Renal denervation can lower heart rate in unmedicated hypertensive patients
Ambulatory heart rate reduction after catheter-based renal denervation in hypertensive patients not receiving anti-hypertensive medications: data from SPYRAL HTN-OFF MED, a randomized, sham-controlled, proof-of-concept trial
Introduction and methods
Renal denervation (RDN) to lower blood pressure (BP) showed promising results in uncontrolled studies [1,2] and in comparative, controlled studies evaluating antihypertensive drugs plus RDN [3]. The proof-of-concept SPYRAL HTN-OFF MED study evaluated RDN in a randomized sham-controlled study design and provided evidence for a significant reduction of BP in patients without medications [4].
High resting heart rate (HR) is associated with CV morbidity and mortality in the general population [5] and increased incidence of hypertension [6,7]. In a high-risk population in which a majority had hypertension, elevated HR was predictive of incident heart failure [8].
A single-center study [9] and the Global Symplicity Registry [10] revealed a reduction of HR after RDN in patients with resistant hypertension. In the Symplicity Registry, over 50% of patients received beta blockers and other anti-hypertensive drugs, which may have confounded the effect of RDN on HR.
This is a posthoc analysis of the SPYRAL HTN-OFF MED to evaluate the effect of RDN on 24-hour ambulatory HR in the RDN group (n=38), as compared with in the sham group (n=42) at different daytime (9:00 am to 8:59 pm), morning (7:00 am to 8:59 am) and nighttime periods (1:00 am to 5.59 am). Due to the chosen study population, it avoids confounding by anti-hypertensive medication. HR was detected by ambulatory BP monitors (ABPM). The study included adults (20-80 years) with mild to moderate hypertension (office SBP 150-180 mmHg and office DPB ≥90 mmHg and mean 24-h ambulatory SBP 140-170 mmHg).
Main results
- At 3 months, 24-hour HR was significantly lower in the RDN group vs sham (-2.7 bpm, 95%CI: -4.5 to -1.0, P=0.003), as was 24-h DBP (-4.3 mmHg, 95%CI: -7.1 to -1.5, P=0.003). 24-h SBP showed a tendency to a reduction (-4.6 mmHg, 95%CI: -9.2 to 0.1, P=0.053).
- Daytime HR (-2.2 bpm, 95%CI: -4.5 to 0.2, P=0.073) and maximum morning HR (highest 1 h moving average of ≥3 consecutive HR measurements between 6:00 am and 9:59 am, -4.5 mmHg, 95%CI: -10.0 to 1.1, P=0.111) were decreased nominally, while average morning HR (-4.4 bpm, 95%CI: -8.7 to -0.1, P=0.046) was significantly reduced in the RDN vs sham group.
- No significant differences were seen between the RDN and sham groups with regard to average nighttime and maximum nighttime HR. A significant difference was observed for average peak night-time HR (average of three highest HR measurements during night period, -3.7 bpm, 95%CI: -7.3 to -0.1, P=0.045).
- Minimum morning HR (-3.0 bpm, 95%CI: -5.6 to -0.4, P=0.026) and moving peak morning HR (-7.2 bpm, 95%CI: -11.7 to -2.8, P=0.002) showed a significant between group difference.
- To assess whether baseline HR predicts the response of RDN to both HR and BP, the cohort was divided based on 24-h baseline HR above and below the median (≥ or <73.5 bpm). In those with HR ≥median, significant reductions of average 24-h SBP (-10.7 mmHg), 24-h DBP (-7.5 mmHg) and 24-h HR (-3.3 bpm) were seen with RDN vs. sham. In those with HR < median, the reductions were smaller, without between group differences.
- The group with HR ≥median showed significant reductions of average daytime SBP, DPB and HR, and of average nighttime SBP, DBP and HR and average morning SBP, while those with HR
Conclusion
This posthoc analysis of SPYRAL HTN-OFF MED reveals that RDN reduces HR, with different effects at various times of the day. Lower HR was seen particularly in the morning. Patients with baseline 24-h HR above the median of 73.5 bpm showed greater reduction of 24-h mean HR, daytime and nighttime BP after RDN. These data suggest that higher baseline HR may represent a means to identify patients likely to respond to RDN.
Editorial comment
Two returning questions that surround the procedure of renal denervation, are “which hypertensive patients are most suited for the intervention?” and “how can achieved renal denervation be documented”? The ideal patient candidate for RDN is thought to have the phenotype of neurogenic hypertension, where elevated BP arises from activation of the sympathetic nervous system. Esler [11] notes that quantifying human sympathetic nervous drive, usually done by measurement of the sympathetic transmitter noradrenaline in plasma or urine, is rather imprecise. In the case of essential hypertension, activation of the renal sympathetic outflow is important, but its testing is complicated. It has been hypothesized that this testing may be bypassed by selecting patient phenotypes signifying de facto neurogenic hypertension, but this approach has not been tested rigorously.
The current study now suggests that elevated 24-h HR in hypertension is an identifier of neurogenic hypertension. In unmedicated patients with a 24-h ambulatory HR above the median value of 73.5 bpm, RDN was associated with a drop in average 24-h SBP of 10.7 mmHg, as compared with no fall in SBP in those with HR below the median. That raises the question whether increased 24-h ambulatory HR in patients with essential hypertension is driven by activation of the sympathetic nervous system, for it to be a good identifier of neurogenic hypertension. 24-H ambulatory HR is a consequence of multiple influences. This implies that HR in hypertension can be a useful identifier of neurogenic hypertension, albeit with limitations.
Another relevant aspect is whether activation of the cardiac sympathetic outflow is important in hypertension pathogenesis. This is as yet unclear, as different findings were obtained in the early hyperdynamic phase of hypertension, as compared with obesity-related hypertension. The current study sheds no light on this question.
The current analysis shows a HR drop that most probably represents central sympathetic inhibition, from ablation of excitatory renal afferent nerves. This is however uncertain, as other causes of HR slowing can also play a role.
Taking all this into consideration, Esler asks whether Böhm et al. have uncovered an empirically useful predictor of BP fall with RND, to select patients who will most likely benefit from the procedure? He thinks this may all depend on how important it was for the obtained results that the patients were unmedicated. Some antihypertensive drugs are known to modify HR. He ends by saying ‘It is possible that in medicated hypertensive patients, drug dosing will obscure any capacity for 24-h ambulatory heart rate measurements to predict the blood pressure lowering after renal denervation which holds good in drug-free patients.’ Esler hopes not.
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