Translational Research Primer: Understanding Hypertension Through - - PowerPoint PPT Presentation

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Translational Research Primer: Understanding Hypertension Through - - PowerPoint PPT Presentation

Sep 28, 2022 885 likes •1.33k views

Translational Research Primer: Understanding Hypertension Through Animal &Human Investigation Scott Alan Smith, PhD Translation * Translational Research An effort to build on basic scientific research to create new therapies, medical

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Translational Research Primer:

Understanding Hypertension Through Animal &Human Investigation

Scott Alan Smith, PhD

Translation

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*

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Translational Research

  • An effort to build on basic scientific research to create

new therapies, medical procedures & diagnostics.

  • It is the “translation” of basic scientific findings in a

laboratory setting into potential treatments for disease.

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Translational Research

  • Step 1: Identify a significant problem
  • Step 2: Design and perform basic experiments

(pre-clinical studies)

  • Step 3: Design and perform clinical experiments
  • Step 4: Identify novel targets and/or methods for

treatment

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Advantages of Using Animal Models

  • Increased control of experimental conditions
  • Enhanced isolation of system or process of interest
  • Mechanistic studies at the cellular & molecular level available
  • Disease models readily available and/or inducible
  • Genetic manipulation of models available in some species
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Camilla Martin Christian Eriksen Eskild Ebbesen Thomas Bjorn

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exampleS

Caroline Wozniacki

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  • Disease characterized by chronic high blood pressure
  • In US, 32% of national population aged 20 or older has

hypertension

  • Major risk factor for development of heart disease,

peripheral arterial disease, stroke, heart failure, etc.

  • Accounts for 13.5% of all deaths
  • Estimated that 1.5 billion people will suffer from

hypertension by 2025 (1/3 of world’s population)

Hypertension

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Significant National & Global Health Problem

Additional and/or improved strategies are urgently needed to prevent and treat hypertension

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  • Medications
  • Diet (low salt)
  • Exercise
  • Bioelectronic Devices

Current Strategies to Treat Hypertension

Hold op

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Exercise is Medicine Example

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  • Heightens muscle endurance & metabolic efficiency
  • Enhances heart function
  • Improves glucose handling & insulin sensitivity
  • Reduces body weight & fat deposition
  • Decreases resting blood pressure

Why Exercise?

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Advarsel!!! Warning!!!

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The Pressor Response to Static Exercise is Exaggerated in Hypertensive Patients 20 40 60 80 100

D SBP D DBP

Isometric Handgrip (30% MVC)

NT (119/79) HT (162/112)

* *

Kazatani et al. Am J Ther 2: 165-169, 1995

mm Hg

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From Smith SA, Mitchell JH & Garry MG. Exp Physiol, 91: 89-102, 2006

Why?

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The Exercise Pressor Reflex is Overactive in Hypertension

Smith et al. J Physiol 577: 1009-1020, 2006

WKY: MAP = 89±8 mm Hg SHR: MAP = 149±5 mm Hg

Mizuno et al. Am J Physiol 300: H968-H977, 2011

D MAP (mm Hg) 20 40 60 D HR (beats min-1) 5 10 15 20

* *

D Tension (kg) 0.0 0.5 1.0 1.5 2.0 WKY SHR

WKY SHR

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SHR

X

Mizuno et al. Am J Physiol 300: H968-H977, 2011 Mizuno et al. J Physiol 589: 6191-6204, 2011

Effects of Blocking Skeletal Muscle Sensory Transmission in Hypertensive Rats

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Translation

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Intrathecal Fentanyl Infusion

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Time (min) ∆ Mean blood pressure (mmHg)

*P < 0.05 HT CTRL vs. NT †P < 0.05 HT CTRL vs. HT FENT

HT CTRL HT FENT NT

*† *† *† *† *†

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Treatment Targets

Reflex sensory traffic from skeletal muscle

  • Reduce risk of dangerous cardiovascular event during exercise
  • Allow exercise of increased intensity & duration
  • Enhance benefits of exercise training in hypertension
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Dietary Interventions Example

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Potential Target: Dietary Phosphate (Pi)

  • Inorganic phosphates (Pi) used as preservatives, flavor enhancers and color stabilizers
  • Pi additives present in 44% of top selling grocery items
  • Examples - prepared frozen foods, packaged meats, bread & baked goods, soups, sodas
  • Estimates suggest US adults consume approximately twice the recommended daily allowance

Phosphate Consumption BP?

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Collaborative Research Team

Pre-Clinical Studies Clinical Studies

Physiologist

  • W. Vonpatanasin, MD
  • S. Smith, PHD

Physiologist

  • M. Mizuno, PhD
  • L. Sandon, PhD, RD, LD

Cardiologist Dietician

Translational Research

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Pre-Clinical Studies

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Pre-Clinical Study Design

Normal Phosphate Diet (0.6% Pi) High Phosphate Diet (1.2% Pi) Males & Females 3 Months

Baseline MAP (mmHg) Normal Pi = 93±4 High Pi = 120±5

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Responses to Exercise Pressor Reflex Activation

From Mizuno et al. Am J Physiol, 311: R39-R48, 2016

0.6% Pi 1.2% Pi

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Translation

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Study Population

  • Subjects with Prehypertension (BP 120-139/80-89 mmHg)
  • 50% female
  • 50% African Americans
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Clinical Studies: Randomized Cross-over Design

Low Pi diet (700 mg/d) High Pi diet (1,200 mg/d) 4 wks Low Pi diet (700 mg/d) High Pi diet (1,200 mg/d) 4 wks Run-in Phase 2 wks

Washout phase 2 wks

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muscle SNA

Hand Grip 30% MVC

Effects of High Pi on Neural control of BP

SNA at rest and during handgrip. Measure after 4 weeks of high vs. low Pi diet.

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MSNA during Exercise

24 Hour Urine Phosphate = 818 mg 24 Hour Urine Phosphate = 1102 mg

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High-Phosphate Diet Induces Exercise Intolerance and Impairs Fatty Acid Metabolism

  • High Pi consumption decreases treadmill exercise time and spontaneous

activity level in mice

  • High Pi consumption downregulates key genes involved in fatty acid
  • xidation in mice
  • In humans, higher serum phosphate levels are associated with decreased

physical activity

  • P. Peri-Okonny et al. Circulation 139: 1422-1434, 2019
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Treatment Target

Phosphate consumption

  • Dietary phosphate consumption may prove a novel cardiovascular

risk factor that can be easily modified for the prevention or treatment of hypertension.

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Bioelectronic Devices Example

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Schlaich et al. J Am Coll Cardiol 62: 2031-2045, 2013

SNA SNA SNA SNA SNA

Response to Renal Injury/Ischemia:

Evidence from Animals and Humans

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Translation

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Schlaich et al. J Am Coll Cardiol 62: 2031-2045, 2013

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Symplicity HTN-1 Investigators, Hypertension 57: 911-917, 2011

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Treatment Target

Efferent and Afferent Renal Nerves

  • Catheter-based renal nerve ablation has been shown to

significantly lower systolic and diastolic blood pressure and may prove a viable long-term treatment for hypertension.

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Take Home Message

Translational research is the KEY to the practical application of basic science discoveries to the development and implementation of new ways to prevent, diagnose and treat disease.

2-Time Olympian 1968 Olympics (Mexico City) – 8th Single Sculls 1972 Olympics (Munich) – 4th Double Sculls World Champion 1970 – World Champion, World Rowing Championships

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Thank you!!!

Lars Ulrich

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