Multi-Organ Genetic Scoring is Related to the Response to Renal Denervation in Patients With Hypertension. Geneticure genotyped subjects from the Medtronic OFF-MED renal denervation trial to assess the relationship between the genetic scoring (in which patients with a high score were hypothesized to be greater responders) and 24hour blood pressure changes from baseline to three months. There was a significant relationship between the Geneticure score and response to renal denervation. When divided into a median split of the Geneticure score, those with a high responder score had a ~14mmHg drop in blood pressure and those with a low score had no change in blood pressure, a statistically significant difference (p<0.001). When dividing the patients into tertiles, the highest tertile demonstrated a drop in blood pressure of ~13mmHg, the middle tertile a drop of ~6mmHg, and the low tertile an increase in BP of ~5mmHg.

1. Multi-Organ Genetic Scoring is Related to the
Response to Renal Denervation in Patients
With Hypertension
Eric M. Snyder, PhD1, FAHA, FACSM, Ryan
Sprissler, PhD1,2, and Thomas P. Olson, PhD,
FAHA, FACSM1,3
1. Geneticure, Inc., Rochester, MN
2. University of Arizona, Tucson, AZ
3. Mayo Clinic College of Medicine, Rochester, MN

2. Conflict of Interest Disclosure
Drs. Snyder, Sprissler, and Olson all have interest in Geneticure, Inc., which
develops multi-gene tests to inform the responsiveness to medication
selection and devices (including renal denervation) for patients with chronic
diseases.
2

3. Renal Denervation, Importance of Identification of Non-Responders
3
• Renal denervation (RDN) results in a slight reduction in blood pressure (BP) when
compared to sham procedure
• Studies from the past few years have demonstrated a reduction in 24hr systolic BP (SBP) from 0 to
~7mmHg, comparing RDN to sham
• Current meta-analysis of the procedure shows an average reduction of 3.61mmHg in 24hr SBP across
all devices (n>1300)1
• Approximately 20-30% of patients receiving the procedure have no change or an
increase in BP, even in studies that do not have medications
• This occurs across all denervation procedures (ultrasound, radiofrequency ablation, etc.)
• In some studies, the increase in BP is GREATER in individuals with RDN vs. sham
• It is critical to identify the patients who will demonstrate an increase in BP following
RDN, as previously-demonstrated increases in BP at levels shown in the post-RDN data
have been associated with dramatic increases in major cardiovascular events
1. https://www.jacc.org/doi/abs/10.1016/j.jcin.2021.09.020

4. Average Response to Renal Denervation in Recent Trials
• A minimum clinically meaningful reduction in BP is typically defined as >5mmHg1
• The most recent OFF-MED trial demonstrated a difference in 24hr SBP of 3.9mmHg2
• Two recent trials, in which ~30% of subject data was derived using Last Observation Carried Forward,
showed some differences in BP with long-term follow-up in RDN patients, vs. Sham3,4
• Importantly, almost all statistical significance was lost in these two trials when raw (non-carried
forward) data was presented, suggesting the carry forward of last measured data was artificially
driving the results (data in Appendix of each trial)
• In the latest of these “real world” follow-up data sets, the only data that was significant was time in
therapeutic range (TTR, meaning % at goal BP) which was 18% with RDN and 9% in sham4
• Interestingly, a TTR of <25% has been defined as “poor” and is associated with a 23% risk of
increased mortality in hypertensive patients5
• In contrast, in previous work, patients with a TTR of 75% present a 6.5% risk of mortality.
1. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00590-0/fulltext: 2. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30554-7/fulltext: 3.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00455-X/fulltext: 4. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01787-1/fulltext: 5.
https://www.ahajournals.org/doi/full/10.1161/JAHA.117.007131

5. Variability in Response to Renal Denervation
5
ON-MED Pilot Results
(radiofrequency)1
OFF-MED Proof Of Concept Results
(radiofrequency)2
RADIANCE-HTN SOLO3
• BP does not change to a clinically meaningful value, or
increases, in a subset of population, with (ON-MED) and
without (OFF-MED and SOLO) medication use
• Identification of these individuals is critical for patient
safety, but will also increase the number of subjects willing
to have the procedure4
1. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)30951-6/fulltext: 2. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32281-X/fulltext: 3.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31082-1/fulltext: 4. https://news.medtronic.com/2021-11-04-Medtronic-study-shows-patients-with-high-blood-pressure-are-interested-in-
an-interventional-procedure-treatment-option

6. Hypothesis
• Several organ systems are differently important in the response to RDN
• Previous detailed work in animals and humans has demonstrated that:
• Patients with high sympathetic nervous system (SNS) activity respond to RDN1,2
• Those with a spike in BP following stimulation of the renal nerve tend to respond to RDN3
• Renal denervation results in left-ventricular remodeling that is similar to that seen with β-blockade4
• In the Symplicity for HTN-3 trial (which showed no difference between RDN and sham), non-black individuals (who also
respond better to β-blockers) had a trend towards a significant response with RDN vs. Sham
• Renal denervation alters the expression of the angiotensin-converting enzyme and the angiotensin-II receptor5, 6
• Therefore, we genotyped 32 sites in the SNS, cardiac, renin-angiotensin aldosterone, and renal systems
and weighted them for importance in RDN
• Our algorithm considers high functionality in genes encoding SNS activity to be of the greatest importance in
responders followed by functionality in genes encoding the β-adrenoreceptors, genes within RAAS, and finally
the renal system
• Organ systems were weighted and summed with the hypothesis that patients with a high Geneticure score
would have greater BP reductions when compared to those with a low score following RDN
6
1. Manios et al. Am. J. Hypertension, 2008: 2. ENCOReD trial: Persu et al. J. Hypertension, 2018: 3. De Jong et al. Hypertension, 2016: 4. Li, Z.Z., H. Jiang, D. Chen, et al., Physiol Res, 2015. 64(5): p. 653-62. 5.
https://academic.oup.com/ajh/article/29/1/63/2594703: 6. https://www.hindawi.com/journals/ijn/2022/8731357/

7. Study Design
• Study was designed with Medtronic to assess the relationship between the Geneticure for RDN
score and BP response to RDN
• All genotype scoring was performed blinded to the RDN response
• Patients were prospectively genotyped using a buccal swab
• For inclusion, patients had to be OFF-MED study participants and had to have already met the
primary end point for the Medtronic OFF-MED pivotal trial
• 29 subjects opted in to the Geneticure trial, met the inclusion criteria, and had complete BP data
• All subjects were consented with IRB approval prior to study initiation at each of four sites
• 24hr and Office BP data was provided by Medtronic, following genetic scoring
• Given the preliminary nature of the trial and that we do not yet know the “critical” cut off for the
Geneticure score, data were assessed using correlation, grouping the Geneticure score by median,
and grouping the Geneticure score by tertiles
7

8. Results: Relationship Between Geneticure Multi-Gene Scoring and
Response to RDN in Hypertensives (OFF-MED Patients)
8
SBP DBP

9. Results: Change in 24hr SBP According to Geneticure Score Median Split
(left) and by Division of Geneticure Score Tertiles (right)
9

10. Results and Conclusion
10
SBP < 140mmHg
RDN and Low Gcure Score 8%
RDN and High Gcure Score 35%
p=0.07
RDN and Tertile 1 13%
RDN and Tertile 2 17%
RDN and Tertile 3 44%
p-ANOVA=0.24
OFF-MED
Median Split
Tertiles
Table 1. Percent of Patients with BP under
control using 24hr SBP as cut-off
• Our results demonstrate a clear relationship between a weighted multi-gene
score and change in BP following RDN
• Patients with a low Geneticure score (who we hypothesized to be non-
responders) had no change, or an increase in BP
• Patients with a high Geneticure score demonstrated drop in BP that is more
than double that of previous trials
• Importantly, patients with a high Geneticure score were more likely to have
their BP under control (table 1) when compared to those with a low
Geneticure score
• The identification of responders and non-responders to RDN is critical for
patient safety and adoption of this procedure
• While the present trial is small, the effect size and impact on this field is
substantial
• Recent work from Medtronic demonstrated that 24.3% of patient
candidates would be willing to have RDN with a 5mmHg drop, which
increases to 76.5% with a drop of 10mmHg1
• Larger retrospective analyses and prospective trials are needed to confirm
these results
1. https://news.medtronic.com/2021-11-04-Medtronic-study-shows-patients-with-
high-blood-pressure-are-interested-in-an-interventional-procedure-treatment-option