Aortic stiffness increases with age and vascular risk factor exposure and is associated with increased risk for structural and functional abnormalities in the brain. High ambient flow and low ...impedance are thought to sensitize the cerebral microcirculation to harmful effects of excessive pressure and flow pulsatility. However, haemodynamic mechanisms contributing to structural brain lesions and cognitive impairment in the presence of high aortic stiffness remain unclear. We hypothesized that disproportionate stiffening of the proximal aorta as compared with the carotid arteries reduces wave reflection at this important interface and thereby facilitates transmission of excessive pulsatile energy into the cerebral microcirculation, leading to microvascular damage and impaired function. To assess this hypothesis, we evaluated carotid pressure and flow, carotid-femoral pulse wave velocity, brain magnetic resonance images and cognitive scores in participants in the community-based Age, Gene/Environment Susceptibility - Reykjavik study who had no history of stroke, transient ischaemic attack or dementia (n = 668, 378 females, 69-93 years of age). Aortic characteristic impedance was assessed in a random subset (n = 422) and the reflection coefficient at the aorta-carotid interface was computed. Carotid flow pulsatility index was negatively related to the aorta-carotid reflection coefficient (R = −0.66, P<0.001). Carotid pulse pressure, pulsatility index and carotid-femoral pulse wave velocity were each associated with increased risk for silent subcortical infarcts (hazard ratios of 1.62-1.71 per standard deviation, P<0.002). Carotid-femoral pulse wave velocity was associated with higher white matter hyperintensity volume (0.108 ± 0.045 SD/SD, P = 0.018). Pulsatility index was associated with lower whole brain (−0.127 ± 0.037 SD/SD, P<0.001), grey matter (−0.079 ± 0.038 SD/SD, P = 0.038) and white matter (−0.128 ± 0.039 SD/SD, P<0.001) volumes. Carotid-femoral pulse wave velocity (−0.095 ± 0.043 SD/SD, P = 0.028) and carotid pulse pressure (−0.114 ± 0.045 SD/SD, P = 0.013) were associated with lower memory scores. Pulsatility index was associated with lower memory scores (−0.165 ± 0.039 SD/SD, P<0.001), slower processing speed (−0.118 ± 0.033 SD/SD, P<0.001) and worse performance on tests assessing executive function (−0.155 ± 0.041 SD/SD, P<0.001). When magnetic resonance imaging measures (grey and white matter volumes, white matter hyperintensity volumes and prevalent subcortical infarcts) were included in cognitive models, haemodynamic associations were attenuated or no longer significant, consistent with the hypothesis that increased aortic stiffness and excessive flow pulsatility damage the microcirculation, leading to quantifiable tissue damage and reduced cognitive performance. Marked stiffening of the aorta is associated with reduced wave reflection at the interface between carotid and aorta, transmission of excessive flow pulsatility into the brain, microvascular structural brain damage and lower scores in various cognitive domains.
Aortic stiffening increases the transfers of high pressure and flow pulsatility to small cerebral vessels potentially causing the accumulation of vascular brain injury. Our aim was to investigate the ...prospective association of aortic stiffness with the risks of incident mild cognitive impairment and dementia.
We studied 1101 dementia-free Framingham Offspring study participants (mean age, 69±6 years; 54% women). Aortic stiffness was measured as carotid-femoral pulse wave velocity using applanation tonometry and modeled as a linear variable and the top 2 quintiles (>11.4 m/s). Outcomes were the 10-year risk of incident mild cognitive impairment and dementia, including clinically characterized Alzheimer disease. We observed 106, 77, and 59 events of mild cognitive impairment, all-cause dementia, and clinical Alzheimer disease, respectively.
After adjustment for age and sex, higher continuous aortic stiffness predicted an increased risk of mild cognitive impairment (hazard ratio, 1.40 95% confidence interval, 1.13-1.73), all-cause dementia (hazard ratio, 1.45 95% confidence interval, 1.13-1.87), and Alzheimer disease (hazard ratio, 1.41 95% confidence interval, 1.06-1.87). In risk factor-adjusted statistical models, aortic stiffness remained a significant predictor of mild cognitive impairment but not incident dementia. In nondiabetic patients, the top 2 quintiles of aortic stiffness were associated with a higher risk of incident all-cause dementia across all statistical models.
Aortic stiffness was an independent predictor of incident mild cognitive impairment in the whole sample and with incident dementia in nondiabetic patients. Our findings suggest aortic stiffness as a potentially modifiable risk factor for clinical cognitive impairment and dementia.
Arterial stiffness increases with age and is associated with an increased risk of adverse outcomes on short-term follow-up (typically <10 years). Data regarding associations of arterial stiffness ...with health outcomes on longer-term follow-up are lacking.
We evaluated 7283 Framingham Study participants (mean age 50 years, 53% women) who underwent assessment of carotid-femoral pulse wave velocity (a marker of arterial stiffness) via applanation tonometry at one or more routine examinations. We used time-dependent Cox proportional hazards regression models to relate carotid-femoral pulse wave velocity to the incidence of health outcomes (updating carotid-femoral pulse wave velocity and all covariates at serial examinations).
On long-term follow-up (median 15 years; minimum-maximum, 0-20), participants developed cardiometabolic disease (hypertension 1255 events; diabetes 381 events), chronic kidney disease (529 events), dementia (235 events), cardiovascular disease (684 events) and its components (coronary heart disease 314 events, heart failure 191 events, transient ischemic attacks or stroke 250 events), and death (1086 events). In multivariable-adjusted models, each SD increment in carotid-femoral pulse wave velocity was associated with increased risk of hypertension (hazard ratio HR, 1.32 95% CI, 1.21-1.44), diabetes (HR, 1.32 95% CI, 1.11-1.58), chronic kidney disease (1.19 95% CI, 1.05-1.34), dementia (HR 1.27 95% CI, 1.06-1.53), cardiovascular disease (HR, 1.20 95% CI, 1.06-1.36) and its components (coronary heart disease, HR 1.37 95% CI, 1.13-1.65; transient ischemic attack/stroke, HR, 1.24 95% CI, 1.00-1.53), and death (HR, 1.29 95% CI, 1.17-1.43). The association with heart failure was borderline nonsignificant (HR, 1.21 95% CI, 0.98-1.51,
=0.08).
Our prospective observations of a large community-based sample establish the long-term prognostic importance of arterial stiffness for multiple health outcomes.
Orthostatic hypotension (OH) and hypertension (OHT) are aberrant blood pressure (BP) regulation conditions associated with higher cardiovascular disease risk. The relations of OH and OHT with heart ...failure (HF) risk in the community are unclear and there remains a paucity of data on the relations with HF subtypes HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF).
Relate OH and OHT with HF risk and its subtypes.
Prospective observational cohort.
Community-based individuals in the Framingham Heart Study Original Cohort.
1,914 participants (mean age 72 years; 1159 women) attending examination cycle 17 (1981-1984) followed until December 31, 2017 for incident HF or death.
OH or OHT, defined as a decrease or increase, respectively, of ≥20/10 mmHg in systolic/diastolic BP upon standing from supine position.
At baseline, 1,241 participants had a normal BP response (749 women), 274 had OH (181 women), and 399 had OHT (229 women). Using Cox proportional hazards regression models, we related OH and OHT to risk of HF, HFrEF, and HFpEF compared to the absence of OH and OHT (reference), adjusting for age, sex, body mass index, systolic and diastolic BP, hypertension treatment, smoking, diabetes, and total cholesterol/high-density lipoprotein.
On follow-up (median 13 years) we observed 492 HF events (292 in women; 134 HFrEF, 116 HFpEF, 242 HF indeterminate EF). Compared to the referent, participants with OH n = 84/274 (31%) HF events had a higher HF risk (Hazards Ratio HR 1.47, 95% CI 1.13-1.91). Moreover, OH was associated with a higher HFrEF risk (HR 2.21, 95% CI 1.34-3.67). OHT was not associated with HF risk.
Orthostatic BP response may serve as an early marker of HF risk. Findings suggest shared pathophysiology of BP regulation and HF, including HFrEF.
We investigated the temporal causal longitudinal associations of carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, and carotid intima-media thickness (cIMT) progression ...with the risk of dysglycemia, insulin resistance, and dyslipidemia.
We included 3862, 17.7-year-old, participants from the Avon Longitudinal Study of Parents and Children, followed up for 7 years. cfPWV, cIMT, and fasting plasma samples were repeatedly measured. We computed homeostatic model assessment (HOMA) of insulin resistance and percent pancreatic beta-cell function. Data were analyzed using logistic regression, linear mixed-effect, and cross-lagged structural equation models.
A higher cfPWV at 17.7 years was associated with higher insulin at age 24.5 years (odds ratio, 1.25 CI, 1.08-1.44;
=0.003), which slightly attenuated after covariates adjustment. Higher cIMT at 17.7 years was associated with lower insulin (odds ratio, 0.06 0.01-0.95;
=0.046) at 24.5 years, after covariate adjustments. In mixed-effect models, the 7-year progression in cfPWV (predictor) was directly associated with the increase in triglyceride (outcome). cIMT progression was associated with the 7-year increase in LDL (low-density lipoprotein), triglyceride, and glucose. In cross-lagged models, higher cfPWV at 17.7 years was associated with higher insulin (
=0.06, SE, 0.12,
=0.014), HOMA of insulin resistance, and HOMA-percent pancreatic beta-cell function at 24.5 years. However, insulin, HOMA of insulin resistance, and HOMA-percent pancreatic beta-cell function at 17.7 years were not associated with cfPWV at 24.5 years. Higher cIMT at 17.7 years was associated with reduced insulin, HOMA of insulin resistance, and HOMA-percent pancreatic beta-cell function at 24.5 years, but not vice versa. Higher glucose at 17.7 years was associated with higher cfPWV and cIMT at 24.5 years only.
Arterial stiffness in adolescence may be a causal risk factor for hyperinsulinemia and insulin resistance in young adulthood.
Heart failure (HF) is a heterogeneous clinical syndrome with varying prognosis. Subphenotyping of HF is a research priority to advance our understanding of the syndrome. We formulated a ...subphenotyping schema and compared long-term mortality risk among the HF subphenotypes in the community-based Framingham Study.
In hierarchical order, we grouped participants with new-onset HF (stratified by HF with reduced HFrEF vs. preserved ejection fraction HFpEF) according to the presence of: (1) coronary heart disease (CHD), (2) metabolic syndrome (MetS), (3) hypertension, and (4) 'other' causes. Age at HF onset was lowest in people with the MetS (mean 76 vs. 77 years for HFrEF and HFpEF, respectively) and highest in those with hypertension only (mean 82 and 85 years for HFrEF and HFpEF, respectively). For HFrEF, 10-year cumulative mortality and hazards ratios HR were 87% for CHD (n = 219; referent group), 88% for MetS (n = 105; HR 0.95 95% CI 0.73-1.23), 82% for hypertension (n = 104; HR 0.71 0.55-0.91), and 78% for other (n = 37; HR 0.81 0.55-1.19). Corresponding 10-year cumulative mortality and HR data for HFpEF were: 85% for CHD (n = 84; referent), 83% for MetS (n = 118; HR 0.98 0.72-1.33), 81% for hypertension (n = 127; HR 0.71 0.52-0.95), and 76% for other (n = 43; HR 0.76 0.50-1.14). In a sample without overt heart failure (n = 5536), several echocardiographic and vascular indices showed graded worsening of age- and sex adjusted-values among those having CHD, MetS, hypertension, or obesity, compared with individuals not having these risk factors.
HF subphenotypes characterized by the presence of CHD or metabolic syndrome present at a younger age and are marked by greater mortality risk. The clinical utility of the proposed subphenotyping schema warrants further research.
Summary
Arterial stiffness and excessive pressure pulsatility have emerged as important risk factors for cardiovascular disease. Arterial stiffness increases with age and in the presence of ...traditional cardiovascular disease risk factors, such as hypertension, diabetes and lipid disorders. Pathologic stiffening of large arteries with advancing age and risk factor exposure predominantly involves the elastic aorta and carotid arteries, whereas stiffness changes are relatively limited in muscular arteries. Aortic stiffening is associated with increased pulse wave velocity and pulse pressure, which are related but distinct measures of the pulsatile energy content of the pressure waveform. A dramatic increase in pulsatile energy content of pressure and flow waves in the arterial system places considerable pulsatile stress on the heart, large arteries and distal circulation. Large artery stiffening is associated with abnormalities in microvascular structure and function that may contribute to tissue damage, particularly in susceptible high flow organs such as the brain and kidneys. This brief review summarizes results of recent research on risk factors for and adverse effects of large artery stiffening.
To determine the association of arterial stiffness and pressure pulsatility, which can damage small vessels in the brain, with vascular and Alzheimer-type brain aging.
Stroke- and dementia-free ...Framingham Offspring Study participants (n = 1,587, 61 ± 9 years, 45% male) underwent study of tonometric arterial stiffness and endothelial function (1998-2001) and brain MRI and cognition (1999-2002). We related carotid-femoral pulse wave velocity (CFPWV), mean arterial and central pulse pressure, and endothelial function to vascular brain aging by MRI (total cerebral brain volume TCBV, white matter hyperintensity volume, silent cerebral infarcts) and vascular and Alzheimer-type cognitive aging (Trails B minus Trails A and logical memory-delayed recall, respectively).
Higher CFPWV was associated with lower TCBV, greater white matter hyperintensity volume, and greater prevalence of silent cerebral infarcts (all p < 0.05). Each SD greater CFPWV was associated with lower TCBV equivalent to 1.2 years of brain aging. Mean arterial and central pulse pressure were associated with greater white matter hyperintensity volume (p = 0.005) and lower TCBV (p = 0.02), respectively, and worse verbal memory (both p < 0.05). Associations of tonometry variables with TCBV and white matter hyperintensity volume were stronger among those aged 65 years and older vs those younger than 65 years (p < 0.10 for interaction). Brachial artery endothelial function was unrelated to MRI measures (all p > 0.05).
Greater arterial stiffness and pressure pulsatility are associated with brain aging, MRI vascular insults, and memory deficits typically seen in Alzheimer dementia. Future investigations are warranted to evaluate the potential impact of prevention and treatment of unfavorable arterial hemodynamics on neurocognitive outcomes.
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