Transcript Document

DIETARY SODIUM INTAKE MODULATES RESPONSIVENESS OF DIASTOLIC FUNCTION TO ANGIOTENSIN II IN NORMAL
HEALTHY INDIVIDUALS
Jonathan S Williams1, Scott D. Solomon2, Marina Crivaro2, Marie Gerhard-Herman2, Paul R Conlin1
1Division
of Endocrinology, Diabetes and Hypertension, and 2Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
Introduction
Table 2. Effect of dietary sodium on measures of left
ventricular filling pressures
Table 1. Participant Descriptives
• Diastolic dysfunction:
• Widely prevalent/poorly characterized
• Epidemiology suggests pathological involvement of:
– Renin-angiotensin-aldosterone system (RAAS)
– Dietary sodium intake
N = 13
38 ±14
6/7
25 ±4
117 ±4
68 ±3
Age, y
Gender, M/F
Body Mass Index, kg/m 2
Baseline SBP, mm Hg
Baseline DBP, mm Hg
Low sodium High sodium
P-value
24hr urine Na, mmol
12.7±5.3
272±54
<0.001
• Unclear what role is in normal diastolic function
• Hypothesis: Dietary sodium modulates normal
diastolic function through RAAS mechanisms
24hr urine K, mmol
70.6±8.9
74.9±11.8
0.602
Serum K, mg/dl
4.1±0.1
4.1±0.1
0.844
Serum Na, mg/dl
137±0.6
137±1.4
0.769
Plasma renin (N=3)
activity, ng/ml/h
2.9±2.9
0.2±0.2
0.22
Methods
Aldosterone,ng/dl
30±23
3.0±0.7
0.004
Ang II, pg/ml
74±27
34±5
0.002
• RAAS is the main regulator of volume homeostasis through sodium
metabolism.
• Two week cross-over design (Figure 1)
Means ± SD
– Week 1: 7 days high dietary sodium intake (>200 mEq/day)
– Week 2: 7 days low dietary sodium intake (<10 mEq/day)
• Inpatient GCRC assessment of RAAS and diastolic
function (Tissue Doppler Imaging) at:
• Outcome:
– Response to dietary sodium intake
– Response to Ang II infusion
– Dietary effect of responsiveness to Ang II infusion
140
Ea mm/sec \ SBP mm Hg)
– Baseline
– 30mins after low dose Angiotensin II (Ang II) infusion
(3ng/kg/min)
150
Ea (mm/sec)
*
High Salt
Low Salt
P-value
E/Ea Baseline
4.1 ±0.9
4.5 ±0.8
0.34
E/Ea response
to Ang II
0.09 ±0.52
-0.09 ±0.69
0.57
Note: Doppler measures of E/Ea correlate best with left ventricular
filling pressures. Here there is no significant influence of dietary
sodium or Ang II on filling pressures suggesting effect observed in
tissue Doppler imaging is independent of volume shifts.
Conclusions
• Dietary sodium intake modulates normal diastolic
function independent of blood pressure of filling
pressures
• Responsiveness to Ang II is most evident on a high
sodium diet
130
“Baseline” cardiovascular status
120
SBP, mm Hg
110
Low Salt
80
LS Diet
Overnight
GCRC
admission
Screening
High Sodium intake
Overnight
GCRC
admission
Ang II
Low Sodium intake
(3ng/kg/min)
(3ng/kg/min)
7 days
30 mins
Ang II
7 days
Assessment of:
- TDI
- RAAS
Enhance diastolic
function
Enhanced cardiovascular status
High Salt
Low Sodium Phase
Volume retention
>> excretion
100
90
High Sodium Phase
Circulating
RAAS
Conserve
intravascular
volume
Volume excretion
>> retention
Promote
diuresis
HS Diet
Error bars = SEM
* P = 0.02; LS Ea vs. HS Ea
Circulating
RAAS
High Salt
Circulating
Ang II
Figure 2. Effect of dietary sodium on diastolic function (Ea) and
blood pressure (SBP). Note: Diastolic function improves despite
increase in blood pressure. LS = Low sodium; HS = High sodium
Cardiac tissue
Ang II receptor
upregulation
Increased
responsiveness
Infused Ang II
30 mins
Low Salt
Assessment of:
- TDI
- RAAS
Figure 1. Protocol schema
Results
• Demographic and laboratory descriptives see Table 1
• All subjects demonstrated modulation of diastolic
function (mean early diastolic relaxation velocity, Ea)
with these maneuvers:
– Diastolic relaxation velocities were enhanced on a high
sodium diet despite an increase in blood pressure (Figure 2)
– Ang II infusion led to a significant decrease in diastolic
relaxation only on the high sodium diet (Figure 3)
– Neither dietary sodium intake nor Ang II infusion resulted in
significant alteration in left ventricular filling pressures
(Table 2)
Decrease in diastolic relaxation
velocity (Ea), cm/s
TDI = tissue Doppler imaging; Ang II = angiotensin II infusion;
RAAS = renin-angiotensin-aldosterone system
0
LS Diet
HS Diet
-0.2
-0.4
Circulating
Ang II
Cardiac tissue
Ang II receptor
downregulation
Decreased
responsiveness
Figure 3. Proposed mechanisms of RAAS involvement in diastolic
function. Upper panel: Teleologic basis for altered function; Lower
panel: Interplay of Ang II and dietary sodium on diastolic function
-0.6
-0.8
-1
Clinical Significance
-1.2
-1.4
-1.6
-1.8
-2
*
* P = 0.016
Figure 3. Effect of dietary sodium on responsiveness of diastolic
function (Ea) to Ang II infusion.
• High sodium diet in this study is typical of most
Western diets
• These findings suggest an impaired ability to modulate
diastolic function in response to typical sodium intake
may play a role in clinical abnormalities of diastolic
function
• Future investigation will be conducted to support the
role of tissue RAAS function in hypertension by
focusing on studies that:
– Block or inhibit Ang II action
– Simultaneously measure effect on aortic compliance, a likely
contributor to diastolic function