3. What is microvascular endothelial dysfunction?
“state of enhanced vasoconstriction
and reduced vasodilation”
4. 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
6. 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
7. 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
8. 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
9. 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
10. 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
11. 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
12. Research Questions
Does a HFM affect NO-dependent vasodilation?
Can mild heat stress mitigate the potential decrease in
NO-dependent vasodilation?
13.
Hypothesis
Consumption of a high fat meal will blunt
microvascular endothelial function
AND
Mild heat stress will minimize the
detrimental effects of a high fat meal on
microvascular endothelial function
15. 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
16. 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
17. 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
18.
19.
20.
21. 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.
23. 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)
25. 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
26. 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
28. 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
29. 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
32.
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)
34. 50
70
90
110
130
150
170
190
210
230
250
0 30 60 90 120
Triglycerides(mg/dl)
Time (Minutes)
HFM TRG HFM-WBH TRG Baseline
*
*
* *
*
#
Figure 2. Blood triglyceride response
*, P < 0.05 vs. time 0 within a trial; #, P < 0.05 vs. HFM at same time
point
36. Cutaneous Vascular Conductance
Acute HFM and consequent
elevated blood triglycerides
negatively affect
microvascular endothelial
function
Potentially by interrupting
NO production
0
20
40
60
80
100
Control HFM HFM-WBH
CutaneousVascularConductance(%
Maximal)
*
#
Mild heat stress prior to, and during, consumption of
HFM attenuates peak triglycerides and restores
microvascular endothelial function
37. 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
38. 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
50
100
150
200
250
0 30 60 90 120
Triglycerides(mg/dl)
Time (Minutes)
HFM TRG HFM-WBH TRG Baseline
*
* * *
*
#
39. 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)
40. 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
41. 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
42. 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
43. 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
44. 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
45.
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
47. 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
49. 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
50
60
70
80
90
100
110
120
130
140
150
0 30 60 90 120
Glucose(mg/dl)
Time (Minutes)
HFM GLU HFM-WBH GLU Baseline
*
*
*
50.
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
Editor's Notes
play a key role in the progression of cardiometabolic related diseases and thus act as an important contributor to chronic diseases such as diabetes, hypertension, and dyslipidemia
Nitric oxide is a vital molecule for cardiovascular health and plays an important role in vascular function as it regulates platelet aggregation and vascular tone
Individuals with reduced cardiac output and inadequate peripheral blood flow may benefit from increased blood flow following heat stress (Akasaki et al., Circulation, 2006)
manner by upregulating eNOS and inducing vasodilation of systemic arteries
Mild heat stress has been shown to upregulate Hsp90 and mitigate the vasoconstrictive effects of uncoupled eNOS
. This heating protocol is considered below the pain threshold of 44-45°C (sources) and allows for assessment of NO-dependent microvascular endothelial vasodilation.
Typical response is the initial peak with the prolonged second plateau
Initial peak is a neuronal reflex, plateau is 50-60% NO depende
At a higher temperature plateau reaches around 90% of maximal CVC meaning they have reached the ceiling causing there to be no room for further improvement or to examine a beneficial intervention
Not significantly different from each other
Core temperature averaged 37.7 ± 0.2 °C throughout the control trial, 37.9 ± 0.3°C during the HFM trial, and 38.3 ± 0.2°C during the HFM + WBH trial. Based on these numbers, the heat stress was sufficient to raise core temperature to the goal of ≈0.2-0.3°C above baseline.
A single HFM attenuated cutaneous vascular conductance to local heating. Mild heat stress prior, and during, consumption of a HFM restored cutaneous vascular conductance to local heating. There was no statistical difference between the control trial and the HFM-WBH trial
There was no difference between control and baseline triglycerides (time 0). There was a significant increase in blood triglycerides from baseline for the HFM trial. Mild heat stress blunted the increase in triglycerides such that only the response at minute 120 was significantly greater than baseline. There were no differences in triglycerides between trials except at minute 60.
plausible that postprandial high fat meal and elevated circulating triglycerides are partially, if not fully, responsible for impairing microvascular endothelial function
Primary finding blah blah blah
Hypertriglyceridemia induces oxidative stress and subsequently, inflammation, and this cascade of events results in deleterious physiological effects
including hypertensive, diabetic, and coronary heart disease population
As sauna therapy has repeatedly been examined as a mediator for endothelial function based on its ability to increase NO bioavailability and induce vasodilation of systemic arteries, it is reasonable based on these results, to utilize mild whole body heat stress as noninvasive therapeutic modality for curbing atherosclerosis associated with high fat diets and cardiometabolic diseases.
There were no statistical differences between the control trial and the baseline (time 0) responses for the high fat meal and high fat meal + mild heat stress trials (P = 1.000). Within the high fat meal trial, the value at minute 30 was significantly greater than the baseline (minute 0) value. Within the high fat meal + mild heat stress trial, the value at minute 60 was significantly greater than the value at baseline (minute 0). There were no statistical differences in glucose values between conditions at any time point
Because we don’t know how many blood vessels each dopplar is sampling we have ot standardize it to maximum so that everything is normalized
Flow is volume per unit of time, because we cant see the blood vessels we can’t measure the blood cells
Flux is an index of flow; RBC count
