Reduced Lymphatic Function Predisposes to Calcium Channel Blocker Edema: A Randomized Placebo-Controlled Clinical Trial

Sheyanth Mohanakumar, MD, PhD,1,2 Niklas Telinius, MD, PhD,1,2 Benjamin Kelly, BSc,1,2 and Vibeke Hjortdal, MD, PhD, DMSc1. Lymphatic Research and Biology 2019

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Reduced Lymphatic Function Predisposes to Calcium Channel Blocker Edema: A Randomized Placebo-Controlled Clinical Trial

Sheyanth Mohanakumar, MD, PhD,1,2 Niklas Telinius, MD, PhD,1,2 Benjamin Kelly, BSc,1,2 and Vibeke Hjortdal, MD, PhD, DMSc1. Lymphatic Research and Biology 2019

Background: The current belief is that the calcium channel blocker (CCB)-induced edema is due to a preferential arterial over venous dilatation leading to increased fluid filtration. We challenged this conviction by measuring the lymphatic removal of interstitial fluid during chronic systemic treatment with the CCB, amlodipine. Lymphatic vessels could potentially be an off-target effect of the drugs and play a role in CCB edema.

Methods and Results: Sixteen healthy postmenopausal women completed a 12-week double-blinded randomized placebo-controlled crossover trial. Lymphatic function was assessed by near-infrared fluorescence imaging. The lymphatic function during amlodipine treatment compared with placebo did not show any difference in pumping pressure (53.9–13.9mmHg vs. 54.7–9.4mmHg, p=0.829), contraction frequency (0.4–0.2/min vs. 0.4–0.3/min, p=0.932), refill time (440–438 seconds vs. 442–419 seconds, p=0.990), or propagation velocity of lymph packets (18–10mm/s vs. 15–7mm/s, p=0.124). However, the subjects who developed edema during CCB treatment had a 20% lower baseline lymphatic pumping pressure (48.9–4.4mmHg, n=7) than the subjects not affected by treatment (59.1–1.2mmHg, n=9, p=0.025). Contraction frequency, refill time, and lymph packet velocity showed no differences in baseline values between the two groups.

Conclusion: Our results suggest that CCB does not directly impair lymphatic function. However, our results show that a reduced lymphatic function predisposes to CCB edema, which may explain why some patients develop edema during treatment.

Main findings

  • The preferential arteriolar over venous dilatation leads to an increase in hydrostatic pressure in the capillaries and thereby a rise in fluid filtration, which is widely accepted as the cause of Calcium Channel Blocker (CCB) edema.
  • An increased fluid filtration does not constitute a problem per se as longas the lymphatic vessels are capable of removing the extra fluid load.
  • In this randomized double-blinded clinical trial, we demonstrate that a reduced lymphatic function predisposes to CCB edema, as demonstrated by the 20% reduced lymphatic pumping pressure in the group of patients who developed edema during treatment compared with the group of patients who did not develop edema. Their data does not support their hypothesis that CCBs have a direct effect on the lymphatic vessels.
  • patients who develop edema during CCB treatment have a lower threshold for developing edema in general, shown by the lower maximal lymphatic transport capacity during placebo treatment.
  • In this study, the authors are the first to demonstrate that reduced lymphatic function predisposes to developing peripheral edema during CCB treatment. Long-term treatment with CCBs might aggravate this. The development of CCB edema should make the clinician aware that the patient has a poor functional lymphatic reserve capacity. Theirs results do not suggest that CCBs have a direct inhibitory effect on the lymphatic vasculature.