Cardiometabolic Multimorbidity and Sympathetic Overactivity

Figures

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  Central Illustration. Hepatorenal Denervation Conceptual Framework This illustration summarizes the integrated pathophysiological rationale, anatomical targeting, and potential clinical implications of combined hepatic–renal denervation. (A) Depicted is chronic sympathetic overactivity linking central and peripheral metabolic organs. (B) Illustrated is catheter-based targeting of periarterial sympathetic fibers, highlighting nerve depth distribution and safety constraints. (C) Outlined are potential clinical effects, including improvements in glycemic control, blood pressure, and hepatic steatosis. Arrows indicate direction of physiological effects; shaded zones in (B) represent ablation regions. This conceptual framework is hypothesis-generating and does not imply established clinical efficacy. AA = abdominal aorta; CHA = common hepatic artery; RF = radiofrequency; GDA = gastroduodenal artery; LHA = left hepatic artery; RA = renal artery; RHA = right hepatic artery; SA = splenic artery; SNS = sympathetic nervous system.

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  Figure 1. Hepatorenal Denervation Targeting Strategy This schematic illustrates catheter-based denervation targeting sympathetic nerve fibers surrounding the common hepatic and renal arteries. Energy is delivered to the peri-adventitial space to modulate efferent and afferent sympathetic pathways. The figure demonstrates a representative procedural approach rather than a complete multiorgan denervation strategy. In practice, additional targets (eg, the celiac plexus) or sequential interventions may be considered. Orange rings indicate ablation zones; arrows denote energy delivery pathways. AA = abdominal aorta; CHA = common hepatic artery; GDA = gastroduodenal artery; LHA = left hepatic artery; RA = renal artery; RHA = right hepatic artery; SA = splenic artery.

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  Figure 2. Evidence Hierarchy of Sympathetic Pathways This figure summarizes the proposed biological mechanisms linking sympathetic activity to cardiometabolic regulation, stratified by strength of evidence. Solid lines represent pathways supported by human or large-animal data, including hepatic glucose regulation and renal renin–angiotensin activation. Dashed lines indicate mechanisms supported primarily by preclinical or indirect evidence, such as insulin and glucagon modulation. Dotted lines denote hypothesis-generating pathways involving gut-brain signaling. Line styles reflect evidence strength. BP = blood pressure; GLP-1 = glucagon-like peptide 1; SNS = sympathetic nervous system.

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  Figure 3. Nerve Depth Distribution and Safety Constraints This figure illustrates the relationship between sympathetic nerve distribution and energy penetration depth. Orange dots represent the distribution of sympathetic nerve density, showing that a substantial proportion of nerves (R75%) lie at depths ≥6 mm. Radiofrequency (RF) ablation (red zone) typically achieves 3- to 4-mm penetration, with greater depths (up to ∼4-6 mm) possible under specific conditions, whereas ultrasound-based systems (blue zone) may reach deeper regions. The diagram also highlights safety constraints, as adjacent structures (eg, pancreas, biliary system) may lie within close proximity to the vessel wall. Shaded regions indicate ablation zones. Depth values are schematic, device-dependent, and may vary with anatomical and procedural conditions. R50%/R75% = radius containing 50%/75% of nerve fibers; other abbreviation as in Figure 1.

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  Figure 4. Translational Roadmap for Hepatorenal Denervation This diagram outlines the developmental pathway of combined hepatic–renal denervation. Completed milestones include anatomical characterization, preclinical validation, and early human feasibility studies. Remaining gaps include the absence of sham-controlled randomized trials and limited long-term data on safety, durability, and clinical outcomes. The figure also highlights key confounding factors, such as placebo effects, behavioral modification, and nerve regeneration, which must be addressed in future studies. Color coding indicates development stage (green = completed; yellow/gray = ongoing or unmet milestones). RCT = randomized controlled trial.