Advances in the Pathogenesis and Treatment of Resistant Hypertension

Abstract

Hypertension is a prevalent chronic disease associated with an increased risk of cardiovascular (CV) premature death, and its severe form manifests as resistant hypertension (RH). The accurate prevalence of resistant hypertension is difficult to determine due to the discrepancy in data from various populations, but according to recent publications, it ranges from 6% to 18% in hypertensive patients. However, a comprehensive understanding of the pathogenesis and treatment of RH is essential. This review emphasizes the importance of identifying the causes of treatment resistance in antihypertensive therapy and highlights the utilization of appropriate diagnostic methods. We discussed innovative therapies such as autonomic neuromodulation techniques like renal denervation (RDN) and carotid baroreceptor stimulation, along with invasive interventions such as arteriovenous anastomosis as potential approaches to support patients with inadequate medical treatment and enhance outcomes in RH.

Altered gut microbiota and metabolite profiles provide clues in understanding resistant hypertension

“…Large retrospective studies including hundreds of thousands of hypertensive patients have shown that resistant hypertension is associated with higher rates of ischemic heart disease, heart failure, stroke, end-stage renal disease, and all-cause mortality [11,12]. Studies have proposed that resistant hypertension is associated with hypervolemia, inflammation, and sympathetic nervous system overactivity [8,13], but the pathogenesis of resistant hypertension is unclear.…”

Function of Presynaptic Inhibitory Cannabinoid CB1 Receptors in Spontaneously Hypertensive Rats and Its Modification by Enhanced Endocannabinoid Tone

“…The pathogenesis of arterial hypertension, including primary hypertension which accounts for more than 90% of all hypertensive individuals, is complex and still requires intensive studies [1,2]. The sympathetic nervous system plays a fundamental role in the development and progression of hypertension [3,4].…”

“…The sympathetic overdrive augments plasma catecholamine levels which, in turn, increase vascular resistance and cardiac output [1]. An enhanced level of sympathetic nerve activity and increased intravascular fluid volume are particularly relevant for drug-refractory and drug-resistant hypertensive patients in whom hypertension is uncontrolled despite using ≥5 and ≥3 medications, respectively [2,5]. Therefore, novel adjunctive therapies targeting the sympathetic nervous system, such as renal denervation and carotid baroactivation, have been developed [3][4][5].…”

“…Hypertension affects the endocannabinoid system, which consists of (1) cannabinoid receptors (e.g., CB 1 ), (2) endogenous cannabinoids represented by anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and (3) mechanisms terminating their activity including enzymes like fatty acid amide hydrolase (FAAH; degrades AEA) and monoacylglycerol lipase (MAGL; degrades 2-AG) and endocannabinoid membrane transporters (EMTs) [28]. Examples of endocannabinoid system overactivation in SHR (compared to Wistar-Kyoto rats (WKY), their normotensive controls include (1) higher levels of AEA and/or 2-AG in the blood plasma [29], aorta and small mesenteric arteries [30], (2) increased expression or coupling efficiency of CB 1 receptors in the heart [31], aorta [30,31], small mesenteric arteries [30], brain [32], and (3) decreased EMT activity) [29].…”

Resolvin D1 as a novel target in the management of hypertension

“…With the increase in the number of approaches to the treatment of hypertension, recent international research has highlighted new drug therapeutic targets [including the nitric oxide (NO) pathway, the brain's renin–angiotensin system (RAS), leptin, sodium-glucose cotransporter 2 (SGLT2), endothelin receptor, and more], biotherapy (e.g., vaccines, gastrointestinal microbiota), and mechanotherapy (carotid baroreceptor stimulation, arteriovenous fistula) [1,2]. However, the selectivity and efficacy of drugs targeting newly identified targets remain unknown.…”