Neuro-Hormonal vs Structural Hypertension why they require different approaches Paul A. Sobotka Chief Medical Officer Rox Medical, Inc.

Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company Employee Consultant Rox Medical, Inc. Cibiem, Inc.

Structural verses Neuro Hormonal Hypertension Structural HTN Neuro-Hormonal HTN Adapted from Physiology; Berne & Levy

Elastic Fibers are Terminally Differentiated After the age of 50, HTN is principally Structural Systolic BP Diastolic BP Of course we have known this for 2 decades- the bp and pulse pressure rise with age, and about the age of 50 something not so mysterious develops- pulse pressure widens= the hallmark of changes in underlying causes of hypertension Burt. Hypertension 1995;25:313

Renal Sympathetic Activity Declines with Age Indeed Murray Esler published in 1986 the contribution of renal sympthatic activity to hypertension as a function of age and he observed that renal sympathetic drive falls as patients get older, which implies that renal neuro or renal sympathetic drive is less and less a contributing factor to hypertension in aging. A similar graphic can be made for MSNA and age, which shows that aging is associated with hypertension in a mechanism other than sympthatetic drive. Esler et.al., J Cardiovasc Pharmacol, 1986

The aorta is meant to buffer each heart beat The Windkessel Function of the Aorta

Even a small amount of compliance dramatically reduces peak pressure Non compliance and pistol shot arterial wave forms

Loss of Aortic Elasticity Increases Volume Sensitivity Aging, ISH Volume Sensitivity Circumferential STRESS N/cm2 Circumferential STRAIN (aortic distension)

Loss of Aortic Elastance

Treatment of Structural Hypertension Reduce Effective Arterial Volume Circumferential STRESS N/cm2 Circumferential STRAIN (aortic distension)

Reduction of Arterial Volume with Diuretics 2.4% of total body water is arterial (42l water in a 70kg adult); To reduce effective arterial volume by 1 liter, a diuretic must remove 25% circulating volume; Restoring Windkessel with diuretics inherently activates RAA and is associated with systemic AE. adapted by Cevasco M and Dunlap ME 

Loss of Aortic Elasticity Increases Pulse Wave Velocity Avolio et al; Circ:1983

Young Compliant Arteries Young compliant arteries : Normal PW velocity (8 m/sec) Diastole Systole

Elderly Stiff Arteries Elderly stiff arteries with ISH : Increased PW velocity (12 m/sec) Systole Ventricular-vascular mismatch The reflected wave increases central SBP during late systole:

Futility of Targeting Peripheral Vascular Resistance The model is open to room air, as if all PVR is eliminated

Physiology Profile Hypertension Structural HTN Age > 60y Pulse Pressure > 60 mmHg Pulse Wave Velocity elevated (>10m/s) Treatment targeting functional etiology will be less or not effective in reducing bp (which does not mean that they may not have clinical benefits) RDN (EuroIntervention. 2015 May;11(1):110-6) Medications

75% of Uncontrolled HTN is Structural 68% Uncontrolled Hypertension > 65 years patients are over 50yr % Uncontrolled Isolated Systolic Htn Isolated Systolic Htn aka, ‘Structural Hypertension’ Sys/Dias Htn As we look at which patients are struggling most with control of their hypertension, it is the older patients, over age 50yrs who comprise 85% of the uncontrolled hypertension patients. They are as adherent to medications, but are getting less relief or effect. This is because their hypertension has fundamentally changed to predominantly Isolated Systolic Hypertension or Structural Hypertension do to arterial and aortic stiffening. Isolated Diastolic Htn Franklin et al, Hypertension 2001

Experience with catheter-based renal denervation Ott, ESH 2015 Experience with catheter-based renal denervation BP responce after renal denervation (RDN) is heterogenous Ewen et al, Hypertension 2015;65:193-9)

75% of Uncontrolled HTN is Structural 68% Uncontrolled Hypertension > 65 years patients are over 50yr % Uncontrolled Isolated Systolic Htn Isolated Systolic Htn aka, ‘Structural Hypertension’ Sys/Dias Htn As we look at which patients are struggling most with control of their hypertension, it is the older patients, over age 50yrs who comprise 85% of the uncontrolled hypertension patients. They are as adherent to medications, but are getting less relief or effect. This is because their hypertension has fundamentally changed to predominantly Isolated Systolic Hypertension or Structural Hypertension do to arterial and aortic stiffening. Isolated Diastolic Htn Franklin et al, Hypertension 2001

Mechanical Solution for Structural Hypertension Consider the Rox Coupler a mechanical solution to a structural etiology- retrospective analysis of outcomes with the coupler based on presence of ISH Effect of the ROX coupler implantation in subgroups of Combined hypertension: SBP > 140 and DBP > 90 mmHg Isolated Systolic Hypertension: SBP > 140 and DBP < 90 mmHg C Ott et al. J Am Heart Assoc. 2016 Dec 21. 5(12)

Office systolic BP reduction (mmHg) Ott, ESH 2015 Office blood pressure reduction after 6 months CH ISH Office systolic BP reduction (mmHg) after 6 months p = 0.572* *even after adjustement (age, baseline office systolic BP): CH/ISH has no impact on office BP reduction (p=0.910).

Ambulatory systolic BP reduction (mmHg) Ott, ESH 2015 Ambulatory blood pressure reduction after 6 months CH ISH Ambulatory systolic BP reduction (mmHg) after 6 months p = 0.672* *even after adjustement (age, baseline ambulatory systolic BP): CH/ISH has no impact on office BP reduction (p=0.720).

Mechanical solutions for structural hypertension: Immediate BP reduction (-28/-15 mmHg) Systolic BP 186-180 150-153 ( mmHg ) ~72 ~60 Diastolic BP ( mmHg ) Eliminates the possibility of placebo, sham or Hawthorne effects