Cardiovascular Disease [70-80%]

atherosclerosis [the disease of the arteries]

endothelial dysfunction

Laszlo G. MeszarosDept. Animal PhysiologyUniv. of Kaposvar, HungaryLife Science FoundationAugusta, GA, USA

- A novel diagnostic method- Nutraceutical therapy

“You’re as old as your arteries…”

Some Cardiovascular Disease (CVD) Statistics

Atherosclerosis (AS)

Some more AS statistics – WHO 2008

The most “deadliest” risk factors all relate to AS…

“As old as your arteries…”

Non-optimal circulation: in essence, every organ, tissue affected

AS risk factors and markers

LDL ↑(ApoB/ApoA ↑

Lp-PLA2 ↑)

HDL ↓CRP ↑

MetabolicdiseaseBPsys ↑

Obesity ↑Homo-Cystein ↑

Diabetes

LDL ↑(ApoB/ApoA ↑

Lp-PLA2 ↑)

HDL ↓CRP ↑

MetabolicdiseaseBPsys ↑

Obesity ↑Homo-Cystein ↑

Diabetes

AHA - 2012Diet & Physical Inactivity – 74%

SmokingAlcoholGenetics

(Air) Pollution

AHA - 2012Diet & Physical Inactivity – 74%

SmokingAlcoholGenetics

(Air) Pollution

AS is a degenerative (chronic) disease

Age

Putative causes:error accumulationepigenetics

Anatomy of arteries

Function of arterial cells – Vasodilation 1

Endothelial cell layer (largest endocrine organ):• regulates smooth muscle constriction/dilation• thereby, sets vessel diameter (and?)• (permeability, blood cell – vessel wall interact.)

Vasodilators:• synth.: EDHF (C-natriuretic peptide?), NO• mediates: shear stress, bradykinin, ANP*, VIP*, prostagladines, prostacyclin…

Vasoconstrictors:• synthesize: endothelins• mediates: adrenerg-, muscarinic agonists, vasopressin, thromboxane, hypox.

*Atrial Natriuretic Peptide, Vasoactive Intestinal Peptide

Function of arterial cells – Vasodilation 2

AS , initiation and progression of the disease

AS Stages:

1. Endothelial dysfunction (ED) – NO (aging, free radicals, ADMA) (Flow-mediated dilation ) endothelial activation (early inflammation?) LDL-cholesterol oxidation (free radicals?) – fatty streaks NON-LOCALIZED

Years 2. Recruitment of immune cells, collagen synthesis, calcification, endothelial permeability, apoptosis, SM proliferation – plaques LOCALIZED and/or NON-LOCALIZED

3. Thrombocyte activation, thrombus formation mosly LOCALIZED

Techniques to assess arterial health must consider LOCALITY/NON-LOCALITY.

Vasography: Flow-Mediated Dilation Another Waymethod to assess endothelial function in the arteries

HU (P1000657) and US (US 61483768) patents

Sorting them out…- invasive vs. non-invasive- early vs. late- expensive vs. less expensive- usable for screening vs. …- locality vs. non-locality- simple to use vs. …(requirement of clinical setting)- grading, staging

Costly, clinical setting required:

Angiography – invasive, local

Stress test (ECG) – indirect

Calcium “scoring” (CT) – late stage

Ultrasound – seems user-dependent, local?

Intravascular ultrasound – invasive, local (advantage?)

Techniques to assess arterial health I.

Pulse Wave Velocity (much less costly)- narrower the artery faster the pulse travels (Bernoulli)- detection of pulse appearance at two locations with different distances from the heart

Arterial Stiffness (m/s)

Techniques to assess arterial health II.

Blacher, J.: Impact of Aortic Stiffness on Survival…,Circulation 99:2434 (1999)

Aorta-Femoral

For instance, very good correlation between B-A PWVand coronary calcification:Liu, C-S.: Arterial Stiffness is Highly Correlatedwith Coronary Atherosclerosis, J. Athero. Thromb.18:online (2011)

Localized or not?No, it is not!

Localized or not?No, it is not!

Techniques to assess arterial health III.

FMD (Flow-Mediated Dilation with ultrasound) – the first sign, but…

Bots, ML.et al.: Assessmentof flow-mediated vasodilatation(FMD) of the brachial artery,Eur. Heart J., 26:363 (2004)

Localized or not?No, it is most likely not!

Localized or not?No, it is most likely not!

Techniques to assess arterial health IV.

Wang, K-L. et al.: Wave Reflection and ArterialStiffness…, Hypertension, 55:799 (2010)

AixSphygmoCorArteriografArcSolverCVprofiler…

SI and RI:Pulse TracerBioClip

Millaseau, SC. et al.: Determination of age-related increases in large artery stiffness by digital pulsecontour analysis, Clin. Sci., 103:371 (2002)

According to the theory behind them:evolution is STUPID.

Pulse Contour Analysis (PCA) – less costly

Some problems with PCA

2. Math:Without curve fitting?Pulse contour types

1. The model:“wave reflection”

Vasography = FMD differently and better

Reminder:shear stress ↑, then Ca ↑, which makes NO ↑resulting in vasodilation.

Vasography = FMD differently and better

Methods:- Pressure pulse (PP) recorded by using piezoelectric sensor (UFI, USA)- Volume pulse recorded near-infrared plethysmographic sensor (Norelco, USA)SIMULTANEOUSLY

Data fed into a 12 bit A/D converter

Pulses averaged, then normalized in lengthand heightMax. rate of rise (rsys) computed fromnormalized records by taking thetime-derivative

Significance by ANOVA

Vasography = FMD differently and better

Development of VP is delayed (relative to PP)The delay is larger, max. rate is slower in theelderly

Vasography = FMD differently and better

NG = nitroglycerin, an NO donor

The rate difference between PP and VPdecreases after NG in the elderly

(Max. rate in PP is not altered by NG)

Thus, max. rate in VP measuresendothelial function (just like FMDwith ultrasound, but without the snags)

Vasography = FMD differently and better

A: R = 0.783; P < 0.001B: Difference is significant (P < 0.05)

Vasography = FMD differently and better

The exponential curve is NOT a surprise

Tone + Pulsation (PWV)vs.

Pulsation (rsys)

Vasography = Pulsating FMD (PFMD)

Thanks for listening…