. We found that short-term cold exposure increased pulmonary arterial pressure in Kyrgyz highlanders [4]. Moreover, pulmonary arterial pressure was significantly higher during the cold season compared to the warm season among mountain dwellers [6]. These findings provide the first robust evidence in humans that cold and hypoxia play a crucial role in the development of HAPH. I hope our work will inspire further research into the mechanisms of this phenomenon and ultimately contribute to better health outcomes for high-altitude populations. Finally, I also hope that the researchers working on this topic, like the groups from Switzerland, local Kyrgyz scientists and all others, will join their efforts in future collaborative projects. The author has nothing to report. The author has nothing to report. The author declares no conflicts of interest.