EPIDEMIOLOGY OF EPIDEMIOLOGY OF SALT AND HYPERTENSIONSALT AND HYPERTENSION

Arun ChockalingamArun ChockalingamProfessor & Director of Global HealthProfessor & Director of Global Health

Secretary General, World Hypertension LeagueSecretary General, World Hypertension League

HTA 2008, 4th International Symposium of Hypertension Santa Clara, Cuba

May 27, 2008

HistoricalHistorical Information Information

As long ago as 2,000 B.C., As long ago as 2,000 B.C., when the famous Chinese when the famous Chinese ““Yellow EmperorYellow Emperor” Huang ” Huang Ti recorded salt’s Ti recorded salt’s association with a association with a “hardened pulse”, we “hardened pulse”, we have known of a have known of a relationship between relationship between salt salt and blood pressureand blood pressure..

Hemodynamics of Early Hemodynamics of Early Essential HypertensionEssential Hypertension

Hemodynamics of Established Hemodynamics of Established Essential HypertensionEssential Hypertension

Overall Scheme for Pathogenesis Overall Scheme for Pathogenesis of Essential of Essential Hypertension

Cardiovascular Events and Sodium Sensitivity

Morimoto et al, Morimoto et al, LancetLancet 1997; 350: 1734 1997; 350: 1734

Kaplan-Meier plots showing the relationship between total CV events in hypertensive patients and sodium sensitivity. p < 0.05

Urinary Salt Excretion and Death From strokes in 12 European countries

Adapted from Perry, IJ et al. J Hum Hypertens, 1992; 6:23-25

Increased risk of death related to a 6 g/dayIncreased risk of death related to a 6 g/dayincrease in salt intake (N=2436)increase in salt intake (N=2436)

CHDCHDDeathDeath

CVDCVDDeathDeath

AllAllDeathDeath

1.751.75

1.501.50

1.251.25

1.001.00

1.751.75

0.500.50

Haza

rd R

ati

o

Haza

rd R

ati

o ¶¶

High saltHigh saltintakeintake

Lower saltLower saltintakeintake

*** P<0.001 compared *** P<0.001 compared to lower salt intaketo lower salt intake

¶ Adjusted for age, ¶ Adjusted for age, study year, smoking, study year, smoking, serum total and HDL serum total and HDL cholesterol,cholesterol,systolic blood pressure, systolic blood pressure, and body mass indexand body mass index

Hazard Ratiosassociation of a 6 g/day increase in salt intake with 24-h

urinary Na+ excretion

Hazard Ratiosassociation of a 6 g/day increase in salt intake with 24-h

urinary Na+ excretion

He FJ, MacGregor GA. a meta-analysis of randomized trials. Implications for public health. J Hum Hyptens 2002;16:761-770

Relationship between the net change in urinary Na+

and SBP

Relationship between the net change in urinary Na+

and SBP

The yellow circles The yellow circles represent represent normotensives and the normotensives and the blue circles represent blue circles represent hypertensives. The hypertensives. The slope is weighted by slope is weighted by the inverse of the the inverse of the variance of the net variance of the net change in systolic change in systolic blood pressure. The blood pressure. The size of the circle is in size of the circle is in proportion to the proportion to the weight of the trial.weight of the trial.

He FJ, MacGregor GA. a meta-analysis of randomized trials. Implications for public health. J Hum Hyptens 2002;16:761-770

44

22

00

-2-2

-4-4

-6-6

-8-8

-10-10

-12-12

-30-30 -50-50 -70-70 -90-90 -110-110 -130-130Change in Urinary SodiumChange in Urinary Sodium

(mmol/24h)(mmol/24h)

Change in S

yst

olic

Blo

od

Pre

ssure

Change in S

yst

olic

Blo

od

Pre

ssure

(mm

Hg)

(mm

Hg)

NormotensivesNormotensives

HypertensivesHypertensives

Dose-response relation between 24-h Dose-response relation between 24-h urinary Na+ and BP in two studiesurinary Na+ and BP in two studies

He, FJ et al. Hypertension 2003; 42:1093-109

Double-blind salt reduction study & the DASH-Sodium studyDouble-blind salt reduction study & the DASH-Sodium study

DASH: Dietary Approaches to Stop Hypertension 79 Vs 81 HT/116 Vs 121 HTDouble-blind study: 3 salt intakes, each 4 wks 19 HT

Comparison of the dose-response Comparison of the dose-response relation among 3 studiesrelation among 3 studies

He, FJ et al. Hypertension 2003; 42:1093-109•Double-blind salt reduction studyDouble-blind salt reduction study•DASH-Sodium studyDASH-Sodium study•Metal-analysis of modest salt reduction Metal-analysis of modest salt reduction >> 4 wks 4 wks

Weekly group ave. SBP at lower NaWeekly group ave. SBP at lower Na+ +

level compared with group ave. SBP level compared with group ave. SBP measured at end of higher Nameasured at end of higher Na++ level level

Obarzanek, E et al. Hypertension 2003; 42:459-467(SBP mean 95% CI), (n=188); 60% NT(SBP mean 95% CI), (n=188); 60% NTAge> 45: 65%; 55% F; 58% BlackAge> 45: 65%; 55% F; 58% Black

Mean SBP changes in the Mean SBP changes in the DASH-NaDASH-Na++ trial trial

Adapted from Sacks, FM et al. N Engl J Med 2001; 344:3-10

Solid lines indicate the effects of Solid lines indicate the effects of sodium reduction in the 2 diets; sodium reduction in the 2 diets; hatched lines, the effects of the hatched lines, the effects of the DASH diet at each sodium levelDASH diet at each sodium level

BP by week during the DASH BP by week during the DASH feeding study in 3 dietsfeeding study in 3 diets

Adapted from Appel, LJ et al. N Engl J Med 1997; 336:1117-1124

N=379N=379 ▲▲NaNa++

(mmol/24h)(mmol/24h)▲ ▲ KK+

((mmol/24h)mmol/24h)▲ ▲ NaNa++/K/K+

Control Control DietDiet

+ 142+ 142 + 146+ 146 0.9720.972

Fruit/Veg Fruit/Veg DietDiet

-232-232 +1298+1298 -0.179-0.179

DASH DietDASH Diet -73-73 -1500-1500 -0.049-0.049

% change in MAP in normotensive % change in MAP in normotensive subjects receiving incremental subjects receiving incremental

increases in Naincreases in Na++

Data adapted from Luft et al. Circulation 1979; 60:697-706

Blood pressure at the Blood pressure at the end of 7 days of low (10 end of 7 days of low (10 mmol/d) salt intake was mmol/d) salt intake was taken as baseline. All taken as baseline. All subjects demonstrated an subjects demonstrated an increase in blood increase in blood pressure with salt pressure with salt loading.loading.

Key Messages From Key Messages From IntersaltIntersalt Study Study Strong positive associations of 24 hr urinary Na excretion to BP of Strong positive associations of 24 hr urinary Na excretion to BP of

individuals, to median BP across its 52 population samples, and to individuals, to median BP across its 52 population samples, and to differences in BP with age.differences in BP with age.

The within population association of Na to BP in Intersalt are The within population association of Na to BP in Intersalt are concordant with the cross population findings for 52 samples.concordant with the cross population findings for 52 samples.

Estimates of the effect of median Na excretion higher by 100 Estimates of the effect of median Na excretion higher by 100 mmol/day over a 30 year period (age 55 minus age 25) were a mmol/day over a 30 year period (age 55 minus age 25) were a greater difference of 10-11 mm Hg in SBP and 6 mm Hg in DBP.greater difference of 10-11 mm Hg in SBP and 6 mm Hg in DBP.

These results lend further support to recommendations for mass These results lend further support to recommendations for mass reduction of high salt intake for the prevention and control of reduction of high salt intake for the prevention and control of adverse blood pressure levels and high blood pressure in adverse blood pressure levels and high blood pressure in populations. populations.

Elliott, P et al. BMJ 1996; 312:1249-1253

TONE StudyTONE Study

Whelton, PK et al. JAMA 1998, 279(11):839-846

*Change in BP calculatedFor 953 participants who attended at least 1 study visit after Randomization.

p<.001 bet UC & IG for SBP or DBP Age: 60-80 yrs; BP < 145/85 + 1 Rx

Baseline BP and Change From Baseline to Last Baseline BP and Change From Baseline to Last Visit Prior to Attempted Medication WithdrawalVisit Prior to Attempted Medication Withdrawal

TONE: Trial of TONE: Trial of Nonpharmacologic Nonpharmacologic Interventions in the Elderly Interventions in the Elderly

CV Events During Follow-up of CV Events During Follow-up of TONE Participants According to TONE Participants According to

Intervention AssignmentIntervention Assignment

Whelton, PK et al. JAMA 1998, 279(11):839-846

Trial of Nonpharmacologic Interventions in the ElderlyTrial of Nonpharmacologic Interventions in the Elderly

TONE Study - Mean change in 24-h TONE Study - Mean change in 24-h urinary Naurinary Na++ excretion excretion

Whelton, PK et al. JAMA 1998, 279(11):839-846

Error bars indicate SEMs. Error bars indicate SEMs. The numbers used in the The numbers used in the figure are given in mmol/dfigure are given in mmol/d

NaNa++ reduction group: n=487 reduction group: n=487No NaNo Na++ reduction group: n=488 reduction group: n=488

Trial of Nonpharmacologic Trial of Nonpharmacologic Interventions in the ElderlyInterventions in the Elderly

Trial of Nonpharmacologic Trial of Nonpharmacologic Interventions in the Elderly (TONE): Interventions in the Elderly (TONE):

Mean change in Body weightMean change in Body weight

Whelton, PK et al. JAMA 1998, 279(11):839-846

Weight loss group: n= 291Weight loss group: n= 291No weight loss group: n= 291No weight loss group: n= 291

Error bars indicate SEMs. The numbers Error bars indicate SEMs. The numbers used in the figure are given in kgused in the figure are given in kg

TONE: % of people free of CV TONE: % of people free of CV events and HBP and did not have events and HBP and did not have antihyp. therapy during follow-upantihyp. therapy during follow-up

Whelton, PK et al. JAMA 1998, 279(11):839-846

Change in SBP & DBP (mm Hg) achieved Change in SBP & DBP (mm Hg) achieved in trials of 13 to 60 monthsin trials of 13 to 60 months

Hooper at al. BMJ 2002; 325:628-636

Systematic review of LT effects of advice to reduce dietary salt in adults: Meta analysis of RCTs

Change in urinary NaChange in urinary Na++ (mmol Na/24 hours) (mmol Na/24 hours) achieved in trials of 6 to 12 months, 13 to 60 achieved in trials of 6 to 12 months, 13 to 60

months, and >60 monthsmonths, and >60 months

Hooper at al. BMJ 2002; 325:628-636

Systematic review of LT effects of advice to reduce dietary salt in adults: Meta analysis of RCTs

Intensive interventions, unsuited to 1Intensive interventions, unsuited to 1o o care or care or pop. prevention pgms, provide pop. prevention pgms, provide ONLYONLY a a small reduction in BP and Nasmall reduction in BP and Na++ excretion. excretion.

Effects on deaths and CV events are unclear.Effects on deaths and CV events are unclear. Advice to reduce Na+ intake may Advice to reduce Na+ intake may HELPHELP

people on antihypertensive drugs to stop their people on antihypertensive drugs to stop their meds. while maintaining good BP control. meds. while maintaining good BP control.

Hooper at al. BMJ 2002; 325:628-636

Correlation between salt intake and LV Correlation between salt intake and LV mass in subjects with SBP >121 mm Hgmass in subjects with SBP >121 mm Hg

M-mode echocardiographic LV M-mode echocardiographic LV massmass

Pop-based study focused on Pop-based study focused on lifestyle & salt intakelifestyle & salt intake

Random sample Random sample (51F+ 42M)(51F+ 42M)

7-day food record7-day food record ConclusionConclusion: Synergistic : Synergistic

interaction of dietary salt with BP interaction of dietary salt with BP suggests high Na+ intake may suggests high Na+ intake may sensitize the heart to the sensitize the heart to the hypertrophic stimulus of pressure hypertrophic stimulus of pressure loadload

Adapted from Kupari P et al J. Circulation, 1994; 89:1041 – 1050

The relation of urinary salt excretion The relation of urinary salt excretion to cancer of the stomach (CaS)to cancer of the stomach (CaS)

Background:Background: High salt and High salt and nitrate intake are RFs for CaS. nitrate intake are RFs for CaS. Little is known of their possible Little is known of their possible interaction. interaction.

Methods: Randomly selected Methods: Randomly selected 24-hr urine from 39 pop (5756 24-hr urine from 39 pop (5756 for Na+ and 3303 for nitrate) for Na+ and 3303 for nitrate) from INTERSALT study. from INTERSALT study. Regression analyses in relation Regression analyses in relation to national CaS mortality rates.to national CaS mortality rates.

Conclusion: Salt intake is likely Conclusion: Salt intake is likely the rate-limiting factor for CaS the rate-limiting factor for CaS mortality at population level.mortality at population level.

Adapted from Joossens, JV et al. Int J Epidemiol, 1996; 25 494-504

Salt and Essential HypertensionSalt and Essential Hypertension

Essential hypertension is seen Essential hypertension is seen primarily primarily in societies in societies with average salt intakes of more than 50meq/day (2.3 g with average salt intakes of more than 50meq/day (2.3 g sodium).sodium).

Essential hypertension is Essential hypertension is rare rare in societies with average in societies with average salt intakes of less than 50meq/day (1.2 g sodium). salt intakes of less than 50meq/day (1.2 g sodium).

These observations suggest that the development of These observations suggest that the development of hypertension requires a hypertension requires a threshold levelthreshold level of salt intake. of salt intake.

Elliott P, Stamler J, Nichols R et al. Intersalt revisited: Further analyses of 24 hour sodium excretion Elliott P, Stamler J, Nichols R et al. Intersalt revisited: Further analyses of 24 hour sodium excretion and blood pressure within and across populations. BMJ 1996; 312:1249and blood pressure within and across populations. BMJ 1996; 312:1249

Decrease in salt intake (g) calculated Decrease in salt intake (g) calculated from urinary Nafrom urinary Na++ excretion among Finns excretion among Finns

Laatikainen, T et al. European Journal of Clinical Nutrition 2006; 60:965-970

Linear Regression Analyses (adjusted by age & Survey area):

Annual decrease among

men: 0.14 g (p<0.001);

Women: 0.11 g (p<0.0001)

Only N.Karelia, Kuopio & SW Finland are included in the analysis

National Policy InterventionNational Policy Intervention

““The experience of Finland, which has had a salt The experience of Finland, which has had a salt reduction program running since the late 1970s, reduction program running since the late 1970s, shows that population-wide reduction of dietary shows that population-wide reduction of dietary salt leads to population-wide reductions in blood salt leads to population-wide reductions in blood pressure and parallel reductions in deaths from pressure and parallel reductions in deaths from stroke and heart disease.”stroke and heart disease.”

--- Professor Graham MacGregor, Chairman of WASH

Demographic Factors Influencing Demographic Factors Influencing Salt SensitivitySalt Sensitivity

Race: Blacks have been consistently shown to Race: Blacks have been consistently shown to have a greater frequency of salt sensitivity than have a greater frequency of salt sensitivity than Whites.Whites.

Age: Increasing salt sensitivity has been noted Age: Increasing salt sensitivity has been noted with increasing age. This relationship appears to with increasing age. This relationship appears to be stronger in hypertensive than in normotensive be stronger in hypertensive than in normotensive individuals. individuals.

Weinberger, M.H. Hypertension 1996, 27:481-490

Familial and Genetic FactorsFamilial and Genetic Factors

Salt sensitivity was more likely to be observed Salt sensitivity was more likely to be observed in individuals with the homozygous in individuals with the homozygous haptoglobin 1-1 genotype than in those with haptoglobin 1-1 genotype than in those with the 2-2 genotype and that individuals with the the 2-2 genotype and that individuals with the heterozygotic 2-1 genotype had responses that heterozygotic 2-1 genotype had responses that were intermediate between the other two were intermediate between the other two groups.groups.

Weinberger, M.H. Hypertension 1996, 27:481-490

Physiological Factors Associated Physiological Factors Associated with Salt Sensitivitywith Salt Sensitivity

Renal FunctionRenal Function The Renin-Angiotensin-Aldosterone SystemThe Renin-Angiotensin-Aldosterone System Atrial Natriuretic FactorAtrial Natriuretic Factor The Sympathetic Nervous SystemThe Sympathetic Nervous System Adrenergic ReceptorsAdrenergic Receptors Endothelin and Nitric OxideEndothelin and Nitric Oxide Ion TransportIon Transport InsulinInsulin

Weinberger, M.H. Hypertension 1996, 27:481-490

Deaths averted by population-level Deaths averted by population-level interventionintervention

Asaria et al. Lancet 2007; 370: 2044-53

Salt & tobacco reduction: Estimated Salt & tobacco reduction: Estimated Deaths averted/100K pop (2006-15)Deaths averted/100K pop (2006-15)

Asaria et al. Lancet 2007; 370: 2044-53 Population older than 30 yrs of age

Cost to implement the package of Cost to implement the package of interventionintervention

Asaria et al. Lancet 2007; 370: 2044-53

Key messagesKey messages

23 countries have 80% of burden of CNCD in 23 countries have 80% of burden of CNCD in LMI regions of the world.LMI regions of the world.

In these countries 13.8 m deaths could be averted In these countries 13.8 m deaths could be averted over 10 yrs (8.5 m by salt reduction and 5.5 by over 10 yrs (8.5 m by salt reduction and 5.5 by implementing FCTC)implementing FCTC)

Most deaths averted would be from CVD 975.6%) Most deaths averted would be from CVD 975.6%) followed by Resp dis (15.4%) and cancer (8.7%).followed by Resp dis (15.4%) and cancer (8.7%).

Cost to implement both strategies would be $ 0.4 Cost to implement both strategies would be $ 0.4 in LMIC and $ 0.5-1.0 in UMIC (as of 2005).in LMIC and $ 0.5-1.0 in UMIC (as of 2005).

Asaria et al. Lancet 2007; 370: 2044-53

SUMMARYSUMMARY

Across populations, the level of blood pressure, the Across populations, the level of blood pressure, the incremental rise in blood pressure with age, and the incremental rise in blood pressure with age, and the prevalence of hypertension are related to sodium intake.prevalence of hypertension are related to sodium intake.

Observational studies and RCTs document a consistent Observational studies and RCTs document a consistent effect of sodium consumption on blood pressure. Modest effect of sodium consumption on blood pressure. Modest reduction in average sodium intake (from 31 to 44 mmol/d) reduction in average sodium intake (from 31 to 44 mmol/d) decreases the percentage of prehypertension. decreases the percentage of prehypertension.

Blood pressure is also affected by many other variables, and Blood pressure is also affected by many other variables, and a reduced sodium intake is only a reduced sodium intake is only ONEONE component of component of recommended strategies to lower blood pressure.recommended strategies to lower blood pressure.

Report of the AMA Council on Science and Public HealthDickinson, B et al. Arch Intern Med 2007; 167(14):1460-1468