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Jenny Harvey
The effect of mild heat stress on postprandial high fat meal microvascular endothelial function
Introduction
Definition Mechanisms for dysfunction Sauna bathing
What is microvascular endothelial dysfunction?
“state of enhanced vasoconstriction and reduced vasodilation”
Microvascular Endothelial Function
Unclear how high fat meals (HFM) and hypertriglyceridemia (HTG) affect microvascular endothelial function TPR and glucose uptake occur at microvascular level Microvascular endothelial dysfunction precedes
macrovascular dysfunction Important to determine how HFM affect human
microvascular endothelial function and determine the mechanism for dysfunction
Mechanisms for Microvascular Endothelial Dysfunction
Chronic low-grade inflammation Hypertriglyceridemia Oxidative stress
High fat diet and chronic low-grade inflammation
Postprandial lipid accumulation triggers oxidative stress and an inflammatory response
Link between increased adiposity from high fat diet and chronic low-grade inflammation Relationship to cardiometabolic diseases and microvascular
endothelial function is significant (Brandauer et al., Physiol Rep, 2013; Calder et al., Br J Nutr, 2011)
Hypertriglyceridemia established as a risk factor of cardiovascular disease
Oxidative Stress
Oxidative stress is worsened over postprandial period as free fatty acids accumulate post high fat meal (Wang et al., Am J Physiol Heart Circ Physiol, 2011)
May inhibit endothelial nitric oxide synthase (eNOS) phosphorylation Important precursor for NO production Activated by physiological mechanisms such as
shear stress, estrogens, and insulin
Nitric Oxide (NO)
Reduction in NO bioavailability seems to be a central mechanism for impaired endothelial function
Vital molecule for cardiovascular health as it regulates platelet aggregation and vasodilation within endothelium
NO deficiency creates a vascular environment conducive to inflammation and vasoconstriction
Consumption of a high fat diet
Enhanced vasoconstriction and reduced vasodilation
Chronic oxidative stress and inflammation leading to reduced NO bioavailability
Impaired microvascular endothelial function and increased risk for atherosclerosis
Sauna Therapy
Minimally invasive therapeutic modality that closely mimics the outcomes of exercise potential to reduce negative effects of HFM on endothelial
function curb development of atherosclerosis
Individuals who are unable to exercise because of aging, injury, disease, or organ dysfunction may benefit from sauna treatment
Potential hemodynamic modifications for the healthy population that lasts up to two hours
Heat Therapy as a Mediator of Endothelial Function
Induce vasodilation of systemic arteries
Stimulus for greater NO bioavailability
Shear stress upregulates eNOS phosphorylation
Elevated blood flow on surface of body
Research Questions
Does a HFM affect NO-dependent vasodilation? Can mild heat stress mitigate the potential decrease in
NO-dependent vasodilation?
Hypothesis
Consumption of a high fat meal will blunt microvascular endothelial function
ANDMild heat stress will minimize the
detrimental effects of a high fat meal on microvascular endothelial function
Methods
Participant Recruitment and Screening Participant Instrumentation Protocols Statistical Analysis
Recruitment and Screening
Free of any known cardiovascular or metabolic disease, skin allergy/disease, history of adverse reaction to heat stress, smoking in last 6 months
Not taking any medication for corresponding conditions
4 male and 4 female participants Age 18 - 32
Participant Instrumentation
Blood samples analyzed via Cholestech LDX (Alere, USA) To ensure stable core temperature and to clamp skin
temperature, each participant wore a suit consistently perfused with 33-34°C water
3-lead ECG Blood pressure cuff on right arm
Wireless Telemetry Relatively new technology Subject swallows small, ingestible
“thermometer” pill Pill transmits signal to recording
unit Measures temperature in
digestive tract Measurement depends on
where pill is located (time given to subject)
Can “slip” with changes in posture
Lowered with ingestion of fluids
High Fat Meal Calculation
Fat consumption for each participant was calculated on a basis of 1g fat per kilogram of body weight (Ade et al., EJAP, 2014)
Blue Bell ice cream (chocolate or vanilla) Serving size: 74-88 g Total fat: 9-11g 672.43 ± 53.70 g of ice cream
Participants allotted ~20 minutes to consume the ice cream.
Experimental Protocols
Local heating protocol High fat meal High fat meal + mild heat stress
Local Heating Protocol
10 minutes of baseline Skin heaters increased from 33°C to 39°C at a rate of
0.1°C/second to evoke submaximal vasodilation Plateau of local heating response is ~80% of NO-dependent
(Choi et al., JAP, 2014)
Once participant reaches plateau in RBC flux (~30 min), skin heaters increased to 43°C to elicit maximal vasodilation (Wong et al., JAP, 2006)
(Choi, JAP, 2014)
L-NAME inhibits NO-induced endothelial
vasodilation
(Choi, JAP, 2014)
Experimental Protocol 1: High Fat Meal
Baseline fasting blood sample + 10 min of baseline 33°C water pumped through water perfused suit for 30
min Participants consumed ice cream in ~20 min Additional 60 min of thermoneutral water heating
before turned off Blood samples via finger stick were then measured
every 30 minutes until the 120th min post-HFM
Experimental Protocol 2: High Fat Meal + Mild Heat Stress
Same as protocol 1 + mild heat stress during the HFM Mild heat stress performed by pumping 50°C water
through the water perfused suit for 90 min 30 min prior to ice cream consumption, 60 min post
Aiming for a ~0.2- 0.3°C increase in core temperature above baseline Point at which there is a significant increase in blood flow
without skin reaching the point of maximal vasodilation, so as to leave room for NO-dependent vasodilation to take effect during local heating protocol
Data Analysis
Outcome Measures Statistics
Outcome Measures
Cutaneous Vascular Conductance Control vs. High Fat Meal vs. High Fat Meal + Whole Body
Heat % CVC max = RBC flux ÷ mean arterial pressure (mV/mmHg)
Blood Analysis [Triglycerides] vs. time
Statistical Analysis
SPSS 22 (IBM Corporation)
Mean ± standard error of the mean (SEM) 95% confidence intervals with P-values of < 0.05
considered significant Paired t-tests and one- and two-way repeated
measures analysis of variance with a Bonferroni correction factor was used where appropriate
Results
Blood Pressure Core Temperature %CVCmax
Triglycerides vs. Time
Systolic Blood
Pressure (mmHg)Diastolic Blood
Pressure (mmHg)
Mean Arterial Blood Pressure
(mmHg)
Control 116 ± 5 76 ± 5 89 ± 5
HFM 120 ± 5 77 ± 5 91 ± 5
HFM + WBH 118 ± 6 75 ± 4 90 ± 4
Blood Pressure Data
Average core temp ± SE (°C )
Control 37.31 ± 0.11
HFM 37.27 ± 0.10
HFM + WBH 37.68 ± 0.18 *
Core Temperature
Based on these numbers, the heat stress was sufficient to significantly raise core temperature to the goal of ~0.2-0.3°C
above baseline (P = .042)
Control HFM HFM-WBH0
20
40
60
80
100
Cuta
neou
s Vas
cula
r Con
duct
ance
(% M
ax-
imal
)
*
#
Figure 1. Cutaneous vascular conductance responses
*, P < 0.05 vs. Control; #, P < 0.05 vs. HFM.
0 30 60 90 12050
70
90
110
130
150
170
190
210
230
250HFM TRG HFM-WBH TRG Baseline
Time (Minutes)
Trig
lyce
rides
(mg/
dl)
** * *
*
#
Figure 2. Blood triglyceride response
*, P < 0.05 vs. time 0 within a trial; #, P < 0.05 vs. HFM at same time point
Discussion
Explanation of Results Clinical Implications Limitations
Cutaneous Vascular Conductance
Acute HFM and consequent elevated blood triglycerides negatively affect microvascular endothelial function Potentially by interrupting
NO production
Control HFM HFM-WBH0
20
40
60
80
100
Cuta
neou
s Va
scul
ar C
ondu
ctan
ce (%
M
axim
al)
*
#
Mild heat stress prior to, and during, consumption of HFM attenuates peak triglycerides and restores microvascular endothelial function
Local heating and NO production
Local heating protocol resulted in submaximal cutaneous vasodilation that is largely NO dependent (Choi, JAP, 2014)
Cutaneous vasodilation is a good measure of microvascular endothelial function
Reduction in cutaneous hyperemic response due to reduced NO and impaired microvascular endothelial function
Triglycerides vs. Time
Blood [TG] continued to significantly rise every thirty minutes for 2 hours post HFM
Mild heat stress prior to consumption of high fat meal significantly reduced triglyceride response at minute 60 and attenuated peak triglyceride
0 30 60 90 120507090
110130150170190210230250
HFM TRG HFM-WBH TRG
Baseline
Time (Minutes)
Trig
lyce
rides
(mg/
dl)
** * *
*#
Postprandial High Fat Meal Microvascular Endothelial Function
The majority of the data suggests there is attenuated endothelial-dependent vasodilation two hours post high fat meal even in apparently healthy individuals
Serum triglyceride levels also increase in otherwise healthy individuals following a high fat meal, which further suggests the negative effects of a high fat meal on endothelial function are mediated, in part by, hypertriglyceridemia (Bae et al., Athersclerosis, 2001)
Consumption of a high fat diet
Enhanced vasoconstriction and reduced vasodilation
Chronic oxidative stress and inflammation leading to reduced NO bioavailability
Impaired microvascular endothelial function and increased risk for atherosclerosis
Why sauna therapy?
skin blood flow is a direct result of thermal therapy or heat
Shear stress from blood flow acts as stimulus in the cutaneous microvasculature for NO bioavailability
Indeed, whole body mild heat stress attenuated the rise in triglycerides and improved CVC (%maximal) presumably from additional NO
Clinical Implications: Disease Populations
Well tolerated form of therapy in several disease states (Akasaki et al., Circ J, 2006; Gayda et al., J Clin Hypertens, 2012)
Ability for vascular smooth muscle to respond more adequately as endothelial function improves via sauna therapy Improve exercise tolerance in chronic heart failure
Mild heat stress may stimulate NO-induced vasodilation and HSPs to the point of beneficial and improved blood flow
Delayed onset of pain for peripheral artery disease Improved exercise tolerance
Sauna therapy for healthy populations
Hemodynamic modifications from sauna can last up to two hours (Imamura et al., JACC, 2001)
Cardiac output increases peripheral blood flow and shear stress NO production
Upregulation of NO-driven endothelial vasodilation decreases total peripheral resistance
Limitations and Delimitations
Protocol based on previously established and tested heating protocols We did not specifically inhibit NO and cannot therefore be certain
our results reflect changes in NO-dependent endothelial vasodilation
Use L-NAME via microdialysis to directly assess effect of high fat meal and hypertriglyceridemia on NO-dependent endothelial vasodilation
Conclusion
A single high fat meal attenuates cutaneous vascular conductance
AND
Mild heat stress prior to, and during, the consumption of a high fat meal can restore cutaneous vascular conductance
SUGGESTING
A high fat meal negatively affects microvascular endothelial function and mild heat stress may mitigate these
deleterious affects
Acknowledgements
Thesis Advisor: Dr. Brett Wong
Committee Members: Dr. Jeff Otis Dr.
Benjamin Goerger
External Collaborator: Dr. Bruno Roseguini
Heat Shock Proteins
HSPs help maintain cellular integrity Upregulated both independently and in conjuction
with eNOS (Miyauchi et al., Circ J, 2012)
Increase in number of HSPs following exercise and elevated core temperature
Mechanism for cardioprotection (Milne et al., JAP, 2012)
reduce inflammatory pathways and blunt oxidative stress
0 30 60 90 12050
60
70
80
90
100
110
120
130
140
150
HFM GLU HFM-WBH GLU Baseline
Time (Minutes)
Gluc
ose
(mg/
dl)
*
*
Figure 3. Blood glucose responses
Blood Glucose vs. Time
Possible that blood glucose is having an effect on reduced blood flow response
Seems unlikely WBH + HFM restored CVC
and attenuated peak TG whereas it had no effect on glucose
0 30 60 90 12050
60
70
80
90
100
110
120
130
140
150 HFM GLU HFM-WBH GLUBaseline
Time (Minutes)Gl
ucos
e (m
g/dl
)
*
*
*
Why %CVCmax?
Perimed Instruments, Sweden, 2015
We do not know how many blood vessels each dopplar is sampling
Standardize to maximum so that everything is normalized