title: Novel perspectives on salt and interstitium: from hypertension to heart failure
Creators: name: Rossitto, Giacomo
Publisher: name: University of Glasgow
Year: 2021
Subjects: subject: sodium, salt, interstitium, oedema, congestion, lymphatic system, microvasculature, metabolism, hypertension, heart failure.

description: Sodium (Na+) and water are closely linked in body fluid physiology by the concepts of osmosis and long-term balance. Our traditional understanding of fluid and electrolytes homeostasis has recently been challenged by suggestions of a systemic metabolic shift favouring water preservation when excess Na+ intake is excreted, and of skin as a depot for Na+ accumulation in multiple cardiovascular diseases and risk factors. In particular, a catabolic state would produce endogenous free water and facilitate its renal reabsorption independent of Na+, via urea generation and recycling: in the long term this could adversely impact cardiovascular risk, but has only been shown in preclinical settings. Similarly, the proposed water-independent nature of interstitial Na+ accumulation has the potential to induce local pathogenic changes to the surrounding structures, including the microvasculature, but lacks firm demonstration. The aims of this Thesis were therefore to investigate: 1) the impact of high Na+ intake on renal water-preserving mechanisms and metabolism in a real-life hypertensive population; 2) the nature, distribution and clinical correlates of tissue Na+ accumulation; 3) microvascular function, including capillary-interstitium fluid exchange and lymphatic drainage, in relation to interstitial Na+ accumulation. I herein retrospectively analysed clinical and biochemical blood and 24h-urinary data from consecutive patients with essential hypertension, collected at the time of screening for secondary causes, and found that kidneys can indeed dissociate Na+ and water handling (as estimated by their fractional excretions) when exposed to high Na+ intake. However, this comes at the cost of higher glomerular filtration rate, increased tubular energy expenditure, and protein catabolism at metabolomics signatures. By conducting a chemical analysis of multiple tissues from rodent models of salt sensitivity/salt loading and of skin from patients with hypertension or heart failure with preserved ejection fraction (HFpEF), I showed that tissue Na+ excess upon high Na+ intake is a systemic, rather than skin-specific, water-paralleled phenomenon reflecting the expansion of the extracellular compartment, and subclinical oedema in most cases. Despite the lack of any hypertonic interstitial Na+ accumulation to osmotically drag water out of vessels and facilitate the typical “congestion”, I also identified structural and molecular alterations in the skin blood and lymphatic microvasculature of patients with HFpEF, along with evidence of impaired lymphatic drainage of interstitial fluids upon pressure challenge. In summary, I confirmed the previous suggestions of a Na+-driven metabolic shift in a real-life population of hypertensive patients and largely expanded on the novel concepts of tissue Na+ accumulation. In particular, I disproved its water-independence in both experimental models and human subjects and suggested systemic isotonic Na+ excess as an important and likely prevalent determinant in the pathogenesis of hypertension and other cardiovascular diseases. The biophysical and molecular impact of this subclinical or clinically overt oedema on organ function, as well as the mechanisms of function and dysfunction of lymphatic vessels in the control of interstitial fluid in cardiovascular disease, need further exploration.