increased heart rate and increased dementia risk??

 A recent long-term Swedish study found that increased resting heart rate was associated with cognitive decline and dementia in older adults (see dementia inc heart rate AlzDem2021 in dropbox, or DOI: 10.1002/alz.12495) 

  

Details:  

-- 2147 people at least 60yo in the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) who were initially free from dementia and regularly followed from baseline at 2001-4 until 2013-16, with follow-up exams conducted every 6  years for the younger cohort (age 60, 66, and 72) and every three years for the older cohort (age 78, 81, 84, 87, 90, 93, 96, and 99 years) 

-- mean age 71, 62% female, 12% elementary school education/48% high school/80% university 

-- 44% never smoker/40% former smoker/16% current smoker; light physical activity (walking, biking, light aerobics) every day 38%, several times per week 40%, a few times per month 12%, less frequent 6%, none 5%) 

-- use of beta blockers 19%, use of calcium blockers 2%, digoxin 1% 

-- baseline MMSE score 29,APOE e4 allele carrier 29% 

-- resting heart rate (RHR) was assessed by electrocardiogram at baseline; dementia diagnosis was by using the DSM-IV revised criteria, and global cognitive function assessed by the Mini-Mental State Examination (MMSE), both done at each follow-up visit 

-- there were 3 statistical models used to adjust for potential confounders: model 1 was age, sex, and education; model 2 was further adjusted for smoking, physical activity, and BMI; and model 3 added total cholesterol, hypertension, diabetes, use of beta blockers, verapamil or diltiazem, digoxin, APOE genotype, and prevalent cardiovascular diseases (CVDs: heart failure, ischemic heart disease, atrial fibrillation, and cerebrovascular disease) 

-- endpoints: relationship of higher RHR with dementia and cognitive decline 

  

Results: 

-- during 19,344 person-years of follow-up (median of 11.4 years per person), 289 participants were diagnosed with dementia  (incidence was 14.9 per 1000 person years) 

 

-- dementia, comparing RHR at least 80 bpm with 60-69 bpm: 55% more likely, fully adjusted hazard ratio 1.55 (1.06-2.27) 

        -- fully adjusted HR 1.13 (1.02-1.26) for each 10 bpm increment in pulse 

    -- excluding patients with prevalent cardiovascular disease (ie excluding those known to be at the highest risk for dementia): 

        -- comparing RHR at least 80 with 60-69 bpm: 73% more likely, fully adjusted hazard ratio 1.73 (1.11-2.69) 

            -- fully adjusted HR 1.16 (1.02-1.31) for each 10 bpm increment in pulse 

    -- excluding patients with prevalent and incident cardiovascular disease (ie leaving those at much lower risk): 

        -- comparing RHR at least 80 with 60-69 bpm: twice as likely, fully adjusted hazard ratio 2.13 (1.17-3.88) 

            -- fully adjusted HR 1.27 (1.06-1.52) for each 10 bpm increment in pulse 

    -- overall, there was no evidence of interactions of rapid heart rate, age, sex heart failure, atrial fibrillation, ischemic heart disease, cerebrovascular disease, or APOE genotype (all interactions had a p>0.10, i.e. not close to being statistically significant) 

  

-- cognitive decline, RHR >70-79 was associated with a greater decline in MMSE score than those with a heart rate of 60-69. 

    -- This relationship remained significant even after excluding prevalent CVD at baseline or incident CVDs developed during the follow-up. 

  

-- In further analyses, there was no statistically significant increased risk for dementia in those with a pulse <50 in the fully adjusted analysis. And there were not enough people with pulses of 90 or above to have a meaningful outcome. 

    -- In terms of cognitive decline: those with pulses >90 or <50 did not have an associated greater cognitive decline compared those in the 60-69 range 

  

Commentary: 

-- the global incidence of dementia has increased rapidly, from 43.8 million people in 2016 to an estimated 131 million by 2051, with 68% in low- and middle-income countries 

-- there is no effective cure of dementia at this point, resulting in a huge burden (personal, financial, occupational, social and often all-consuming) on individual patients, their families and friends, and society. 

    -- There actually are some interventions which seem to help: eg a healthy diet, exercise, and social engagement helps (see http://gmodestmedblogs.blogspot.com/2015/12/lifestyle-interventions-and-cognition.html ). and, of course, most importantly, high chocolate intake helps cognitive function (http://gmodestmedblogs.blogspot.com/2014/07/chocolate-and-cognitive-function-etc.html )... 

    -- and, I should add, there was a new medication approved by the FDA, aducanumab, though this was done without any studies showing real clinical benefit and has a remarkably high price tag (see http://gmodestmedblogs.blogspot.com/2021/07/fda-review-of-new-alzheimer-drug.html ) 

        -- by the way, this unproven medication is likely to deplete both Medicare and state Medicaid programs coffers by its huge price tag of $56,000 per year per patient (see alzhemer aducanumab destroying medicare medicaid nejm2021, or DOI: 10.1056/NEJMp2115297). Medicaid covers nearly all drugs approved by the FDA, so this one may be a budget-breaker, limiting services available for actually proven, important interventions: see https://www.statnews.com/2021/10/12/new-alzheimers-drug-threatens-state-medicaid-budgets/ 

  

-- This study was unique in that it followed a broad-based general population, controlled for cardiovascular risk factors (given that many of these themselves are associated with dementia), controlled further for prevalent and incident cardiovascular disease (i.e., those patients are particularly high risk, since they have manifest disease), and still found a significant increased association between higher resting heart rates and dementia. In addition, those with resting heart rates above 70 bpm had a faster decline in general cognitive function as measured by the MMSE, than those with a rate of 60-69 

    -- interestingly, it seemed that those with the lowest cardiovascular risk (by excluding those with prevalent or incident CVD) actually had a higher risk of dementia than those at higher cardiovasc risk 

-- there have been 3 other prospective cohort studies, mostly finding that increased heart rates above 80, versus <60, were associated with more dementia and steeper cognitive decline, though the Women’s Health Initiative did not (though their lowest tertile for blood pressure, the basis for comparison, was 51-66 bpm and may well have included people with significant conduction system disease as a result of cardiac disease) 

-- increased RHR is also associated with increased mortality independent of cognitive decline, which may lead to an under-estimation of the role of RHR in dementia because of the likelihood of an earlier death 

 

-- in terms of potential mechanisms to explain an association between higher heart rates and cognitive decline: 

    -- increased RHR is associated with many cardiovascular events, including heart failure, atrial fibrillation, and potentially ischemic heart disease, which are all risk factors for dementia. So, perhaps there is reverse causation: heart disease itself (which seems to be associated with cognitive decline) may be associated with the tachyarrhythmias

    -- increased sympathetic tone may be the cause of increased RHR and increased cognitive decline: 

            -- increased sympathetic tone is associated with hypertension, diabetes, obesity, and lack of exercise. Imbalance between sympathetic and parasympathetic tones, as seen in some autonomic neuropathies (eg, the diabetic autoneuropathy, which manifests itself initially as tachycardia because of decreased parasympathetic tone) may lead to increased RHR. But autonomic neuropathy itself is associated with mortality and cardiovascular events as well as worse cognitive performance, independent of cardiovascular risk factors 

    -- atherosclerotic disease itself may be associated with cerebral hypoperfusion, microembolism, and cerebrovascular damage 

    -- an increased RHR could also be associated with endothelial dysfunction and arterial stiffness, perhaps through pulsatile stress and shear stress on the arterial walls. perhaps cognitive decline may be associated with cerebral small vessel diseases damage augmented by pulse pressure. 

  

-- The study raises several interesting questions: is there a clinical benefit to using beta blockers in patients who have a heart rate greater than 80? What about the role of exercise or yoga in lowering heart rate? What about those who have atrial fibrillation: should the target pulse be less than 80? 

  

Limitations: 

-- MMSE, though a useful assessment of global cognitive function, does have some limitations: there is a ceiling effect (there may not be much change in the score until there is significant cognitive dysfunction), a learning curve (seems to get better repeated use), and lack of sensitivity to subtle cognitive changes  

-- when the EKGs were done, there was no restriction on coffee or smoking or other food intake prior to the exam, which might have affected the resting heart rate. In addition, there were not serial assessments of the EKG to see if the resting heart rate assessments were stable. And, perhaps some of the participants may have developed atrial fibrillation, undetected, which might have increased cognitive decline through cerebral microemboli?? 

--some measures, such as physical activity, were assessed through a self-administered questionnaire and may not be totally accurate; diagnoses of hypertension, diabetes, and CVDs were based on information from self-report, clinical, laboratory data, medications, and registers from the Swedish National Patient Register)  

-- also, they only measured total cholesterol levels, with no measurement of either LDL or HDL levels. So, the combination of inadequate measurement of physical activity as well as of lipid-related risk does undercut their conclusion that they controlled for cardiovascular risk factors (which have been shown to be important risk factors for cognitive decline)  

  -- and they did not measure of statin use or other meds that might have helped or hurt cognitive decline  

      -- we do accept the standard cardiovasc risk factors as being likely causative of dementia. But is this true or are they just surrogate markers for the real culprits?? Is it hypertension or the effects of excess salt, or deficiencies of potassium that leads to hypertension and dementia? Or chronic stress leading to both hypertension and cognitive decline? Is it dyslipidemia or just an unhealthy diet leading to dementia? Maybe the anti-inflammatory effects of a good diet or exercise are the real culprits leading to dementia? A Mediterranean diet, for example, is anti-inflammatory (and helps the lipids) but prevents diabetes, atrial fibrillation, and seems to improve brain architecture and decreases dementia/cognitive decline (see http://gmodestmedblogs.blogspot.com/2015/11/mediterranean-diet-and-brain-volume.html ). 

      -- and, of interest in this Swedish study, there was a higher risk of dementia in those with likely lower levels of the standard cardiac risk factors, since eliminating those with either prevalent or incident heart disease was associated with a higher hazard ratio than in the overall group (even looking at the less-adjusted models they had, those not controlling for the cardiovasc risk factors, found a higher HR by eliminating those with more severe heart disease) 

-- the study was done in one country, and results may not be generalizable to other areas of the world, with different customs, eating patterns, demographics, social support systems, etc.  

  

So, this study with its long follow-up time, reached the conclusion that elevated resting heart rates may be associated with increased cognitive decline and dementia, but this does raise a few questions:  

-- should we treat those with higher RHR differently? More aggressive cardiovascular risk reduction? Should we push for more exercise, healthier diets, better social supports (eg adult day health in the elderly). And, even if these cardiac risk factors are a surrogate for other causes of cognitive decline, improving them through diet or exercise or stopping smoking may still be important 

-- is there are role for beta-blockers, diltiazem, verapamil in lowering heart rate to decrease cognitive decline?? 

--should we set a lower heart rate goal for those with atrial fibrillation?  

geoff

 

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