Catheter-based Renal Denervation: The Next Chapter Begins

Felix Mahfoud; Markus Schlaich; Michael Böhm; Murray Esler; Thomas Felix Lüscher

Disclosures

Eur Heart J. 2018;39(47):4144-4149. 

In This Article

What was Known?

Hypertension remains the most prevalent modifiable risk factor worldwide.[1] Both, the most recent European and US guidelines on hypertension management recommend to lower systolic blood pressure (SBP) to >120–130 mmHg in most patients with hypertension.[2,3] This is typically achieved by lifestyle interventions and drug treatment. Antihypertensive drugs are widely available, rather cheap and have been shown to not only reduce blood pressure but also to improve cardiovascular outcomes. Non-adherence to anti-hypertensive medication however, is increasingly recognized as a main contributor to insufficient blood pressure control. The rates of non-adherence in hypertension assessed by toxicological analyses are as high as 66%[4] and have been associated with younger age, female gender, number of daily doses, and treatment with diuretics.[5]

The renal sympathetic nerves are involved in the progression and development of hypertension and hypertension-mediated endorgan damage.[6] Several experimental models strongly support the concept of modulating renal sympathetic activity by renal denervation and observational data from the 1950 to 1960's have shown that surgical sympathectomy lowers blood pressure and was associated with substantially improved survival rates in the majority of patients with hypertension.[7,8] These experiences set the stages for the development of catheter-based approaches using radio-frequency, ultrasound, or injection of neurotoxic agents such as alcohol to affect the renal afferent and efferent nerves located in the adventitia of the renal arteries.[9] The initial clinical trials focused on patients with severe therapy resistant hypertension, a population in which conservative approaches have failed to control blood pressure. Indeed, the results from the early trials (Symplicity HTN-1 and HTN-2) were rather positive, documenting large falls in office blood pressure with a favourable safety profile, which made the procedure quite attractive for patients with resistant hypertension (Figure 1).

Figure 1.

Differential effects of training on telomerase activity and telomere length in circulating mononuclear cells. (A) Leucocyte telomere length was determined in genomic DNA isolates by real-time PCR. Beside telomere (T) DNA, the single (S) copy gene 36b4 was amplified to allow calculation of the T/S ratio for each subject at both time points. Data are represented as mean ± SD of T/S ratio per group. (B) Telomerase activity was determined by TRAP assay. Data are represented as mean ± SD of telomerase activity expressed as human embryonic kidney cell equivalents (from Werner CM, Hecksteden A, Morsch A, Zundler J, Wegmann M, Kratzsch J, Thiery J, Hohl M, Bittenbring JT, Neumann F, Böhm M, Meyer T, Laufs U. Differential effects of endurance, interval, and resistance training on telomerase activity and telomere length in a randomized, controlled study. See pages 34–46).

The field suffered a significant setback though in 2014 with the publication of the first randomized, sham-controlled Symplicity HTN-3 trial.[10] This trial failed to prove superiority of renal denervation when compared with medication only. Secondary analysis provided critical insights and established the importance of procedural performance, such as the number of ablations and the relevance of achieving a circumferential, four-quadrant ablation pattern, which was associated with larger blood pressure reductions.[11] Furthermore, 38% of the patients in the renal denervation group and 40% in the sham group had medication changes in the first 6 months despite the protocol mandating to maintain antihypertensive regimens constant.[12] Interestingly, sub-analysis revealed that the neutral findings were predominantly driven by the African-American subgroup, in whom the sham effect was numerically more pronounced (−18 mmHg) than in the renal denervation group (−16 mmHg). These findings have been related to their low renin, volume-dependent form of hypertension, and/or poor medication adherence. Importantly, an extended analysis, including patients from the Symplicity HTN-3 study and the Global Symplicity Registry showed that patients with isolated systolic hypertension and high pulse wave velocity exhibit a blunted effect of renal denervation on blood pressure when compared with patients with systolic-diastolic hypertension.[13]

Importantly, in 2015 the results of the DENERHTN study, a multicentre, open-label, randomized controlled clinical trial with blinded endpoint evaluation investigated renal denervation plus standardized stepped-care antihypertensive treatment vs. stepped-care antihypertensive treatment alone in 106 subjects and demonstrated superiority in the renal denervation with an additional decrease of 5.9 mmHg in daytime ambulatory SBP at 6 months.[14] The prevalence of non-adherence to antihypertensive drugs using toxicological analyses at 6 months was not different in the renal denervation and control group, indicating that regardless of adherence to treatment, renal denervation plus standardized stepped-care antihypertensive treatment was superior to antihypertensive treatment alone.[15]

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