Potential Cognitive Benefits of Intensive Blood Pressure Lowering

Potential Cognitive Benefits of Intensive Blood Pressure Lowering

By Heather Nelson Cortes, PhD and Kevin C Maki, PhD

Currently there are no well-established clinical interventions for the prevention of mild cognitive impairment (MCI) or dementia.  Alzheimer’s disease and dementia are expected to affect 115 million people worldwide by the year 20501.  More than 75% of people over the age of 65 have hypertension, a modifiable risk factor that has been associated with the risk for developing MCI and dementia2-4.  Vascular damage is commonly found in Alzheimer’s disease, along with the β-amyloid and tau pathology5-7, yet research has been inconclusive on the role of blood pressure (BP) reduction and risk for MCI and dementia.


Recently, results from the Systolic Blood Pressure Intervention Trial (SPRINT) Memory and Cognition in Decreased Hypertension (MIND) study were published from the parent SPRINT study8.  SPRINT-MIND was designed to assess the effect of intensive blood pressure treatment/control on the risk for dementia.  The primary outcome was the occurrence of adjudicated probable dementia.  Secondary outcomes included adjudicated MCI and a composite outcome of MCI or probable dementia.


The parent SPRINT study was designed to test the effect of more intensive BP control on cardiovascular (primary end point), renal and cognitive outcomes in subjects with systolic blood pressure (SBP) greater than 130 mm Hg who had an increased cardiovascular risk but did not have diabetes or preexisting stroke9.  In SPRINT, 9361 persons were randomized to either a standard treatment (SBP goal, <140 mm Hg; n = 4683) or to an intensive treatment (SBP goal, <120 mm Hg; n = 4678).  After a median follow up of 3.26 years, SPRINT was stopped early because of the observed benefits in the primary outcome of cardiovascular disease events as well as reduced all-cause mortality9.


Of the 9361 subjects randomized in SPRINT, 91.5% (n = 8562) completed at least 1 follow-up cognitive assessment as part of SPRINT-MIND.  The median intervention period was 3.34 years with a total median follow-up of 5.11 years, including time after the intervention ended.  In the intensive treatment group, the primary outcome, adjudicated probable dementia, occurred in 149 subjects compared to 176 subjects in the standard treatment group (7.2 vs. 8.6 cases per 1000 person-years; hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.67-1.04, p = 0.10).  Intensive BP control did significantly reduce the risk of MCI (14.6 vs. 18.3 cases per 1000 person-years; HR, 0.81; 95% CI, 0.69-0.95, p = 0.007) and the combined rate of MCI or probable dementia (20.2 vs. 24.1 cases per 1000 person-years; HR, 0.85; 95% CI, 0.74-0.97, p = 0.01)8.


Comment. SPRINT-MIND did not demonstrate a statistically significant effect on the primary outcome of adjudicated probable dementia, possibly due to the early termination of SPRINT and the resulting loss of statistical power.  The study did, however, show reductions in the secondary outcomes of incident MCI (19% lower risk) and the combined outcome of MCI or probable dementia (15% lower risk).  While it is disappointing that the primary outcome showed no significant benefit (a non-significant 17% lower incidence in the intensive BP control group), the reduction in risk for the secondary outcomes is encouraging and suggests a plausible link between intensive BP treatment and prevention of MCI and dementia.  These results support the need for additional research to confirm and extend the SPRINT-MIND findings.  Because dementia and MCI have several risk factors in common with cardiometabolic diseases such as heart disease, stroke and type 2 diabetes, the SPRINT-MIND findings also suggest that there might be potential for reductions in cardiometabolic risk factors beyond BP to play a role in maintaining optimal brain health10



  1. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia:
a systematic review and meta-analysis. Alzheimers Dement. 2013;9(1):63-75.
  2. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/ NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):1269-1324.
  3. Kivipelto M, Helkala EL, Hänninen T, et al. Midlife vascular risk factors and late-life mild cognitive impairment: a population-based study. Neurology. 2001;56(12):1683-1689.
  4. Qiu C, Winblad B, Fratiglioni L. The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurol. 2005;4(8):487-499.
  5. Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007;69(24):2197-2204.
  6. HaroutunianV, Schnaider-Beeri M, Schmeidler J, et al. Role of the neuropathology of Alzheimer disease in dementia in the oldest-old. Arch Neurol. 2008;65(9):1211-1217.
  7. Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C; Medical Research Council Cognitive Function and Ageing Study. Age, neuropathology, and dementia. N Engl J Med. 2009;360(22):2302-2309.
  8. SPRINT MIND Investigators for the SPRINT Research Group, Williamson JD, Pajewski NM, et al. Effect of intensive vs. standard blood pressure control on probable dementia: a randomized clinical trial. 2019; doi:10.1001/jama.2018.21442.
  9. Wright JT Jr, Williamson JD, Whelton PK, et al; SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-2116.
  10. Santos CY, Snyder PJ, Wu WC, Zhang M, Ecehverria A, Alber J. Pathophysiologic relationship between Alzheimer’s disease, cerebrovascular disease, and cardiovascular risk: a review and synthesis. Alzheimers Dement (Amst). 2017;7:69-87.


Nurse measuring patient blood pressure

24-Hour Urinary Collection Data Support Strong Associations between Sodium and Potassium Excretion and Blood Pressure in the National Health and Nutrition Examination Survey

24-Hour Urinary Collection Data Support Strong Associations between Sodium and Potassium Excretion and Blood Pressure in the National Health and Nutrition Examination Survey

By Kristen N Smith, PhD, RD, LD; Mary R Dicklin, PhD; Kevin C Maki, PhD


It is well established that hypertension is an important modifiable risk factor for cardiovascular disease (CVD), which is a leading cause of morbidity and mortality in the United States.2 Excess dietary sodium has been associated with increased blood pressure.3-5 Conversely, higher intake of potassium has been associated with lower blood pressure.6 The ratio of sodium-to-potassium may have a stronger association with blood pressure than either of the two components alone.7

The majority of studies that have examined the above associations have used self-reported dietary measures to estimate intakes. This includes the National Health and Nutrition Examination Survey (NHANES), which has mainly utilized 24-hour dietary recalls. These tactics are fraught with limitations and may not provide a complete and accurate picture due to inaccuracies in self-led data collection and participant recall. Twenty-four-hour dietary recalls may underestimate average sodium intake by 4 to 34% in comparison with 24-hour urinary excretion.8,9

In an examination of 2014 NHANES data, researchers hypothesized that higher sodium excretion (reflecting higher intake) and a greater sodium-to-potassium ratio would be significantly associated with higher blood pressure and odds of hypertension, whereas greater potassium excretion (reflecting higher intake) would be inversely associated with blood pressure and odds of hypertension.


Cross-sectional data were gathered and analyzed from the 2014 NHANES, a nationally representative survey of noninstitutionalized persons in the United States. One half of NHANES non-pregnant participants (age 20 to 69 years) who were examined in the Mobile Examination Center were included in the 24-hour urine collection study (n=1103). Data gathered from 766 participants with complete blood pressure and 24-hour urine collections were included in the analysis with results described below.


Among the participants included in the analysis, over half were classified as hypertensive (weighted prevalence, 28.2%; 95% confidence interval [CI], 21.6-34.8) or prehypertensive (23.1%; 95% CI, 19.5-26.6). Excretion of sodium, potassium and the sodium-to-potassium ratio did not differ by hypertension status (after adjustment for age, sex, race/ethnicity and body mass index).

Sodium excretion (per 1000 mg/d higher) was directly associated with systolic blood pressure (SBP) (4.58 mm Hg; 95% CI, 2.64-6.51) and diastolic blood pressure (DBP) (2.25 mm Hg; 95% CI, 0.83-3.67). Potassium excretion (per 1000 mg/d higher) was inversely associated with SBP (-3.72 mm Hg; 95% CI -6.01 to -1.42). Molar sodium-to-potassium ratio (per 0.5 U higher) was directly associated with SBP (1.72 mm Hg; 95% CI, 0.76-2.68). In the fully adjusted multivariable logistic model, persons within the highest quartile in comparison with the lowest quartile of sodium excretion had significantly greater odds of having hypertension (odds ratio, 4.22; 95% CI, 1.36-13.15).






Beta-coefficient (95% CI)1

Sodium excretion

4.58* (2.64 to 6.51)

2.25* (0.83 to 3.67)

Potassium excretion

-3.72* (-6.01 to -1.42)

-0.25 (-1.91 to 1.42)

Sodium-to-potassium ratio

1.72* (0.76 to 2.68)

0.30 (-0.53 to 1.12)

1Beta-coefficents for sodium and potassium excretion indicate change in mm Hg of blood pressure associated with 1000 mg/d change in excretion. Beta-coefficients for the ratio represent change in mm Hg blood pressure associated with 0.5 U change in molar ratio. Fully adjusted for age, sex, race/ethnicity plus body mass index, education, history of CVD, diabetes status, chronic kidney disease, smoking status and physical activity. Models examining sodium excretion were simultaneously adjusted for potassium excretion, and vide versa.

*p < 0.01 for beta-coefficient in the regression model.


NHANES’ first ever use of the “gold standard” 24-hour urine collection identified a direct association between sodium excretion and blood pressure among US adults.1 Analyses of these cross-sectional data also demonstrated that the sodium-to-potassium ratio was directly associated with SBP, whereas potassium excretion was inversely associated with SBP. These results align with previous findings from studies examining urinary electrolyte excretion and blood pressure.10-12 These conclusions provide additional support for the 2015-2020 Dietary Guidelines for Americans containing the advice to reduce sodium intake and increase intake of potassium-containing foods compared with the current average American diet.13


  1. Jackson SL, Cogswell ME, Zhao L, et al. Association between urinary sodium and potassium excretion and blood pressure among adults in the United States: National Health and Nutrition Examination Survey, 2014. Circulation. 2018;137(3):237-246.
  2. Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart disease and stroke statistics-2017 update: A report from the American Heart Association. Circulation. 2017;135(10):e146-e603.
  3. Medicine Io. Sodium and Chloride. Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate. Washington, DC: The National Academies Press 2005.
  4. Cook NR, Cutler JA, Obarzanek E, et al. Long term effects of dietary sodium reduction on cardiovascular disease outcomes: observational follow-up of the trials of hypertension prevention (TOHP). BMJ. 2007;334(7599):885-888.
  5. He FJ, MacGregor GA. A comprehensive review on salt and health and current experience of worldwide salt reduction programmes. J Hum Hypertens. 2009;23(6):363-384.
  6. Aburto NJ, Hanson S, Gutierrez H, Hooper L, Elliott P, Cappuccio FP. Effect of increased potassium intake on cardiovascular risk factors and disease: systematic review and meta-analyses. BMJ. 2013;346:f1378.
  7. Perez V, Chang ET. Sodium-to-potassium ratio and blood pressure, hypertension, and related factors. Adv Nutr. 2014;5(6):712-741.
  8. Freedman LS, Commins JM, Moler JE, et al. Pooled results from 5 validation studies of dietary self-report instruments using recovery biomarkers for potassium and sodium intake. Am J Epidemiol. 2015;181(7):473-487.
  9. Espeland MA, Kumanyika S, Wilson AC, et al. Statistical issues in analyzing 24-hour dietary recall and 24-hour urine collection data for sodium and potassium intakes. Am J Epidemiol. 2001;153(10):996-1006.
  10. Liu L, Ikeda K, Yamori Y. Twenty-four hour urinary sodium and 3-methylhistidine excretion in relation to blood pressure in Chinese: results from the China-Japan cooperative research for the WHO-CARDIAC Study. Hypertens Res. 2000;23(2):151-157.
  11. Hedayati SS, Minhajuddin AT, Ijaz A, et al. Association of urinary sodium/potassium ratio with blood pressure: sex and racial differences. Clin J Am Soc Nephrol. 2012;7(2):315-322.
  12. Mente A, O'Donnell MJ, Rangarajan S, et al. Association of urinary sodium and potassium excretion with blood pressure. N Engl J Med. 2014;371(7):601-611.
  13. U.S. Depart of Health and Human Services and U.S. Department of Agriculture. 2015 - 2020 Dietary Guidelines for Americans. 8th Edition. December 2015. Available at https://health.gov/dietaryguidelines/2015/guidelines.



Mendelian Randomization – Nature’s Clinical Trial – is Providing New Insights About the Causes and Potential Treatments for Cardiometabolic Diseases

Mendelian Randomization

Mendelian Randomization – Nature’s Clinical Trial – is Providing New Insights About the Causes and Potential Treatments for Cardiometabolic Diseases

By Kevin C. Maki, PhD

In a recent issue of JAMA Cardiology, Lyall and colleagues1 report that a score based on 97 genetic variants related to body mass index (BMI) was associated with increased risks for hypertension [odds ratio (OR) per 1-SD higher genetically-driven BMI of 1.64, 95% confidence interval (CI) 1.48-1.83], type 2 diabetes mellitus (OR 2.53; 95% CI 2.04-3.13) and coronary heart disease (CHD; OR 1.35; 95% CI 1.09-1.69).  Notably, the genetic BMI score was not associated with stroke risk.

Because the genetic score provides a measure of exposure over a lifetime to genetic variants that increase BMI, it is a relatively unconfounded marker that is less likely to be influenced by reverse causality than BMI itself.  Genotypes are assigned randomly when passed from parents to offspring during meiosis.2 The population genotype distribution should therefore be unrelated to the distribution of confounding variables.2  Accordingly, Mendelian randomization can be thought of as experiments of nature, similar to what is accomplished through randomization in a clinical trial.  The new results from Lyall et al.1 add evidence to support a causal relationship between increased BMI and cardiometabolic diseases.

Results reported in another recent paper by Dale and colleagues3 using Mendelian randomization also suggest causal roles for abdominal (waist-hip ratio adjusted for BMI; WHRadjBMI) and total adiposity (BMI) regarding risks for CHD and type 2 diabetes mellitus.  Each 1-SD higher WHRadjBMI (about 0.08 U) was associated with an excess risk of CHD (OR 1.48; 95% CI 1.28-1.71), similar to findings for BMI (SD about 4.6 kg/m2; OR 1.36; 95% CI, 1.22-1.52). WHRadjBMI, but not BMI, was associated with higher risk of ischemic stroke (OR 1.32; 95% CI, 1.03-1.70).  For type 2 diabetes mellitus, both variables had significant associations: OR 1.82 (95% CI 1.38-2.42) per 1-SD higher WHRadjBMI and OR 1.98 (95% CI 1.41-2.78) per 1-SD higher BMI.  These results are consistent with those reported by Lyall et al.1

Prior studies using Mendelian randomization have provided evidence for and against causality for several potentially modifiable risk factors for cardiometabolic diseases.  Evidence for causality has been provided for various lipoprotein-related variables and risks for atherosclerotic cardiovascular disease, including:4

  • Low-density lipoprotein cholesterol;
  • Triglycerides and triglyceride-rich lipoprotein cholesterol;
  • Lipoprotein (a).

Evidence against direct causality has been produced through Mendelian randomization for:4

  • High-density lipoprotein cholesterol;
  • C-reactive protein.

However, it should be noted that for high-density lipoprotein cholesterol and C-reactive protein, lack of association should not be interpreted to mean that these are not important risk indicators, only that the levels of these variables likely reflect other processes that are more directly involved in causal pathways.

The real promise of Mendelian randomization is to identify novel, modifiable targets for which new therapies can be developed.  This process was nicely illustrated by the identification of proprotein convertase subtilisin kexin type 9 (PCSK9) variants as predictors of CHD risk5, which ultimately led to the development of a new class of pharmaceuticals, the PCSK9 inhibitors.6


  1. Lyall DM, Celis-Morales C, Ward J, et al. Association of body mass index with cardiometabolic disease in the UK Biobank: a Mendelian randomization study. JAMA Cardiol. July 5, 2017 [Epub ahead of print].
  2. Thanassoulis G, O’Donnell CJ. Mendelian randomization: nature’s randomized trial in the post-genome era. JAMA. 2009;301:2386-2387.
  3. Dale CE, Fatemifar G, Palmer TM, et al. Causal associations of adiposity and body fat distribution with coronary heart disease, stroke subtypes, and type 2 diabetes mellitus: a Mendelian randomization study. Circulation. 2017;135:2373-2388.
  4. Lacey B, Herrington WH, Preiss D, Lewington S, Armitage J. The role of emerging risk factors in cardiovascular outcomes. Curr Atheroscler Rep. 2017;19:28.
  5. Cohen JC, Boerwinkle E, Mosley TH, Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264-1272.
  6. Durairaj A, Sabates A, Nieves J, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and its inhibitors: a review of physiology, biology, and clinical data. Curr Treat Options Cardio Med. 2017;19:58.
Mendelian Randomization

Results From a Systematic Review and Network Meta-Analysis Suggest that Lower Systolic Blood Pressure Targets Are More Effective for Reducing Risks for Cardiovascular Disease Events and Mortality

Reducing Risks for Cardiovascular Disease Events

Results From a Systematic Review and Network Meta-Analysis Suggest that Lower Systolic Blood Pressure Targets Are More Effective for Reducing Risks for Cardiovascular Disease Events and Mortality

Clinical trials have documented that lowering blood pressure reduces cardiovascular disease (CVD) and early death.1 However, the optimal target(s) for reduction of systolic blood pressure (SBP) are uncertain.1-4 Scientists from Tulane University School of Public Health and Tropical Medicine and the School of Medicine, along with scientists from the Medical College of Soochow University, China, conducted a systematic review and meta-analysis to assess the association of mean achieved SBP levels with the risk of CVD and all-cause mortality in adults with hypertension treated with antihypertensive therapy.5 From a MEDLINE and EMBASE search of articles through December 2015, Dr. Joshua Bundy and his colleagues identified 42 clinical trials of 144,200 patients that met their pre-defined criteria of random allocation to an antihypertensive medication, control, or treatment target that reported a difference in mean achieved SBP of 5 mm Hg or more between the groups compared.  The results showed that there was a linear association between mean achieved SBP and risks of CVD and mortality.  An achieved SBP of 120-124 mm Hg had the lowest risk.  Subjects in this lowest category had a hazard ratio (HR) of 0.82 (95% confidence interval [CI] 0.67-0.97) compared to subjects with even slightly higher SBP of 125-129 mm Hg, and this continued linearly through all of the 5 mm SBP cutpoints up to the comparison with the highest level of SBP ≥160 mm Hg, for which the HR for SBP of 120-124 mm Hg was 0.36 (95% CI 0.26-0.51). Similarly, subjects with an achieved SBP of 120-124 mm Hg had a HR for all-cause mortality of 0.74 (95% CI 0.57-0.97) compared with subjects in the 125-129 mm Hg category, and the benefit to all-cause mortality continued to as much as 0.47 (95% CI 0.32-0.67) when compared to subjects with SBP ≥160 mm Hg.


The 2003 7th Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of Blood Pressure recommended SBP goals of <130 mm Hg for patients with type 2 diabetes or chronic kidney disease and <140 mm Hg for individuals at least 60 years of age.1  The 8th Report of the Joint Committee released in 2014, raised these treatment targets to <140 and <150 mm Hg, respectively.2  The investigators of the Systolic Blood Pressure Intervention Trial (SPRINT) examined the association with CVD and all-cause mortality risks of the more intensive treatment goal (SBP <120 mm Hg) compared to <140 mm Hg among men and women with hypertension and at high CVD risk (but without diabetes or stroke).3  The mean achieved SBP was 121.5 mm Hg in the intensive-treatment group and 134.6 mmHg in the standard-treatment group. During a median follow-up of 3.3 years, a 25% reduction in the primary composite outcome of CVD events (HR, 0.75; 95% CI, 0.64-0.89; P < .001) and a 27% reduction in all-cause mortality (HR, 0.73; 95% CI, 0.60-0.90; P = .003) were observed.  However, some were concerned that those results were not necessarily generalizable for a variety of reasons.

Current guidelines provide inconsistent recommendations regarding the optimal SBP target, particularly in older adults.  Earlier this year, the American College of Physicians and the American Academy of Family Physicians released their joint guideline with evidence-based  recommendations on the benefits and harms of higher (<150 mm Hg) versus lower (≤140 mm Hg) SBP targets for hypertension in adults at least 60 years of age.4  They reported that mortality, incidence of stroke, and cardiac events were all reduced with the lower SBP target, but that treating to a lower target did not further reduce mortality, quality of life, or functional status in the target patient population.  They also reported increased withdrawals due to adverse events, as well as increased cough, hypotension, and risk of syncope with treating to the lower vs. higher SBP targets.  A report from the panel appointed to the Eighth Joint National Committee, recommended a SBP treatment target of 150 mm Hg for adults aged 60 years or older.2

On the other hand, in an analysis6 of data from 2636 SPRINT participants who were ≥75 years of age (mean age, 79.9 years; 37.9% women), at a median follow-up of 3.1 years, there were significantly lower rates of the primary composite outcome, HR = 0.66 (95%CI, 0.51-0.85) and all-cause mortality HR = 0.67 (95%CI, 0.49-0.91). The overall rate of serious adverse events was not different between treatment groups (48.4% in the intensive treatment group vs 48.3% in the standard ≥treatment group.

The multiple sets of hypertension guidelines and recommendations create confusion about the most appropriate blood pressure targets for patients with hypertension.  The results from the meta-analysis by Bundy et al.5 support the interpretation of the SPRINT investigators that a lower target is associated with reduced CVD and mortality risk.  Results from the subgroup analysis from SPRINT of elderly participants with a mean age of nearly 80 years suggest that a lower SBP target may produce benefits without unacceptable adverse effects even at advanced ages.  These findings suggest that reassessment of the body of evidence for the currently recommended SBP targets may be warranted.



  1. Chobanian AV, Bakris GL, Black HR, et al. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206-1252.


  1. James PA, Oparil S, Carter BL, et al. 2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520.


  1. Wright JT, Jr., Williamson JD, Whelton PK, et al.; SPRINT Research Group. A randomized trial of intensive versus standardized blood-pressure control. N Engl J Med. 2015;373:2103-2116.


  1. Qaseem A, Wilt Tj, Rich R, et al.; Clinical Guidelines Committee of the American College of Physicians and the Commission on Health of the Public and Science of the American Academy of Family Physicians. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: A clinical practice guidelines from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2017;166:430-437.


  1. Bundy JD, Li C, Stuchlik P, Bu X, et al. Systolic blood pressure reduction and risk of cardiovascular disease and mortality: a systematic review and network meta-analysis. JAMA Cardiol. 2017; May 31, 2017 [Epub ahead of print].


  1. Williamson JD; Supiano MA, Applegate WB et al. Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged ≥75 Years. A Randomized Clinical Trial. JAMA. 2016;315:2673-2682.



Reducing Risks for Cardiovascular Disease Events