Carotid Artery Stiffness Mechanisms Are Associated With End Organ Damage and All-Cause Mortality: MESA (Multi-Ethnic Study of Atherosclerosis).

Background Arterial stiffness can be separated into 2 main mechanisms: (1) load-dependent stiffening from higher blood pressure and (2) structural stiffening due to remodeling of the vessel wall. The relationship between stiffness mechanisms and end organ damage is unknown. Methods and Results MESA (Multi-Ethnic Study of Atherosclerosis) participants with carotid ultrasound were included in this study (n=6147). Carotid pulse wave velocity (cPWV) was calculated to represent total stiffness. Structural stiffness was calculated by adjusting cPWV to a 120/80 mm Hg blood pressure with participant-specific models. Load-dependent stiffness was the difference of total and structural stiffness. Associations with incident chronic kidney disease (CKD), dementia, and mortality were assessed with adjusted Cox models. During 14.3±4.8 years of follow-up, 773 CKD events, 535 dementia events, and 1529 deaths occurred. Total cPWV was associated with mortality (hazard ratio [HR], per 1 m/s, 1.04 [95% CI, 1.01-1.08], P=0.02) and dementia (HR, 1.06 [95% CI, 1.01-1.12], P=0.03) but not CKD (HR, 1.03 [95% CI, 0.98-1.08], P=0.33). Structural cPWV was significantly associated with mortality (HR, 1.04 [95% CI, 1.00-1.08], P=0.04) but not CKD (HR, 1.00 [95% CI, 0.94-1.05], P=0.86) or dementia (HR, 1.06 [95% CI, 0.99-1.13], P=0.06). Load-dependent cPWV was significantly associated with CKD (HR, 1.38 [95% CI, 1.17-1.63], P<0.001) but not mortality (HR, 1.11 [95% CI, 0.99-1.25], P=0.07) or dementia (HR, 1.14 [95% CI, 0.94-1.38], P=0.19). Conclusions The mechanisms of arterial stiffness were associated with all-cause mortality and CKD. Structural stiffness was associated with all-cause mortality, and load-dependent stiffness was associated with CKD. Total stiffness was associated with dementia but load-dependent and structural stiffness were not.

Biomechanics models predict increasing smooth muscle tone as a novel therapeutic target for central arterial dysfunction in hypertension.

INTRODUCTION: Vasodilation can paradoxically increase arterial stiffness in older, hypertensive adults. This study modeled increasing smooth muscle tone as a therapeutic strategy to improve central arterial dysfunction in hypertension using participant-specific simulations. METHODS: Participant-specific models of the carotid artery were parameterized from vascular ultrasound measures of nitroglycerin-induced vasodilation in 18 hypertensive veterans. The acute changes in carotid artery mechanics were simulated for changes of ±2, ±4, and ±6% in smooth muscle tone and ±5, ±10, and ±15 mmHg in mean arterial pressure (MAP). The chronic carotid artery adaptations were simulated based on the hypothesis that the carotid artery will remodel wall-cross sectional area to maintain mechanical homeostasis. RESULTS: A 6% increase in smooth muscle tone acutely decreased carotid pulse wave velocity from 6.89 ±â€Š1.24 m/s to 5.83 ±â€Š1.73 m/s, and a 15 mmHg decrease in MAP decreased carotid pulse wave velocity to 6.17 ±â€Š1.23 m/s. A 6% increase in smooth muscle tone acutely decreased wall stress from 76.2 ±â€Š12.3 to 64.2 ±â€Š10.4 kPa, and a 15 mmHg decrease in MAP decreased wall stress to 60.6 ±â€Š10.7 kPa. A 6% increase in smooth muscle tone chronically decreased wall cross-sectional area from 18.3 ±â€Š5.4 to 15.2 ±â€Š4.9 mm 2, and a 15 mmHg decrease in MAP decreased wall cross-sectional area to 14.3 ±â€Š4.6 mm 2 . CONCLUSION: In participant-specific simulation, increasing smooth muscle tone can have a stronger or equivalent effect on carotid artery mechanics compared with decreasing blood pressure. Increasing central arterial smooth muscle tone may be a novel therapeutic target to improve central arterial dysfunction in older, hypertensive adults and should be a focus of future research.

Methods of arterial stiffness calculation and cardiovascular disease events: the multiethnic study of atherosclerosis.

BACKGROUND: A wide variety of different formulae have been used to calculate local arterial stiffness with little external validation in relationship to cardiovascular events. We compared the associations of several arterial stiffness calculations in a large, multiethnic cohort. METHODS: The multi-ethnic study of atherosclerosis (MESA) is a longitudinal study of 6814 adults without clinical cardiovascular disease (CVD) at enrollment. MESA participants with CVD surveillance through year 2018 and carotid ultrasound ( n  = 5873) or aorta MRI ( n  = 3175) at the baseline exam (2000-2002) were included. We analyzed 21 different calculations of local arterial stiffness. Cross-sectional and longitudinal statistical analyses were performed in addition to Cox hazard modeling for associations with CVD events (myocardial infarction, resuscitated cardiac arrest, stroke, adjudicated angina, and cardiovascular death). RESULTS: Carotid artery stiffness calculations had variable correlations with each other ( r  = 0.56-0.99); aortic stiffness measures were similar ( r  = 0.66-0.99). Nevertheless, for CVD events, the hazard ratio (HR) per standard deviation change were similar for all carotid stiffness calculations with HRs in the range of 1.00-1.10 (equivalence P  < 0.001). For the aorta, aortic distensibility coefficient had a stronger association with CVD events (HR 1.18 [1.02-1.37]) compared to aorta Peterson's elastic modulus (HR 0.98 [0.89-1.07]) and aorta pulse wave velocity (HR 1.00 [0.90-1.11]). HRs between all other aortic stiffness calculations were equivalent ( P  < 0.01). CONCLUSION: Different methods of calculating local arterial stiffness largely gave equivalent results, indicating that the variety of different arterial stiffness calculations in use do not cause inconsistent findings.

Exercise increases arterial stiffness independent of blood pressure in older Veterans.

BACKGROUND: Exercise-induced changes in arterial function could contribute to a hypertensive response to exercise (HRE) in older individuals. We performed the present analysis to define the acute arterial stiffness response to exercise in ambulatory older adults. METHODS: Thirty-nine Veterans (>60 years old), without known cardiovascular disease, participated in this study, including 19 Veterans who were hypertensive (70.8 ±â€Š6.8 years, 53% women) and 20 Veterans who were normotensive (72.0 ±â€Š9.3 years, 40% women). Arterial stiffness parameters were measured locally with carotid artery ultrasound and regionally with carotid-femoral pulse wave velocity (cfPWV) before and during the 10 min after participants performed a Balke maximal exercise treadmill stress test. RESULTS: The arterial stiffness response to exercise was similar for control and hypertensive participants. At 6 min postexercise, cfPWV was significantly increased (Δ1.5 ±â€Š1.9 m/s, P  = 0.004) despite mean blood pressure (BP) having returned to its baseline value (Δ1 ±â€Š8 mmHg, P  = 0.79). Arterial mechanics modeling also showed BP-independent increases in arterial stiffness with exercise ( P  < 0.05). Postexercise cfPWV was correlated with postexercise SBP ( r  = 0.50, P  = 0.004) while baseline cfPWV ( r  = 0.13, P  = 1.00), and postexercise total peripheral resistance ( r  = -0.18, P  = 1.00) were not. CONCLUSION: In older Veterans, exercise increases arterial stiffness independently of BP and the arterial stiffness increase with exercise is associated with increased postexercise SBP. BP-independent increases in arterial stiffness with exercise could contribute to a HRE in older adults.

Association of statin therapy with progression of carotid arterial stiffness: the Multi-Ethnic Study of Atherosclerosis (MESA).

Arterial stiffness progresses with age and is a predictor of adverse cardiovascular disease events. Studies examining associations of statin therapy with arterial stiffness have yielded mixed results. Associations between the duration and intensity of statin therapy and arterial stiffness have not been studied in a prospective multiethnic cohort. MESA participants (n = 1242) with statin medication use data at each exam (1-5) and who had undergone B-mode carotid ultrasound at baseline and at Exam 5 after (mean ± [SD]) 9.4 ± 0.5 years were analyzed. Carotid arterial stiffness was measured using the distensibility coefficient (DC) and Young's elastic modulus (YEM). Linear regression models were used to evaluate associations between DC and YEM and statin treatment duration and intensity. At baseline, participants were 66.5 ± 8.1 years old, 41% female, 36% White, 30% African American, 14% Chinese American, and 20% Hispanic. The mean baseline low-density lipoprotein cholesterol (LDL-C) was 149.5 ± 14.5 mg/dL. After adjusting for age, sex, race/ethnicity, and CVD risk factors, the percent changes in DC and YEM were found to not be significantly different in individuals on statin therapy at any combination of visits (1-4) compared to participants never on statin therapy (all p > 0.32). There were also no differences in the percent change in DC and YEM based on statin therapy intensity by quartile (all p > 0.14) over the 10-year follow-up period. Based on the aforementioned results, statin therapy was not associated with changes in carotid artery stiffness over nearly a decade of follow-up regardless of therapy duration or intensity.

Carotid Artery Stiffness Mechanisms in Hypertension and Their Association with Echolucency and Texture Features: The Multi-ethnic Study of Atherosclerosis (MESA).

Arterial stiffness, echolucency and texture features are altered with hypertension and associated with increased cardiovascular disease risk. The relationship between these markers and structural and load-dependent artery wall changes in hypertension are poorly understood. The Multi-ethnic Study of Atherosclerosis (MESA) is a longitudinal study of 6814 adults from six communities across the United States designed to study subclinical cardiovascular disease. From B-mode imaging of the right common carotid artery at the baseline MESA examination, we calculated carotid artery Young's elastic modulus (YEM, n = 5894) and carotid artery gray-scale texture features (n = 1403). The standard YEM calculation represented total arterial stiffness. Structural stiffness was calculated by adjusting YEM to a standard blood pressure of 120/80 mm Hg with participant-specific models. Load-dependent stiffness was the difference between total and structural stiffness. We found that load-dependent YEM was elevated in hypertensive individuals compared with normotensive individuals (35.7 ± 105.5 vs. -62.0 ± 112.4 kPa, p < 0.001) but that structural YEM was similar (425.3 ± 274.8 vs. 428.4 ± 293.0 kPa, p = 0.60). Gray-scale measures of heterogeneity in carotid artery wall texture (gray-level difference statistic contrast) had small but statistically signification correlations with carotid artery stiffness mechanisms. This association was positive for structural YEM (0.107, p < 0.001), while for load-dependent YEM, the association was negative (-0.064, p = 0.02). In conclusion, increased arterial stiffness in hypertension was owing solely to the non-linear mechanics of having higher blood pressure, not structural changes in the artery wall, and high load-dependent stiffness was associated with a more homogenous carotid artery wall texture. This is potentially related to arterial remodeling associated with subclinical atherosclerosis and future cardiovascular disease development. These results also indicate that gray-scale texture features from ultrasound imaging had a small but statistically significant association with load-dependent arterial stiffness and that gray-scale texture features may be partially load dependent.

Effects of nitroglycerin-induced vasodilation on elastic and muscular artery stiffness in older Veterans.

Vascular smooth muscle tone may play an important role in the physiology of increased arterial stiffness that occurs with aging. This study evaluated the impact of smooth muscle tone on arterial stiffness in older individuals following nitroglycerin-induced vasodilation in elastic and muscular arteries. Forty older Veterans (≥60 years old) without known cardiovascular disease were included in this study. Twenty Veterans were included as hypertensive participants (70.8 ± 6.6 years, 10 females), and 20 were included as normotensive controls (72.0 ± 9.3 years, 8 females). Nitroglycerin (NTG)-induced changes in arterial stiffness were measured locally with vascular ultrasound in the carotid and brachial arteries and regionally by carotid-femoral pulse wave velocity (cfPWV) with tonometry. With NTG treatment, both hypertensive participants and normotensive controls Veterans showed increased carotid PWV (6.4 ± 1.3 m/s to 7.2 ± 1.4 m/s, Δ 0.8 ± 1.1 m/s, p = 0.007) and cfPWV (8.6 ± 1.9 m/s to 9.5 ± 2.4 m/s, Δ 0.9 ± 2.3 m/s, p = 0.020) but did not show changes in brachial PWV (11.2 ± 2.4 m/s to 11.1 ± 2.2 m/s, Δ -0.2 ± 2.5 m/s, p = 0.72). The carotid artery was dilated more in control participants than hypertensive Veterans (Δ 0.54 ± 0.19 mm vs. 0.42 ± 0.12 mm, p = 0.022). Brachial artery dilation was similar between the two groups (Δ 0.55 ± 0.26 mm vs. 0.51 ± 0.20 mm, p = 0.46). In older Veterans without known cardiovascular disease, NTG-induced vasodilation increased elastic artery stiffness but did not change muscular artery stiffness. Increased central arterial stiffness and a decrease in the arterial stiffness gradient could offset some of the benefits of lowering blood pressure in older patients who are prescribed vasodilators as an antihypertensive therapy. Elastic artery stiffening with vasodilation warrants further investigation, as it may be important for antihypertensive medication selection and influence CVD development.

Carotid Artery Stiffness Mechanisms Associated With Cardiovascular Disease Events and Incident Hypertension: the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Elastic arteries stiffen via 2 main mechanisms: (1) load-dependent stiffening from higher blood pressure and (2) structural stiffening due to changes in the vessel wall. It is unknown how these different mechanisms contribute to incident cardiovascular disease (CVD) events. METHODS: The MESA (Multi-Ethnic Study of Atherosclerosis) is a longitudinal study of 6814 men and women without CVD at enrollment, from 6 communities in the United States. MESA participants with B-mode carotid ultrasound and brachial blood pressure at baseline Exam in (2000-2002) and CVD surveillance (mean follow-up 14.3 years through 2018) were included (n=5873). Peterson's elastic modulus was calculated to represent total arterial stiffness. Structural stiffness was calculated by adjusting Peterson's elastic modulus to a standard blood pressure of 120/80 mm Hg with participant-specific models. Load-dependent stiffness was the difference between total and structural stiffness. RESULTS: In Cox models adjusted for traditional risk factors, load-dependent stiffness was significantly associated with higher incidence of CVD events (hazard ratio/100 mm Hg, 1.21 [95% CI, 1.09-1.34] P<0.001) events while higher structural stiffness was not (hazard ratio, 1.03 [95% CI, 0.99-1.07] P=0.10). Analysis of participants who were normotensive (blood pressure <130/80, no antihypertensives) at baseline exam (n=2122) found higher load-dependent stiffness was also associated with significantly higher incidence of hypertension (hazard ratio, 1.53 [95% CI, 1.35-1.75] P<0.001) while higher structural stiffness was not (hazard ratio, 1.03 [95% CI, 0.99-1.07] P=0.16). CONCLUSIONS: These results provide valuable new insights into mechanisms underlying the association between arterial stiffness and CVD. Load-dependent stiffness was significantly associated with CVD events but structural stiffness was not.

Smooth muscle tone alters arterial stiffness: the importance of the extracellular matrix to vascular smooth muscle stiffness ratio.

BACKGROUND: Recent studies show that vascular smooth muscle (VSM) is more important to elastic artery mechanics than previously believed. It remains unclear whether increased VSM tone increases or decreases arterial stiffness. METHODS AND RESULTS: We developed a novel arterial mechanics model based on pressure-diameter relationships that incorporates the contributions of extracellular matrix (ECM) and VSM to arterial stiffness measures. This model is advantageous because it simple enough to use with limited clinical data but has biologically relevant parameters which include ECM stiffness, VSM stiffness, and VSM tone. The model was used to retrospectively analyze the effects of nitroglycerin-induced vasodilation in four clinical studies. Stiffness parameters were modeled for five arterial regions including both elastic and muscular arteries. The model describes complex experimental data with changing VSM tone and blood pressure. Our analysis found that when ECM is less stiff than VSM, increasing VSM tone increases arterial stiffness. The opposite is seen when ECM is stiffer than VSM, increasing VSM tone decreases stiffness. Our results also suggest that VSM tone is a compensatory mechanism for elevated ECM stiffness in hypertensive individuals. CONCLUSION: Based on retrospective analysis of four clinical studies, we propose a simple hypothesis for the role of VSM tone on arterial stiffness: increased VSM tone increases arterial stiffness when VSM is stiffer than ECM and decreases arterial stiffness when ECM is stiffer than VSM. This hypothesis and the methods used in this study could have important implications for understanding arterial physiology in both hypertension and cardiovascular disease and deserve further exploration.

Carotid Artery Stiffening With Aging: Structural Versus Load-Dependent Mechanisms in MESA (the Multi-Ethnic Study of Atherosclerosis).

Elastic arteries stiffen via 2 main mechanisms: (1) load-dependent stiffening from higher blood pressure and (2) structural stiffening due to changes in the vessel wall. Differentiating these closely coupled mechanisms is important to understanding vascular aging. MESA (Multi-Ethnic Study of Atherosclerosis) participants with B-mode carotid ultrasound and brachial blood pressure at exam 1 and exam 5 (year 10) were included in this study (n=2604). Peterson and Young elastic moduli were calculated to represent total stiffness. Structural stiffness was calculated by adjusting Peterson and Young elastic moduli to a standard blood pressure of 120/80 mm Hg with participant-specific models. Load-dependent stiffness was the difference between total and structural stiffness. Changes in carotid artery stiffness mechanisms over 10 years were compared by age groups with ANCOVA models adjusted for baseline cardiovascular disease risk factors. The 75- to 84-year age group had the greatest change in total, structural, and load-dependent stiffening compared with younger groups (P<0.05). Only age and cessation of antihypertensive medication were predictive of structural stiffening, whereas age, race/ethnicity, education, blood pressure, cholesterol, and antihypertensive medication were predictive of increased load-dependent stiffening. On average, structural stiffening accounted for the vast majority of total stiffening, but 37% of participants had more load-dependent than structural stiffening. Rates of structural and load-dependent carotid artery stiffening increased with age. Structural stiffening was consistently observed, and load-dependent stiffening was highly variable. Heterogeneity in arterial stiffening mechanisms with aging may influence cardiovascular disease development.

Transcranial Color-Coded Doppler Cerebral Hemodynamics Following Aerobic Exercise Training: Outcomes From a Pilot Randomized Clinical Trial.

Introduction: An active lifestyle with regular exercise is thought to decrease or delay the onset of Alzheimer dementia through increasing blood flow to the brain. We examined the mean flow velocity (MFV) and pulsatility index (PI) in the middle cerebral arteries of individuals randomized into two groups-a Usual Physical Activity (UPA) group and an Enhanced Physical Activity (EPA) exercise intervention group-to determine if exercise training is related to changes in cerebral blood flow. Methods: We examined 23 participants, randomized into a UPA group (n=12) and an EPA group (n=11), with transcranial color-coded Doppler (TCCD) and cardiorespiratory fitness (VO2peak, mL/kg/min) testing at baseline and following a 26-week intervention. TCCD was used to measure MFV and PI. Participants in the EPA group completed supervised aerobic exercise training for 26 weeks. Kendall's tau b correlation was used to examine relationships between variables. The Wilcoxon Rank Sum tests were used to examine changes between the UPA and EPA groups. Results: There was no significant change in MFV or PI in the UPA group or the EPA group (p-values >0.05) between baseline and 26 weeks; the change between the UPA and EPA groups was also not significant (p=0.603). There was no evidence of an association between change in VO2peak and change in MFV or PI (all p-values >0.05). Participants in the EPA group significantly increased their VO2peak compared to the UPA group (p=0.027). Conclusion: This study did not demonstrate evidence of a significant change in the MFV in the middle cerebral arteries or evidence of a significant change in the PI between UPA and EPA groups. Future studies should be performed in larger cohorts and should consider use of personalized exercise programs to maximize understanding of how cerebrovascular hemodynamics change in structure and function with exercise for adults at risk for Alzheimer dementia.

Non-invasive estimation of pulmonary hemodynamics from 2D-PC MRI with an arterial mechanics method.

Pulmonary Hypertension (PH) is a challenging cardiopulmonary disease diagnosed when the mean pulmonary artery pressure (mPAP) is greater than 20 mmHg. Unfortunately, mPAP can only be measured through invasive right heart catheterization (RHC) motivating the development of novel non-invasive estimates. Pulmonary hypertension patients (n = 7) and control subjects (n = 8) had 2D phase contrast (PC) MRI of the main pulmonary artery during rest and moderate exercise. A novel method utilizing arterial mechanics was used to estimate mPAP and other pulmonary hemodynamics measures from the 2D PC images. mPAP estimated from MRI was greater in the PH group than the control group at both rest (24 ± 10 vs 12 ± 5 mmHg) and exercise (40 ± 8 vs 17 ± 9 mmHg). Area under the curve (AUC) calculated from receiver operator curve (ROC) analysis showed MRI estimated mPAP had excellent diagnostic ability to diagnose PH patients vs control subjects at rest and exercise (rest AUC = 0.91 [0.76 - 1.0], exercise AUC = 0.96 [0.88 - 1.0]). These are promising proof-of-concept results that pulmonary hemodynamics could be non-invasively estimated from an MRI and arterial mechanics approach. Future studies to determine the clinical utility of this method are needed.

Harnessing Mobile Health Technology for Secondary Cardiovascular Disease Prevention in Older Adults: A Scientific Statement From the American Heart Association.

Secondary prevention of cardiovascular disease (CVD), the leading cause of morbidity and mortality, is critical to improving health outcomes and quality of life in our aging population. As mobile health (mHealth) technology gains universal leverage and popularity, it is becoming more user-friendly for older adults and an adjunct to manage CVD risk and improve overall cardiovascular health. With the rapid advances in mHealth technology and increasing technological engagement of older adults, a comprehensive understanding of the current literature and knowledge of gaps and barriers surrounding the impact of mHealth on secondary CVD prevention is essential. After a systematic review of the literature, 26 studies that used mHealth for secondary CVD prevention focusing on lifestyle behavior change and medication adherence in cohorts with a mean age of ≥60 years were identified. Improvements in health behaviors and medication adherence were observed, particularly when there was a short message service (ie, texting) component involved. Although mobile technologies are becoming more mainstream and are starting to blend more seamlessly with standard health care, there are still distinct barriers that limit implementation particularly in older adults, including affordability, usability, privacy, and security issues. Furthermore, studies on the type of mHealth that is the most effective for older adults with longer study duration are essential as the field continues to grow. As our population ages, identifying and implementing effective, widely accepted, cost-effective, and time-efficient mHealth interventions to improve CVD health in a vulnerable demographic group should be a top health priority.

Persistent Asthma Is Associated With Increased Risk for Incident Atrial Fibrillation in the MESA.

BACKGROUND: Asthma and atrial fibrillation (AF) share an underlying inflammatory pathophysiology. We hypothesized that persistent asthmatics are at higher risk for developing AF and that this association would be attenuated by adjustment for baseline markers of systemic inflammation. METHODS: The MESA (Multi-Ethnic Study of Atherosclerosis) is a prospective longitudinal study of adults free of cardiovascular disease at baseline. Presence of asthma was determined at exam 1. Persistent asthma was defined as asthma requiring use of controller medications. Intermittent asthma was defined as asthma without use of controller medications. Participants were followed for a median of 12.9 (interquartile range, 10-13.6) years for incident AF. Multivariable Cox regression models were used to assess associations of asthma subtype and AF. RESULTS: The 6615 participants were a mean (SD) 62.0 (10.2) years old (47% male, 27% black, 12% Chinese, and 22% Hispanic). AF incidence rates were 0.11 (95% CI, 0.01-0.12) events/10 person-years for nonasthmatics, 0.11 (95% CI, 0.08-0.14) events/10 person-years for intermittent asthmatics, and 0.19 (95% CI, 0.120.49) events/10 person-years for persistent asthmatics (log-rank P=0.008). In risk-factor adjusted models, persistent asthmatics had a greater risk of incident AF (hazard ratio, 1.49 [95% CI, 1.03-2.14], P=0.03). IL (Interleukin)-6 (hazard ratio, 1.26 [95% CI, 1.13-1.42]), TNF (tumor necrosis factor)-α receptor 1 (hazard ratio, 1.09 [95% CI, 1.08-1.11]) and D-dimer (hazard ratio, 1.10 [95% CI, 1.02-1.20]) predicted incident AF, but the relationship between asthma and incident AF was not attenuated by adjustment for any inflammation marker (IL-6, CRP [C-reactive protein], TNF-α R1, D-dimer, and fibrinogen). CONCLUSIONS: In a large multiethnic cohort with nearly 13 years follow-up, persistent asthma was associated with increased risk for incident AF. This association was not attenuated by adjustment for baseline inflammatory biomarkers.

Longitudinal Effects of Cigarette Smoking and Smoking Cessation on Aortic Wave Reflections, Pulse Wave Velocity, and Carotid Artery Distensibility.

Background We evaluated the effects of smoking and smoking cessation on aortic wave reflections (augmentation index), aortic pulse wave velocity, and carotid artery distensibility and stiffness (distensibility coefficient, Young's elastic modulus). Methods and Results Current smokers underwent carotid, radial, and femoral artery tonometry and carotid ultrasound at baseline and 3 years after a quit attempt. Baseline associations of smoking heaviness markers (exhaled carbon monoxide and cigarettes smoked/d) and effects of smoking cessation at year 3 on changes in arterial measures were assessed using multivariable linear regression models. The 1417 smokers (54% female) were mean (SD) 49.3 (11.6) years old and smoked 17.2 (8.3) cigarettes/d (exhaled carbon monoxide 14.7 [8.2] parts per million). Arterial measures were associated more strongly with age, blood pressure (BP), and waist circumference than with smoking heaviness markers. Augmentation index was associated independently with carbon monoxide (P=0.004). Pulse wave velocity, distensibility coefficient, and Young's elastic modulus had small, inconsistent associations with smoking heaviness markers. At year 3, augmentation index improved with smoking cessation (P=0.006) despite more weight gain (2.54 vs 0.36 kg, P<0.001) and insulin resistance (P=0.001) among abstainers, but distensibility coefficient decreased (P=0.004). Changes in arterial measures were related more strongly to changes in BP than smoking cessation. Conclusions Arterial wave reflection and stiffness measures were associated more strongly with age, BP, and waist circumference than smoking heaviness. Smoking cessation was associated with weight gain and increased insulin resistance. Changes in arterial measures were predicted by changes in BP, highlighting the need to address weight gain and BP changes during a quit attempt.

Effects of Simvastatin on Augmentation Index Are Transient: Outcomes From a Randomized Controlled Trial.

Background Statins improve endothelial function, but their effects on arterial stiffness and aortic blood pressure in middle-aged adults are uncertain. Methods and Results This was a prospective, randomized, double-blind, placebo-controlled trial of middle-aged (40-72 years old) adults who were randomly assigned to receive simvastatin 40 mg (n=44) or placebo (n=44) daily for 18 months to evaluate impact on dementia-related biomarkers (primary end points) and measures of vascular health (secondary end points). This analysis focuses on the predetermined secondary end points of changes in central aortic blood pressure, aortic augmentation index, and brachial artery flow-mediated dilation. Measurements were performed at baseline and after 6, 12, and 18 months. Multivariable models were used to identify predictors of these prespecified vascular end points. Study groups were similar at baseline; low-density lipoprotein cholesterol declined in the statin group but not in the placebo group (P<0.01). There were no significant differences in changes in central blood pressure parameters or flow-mediated dilation (all P>0.2). After 12 months, augmentation index decreased from baseline in the statin group compared with the placebo group (-2.3% [5.5%] versus 1.2% [5.7%], P=0.007), but by 18 months the response in both groups trend toward baseline (-1.1% [5.8%] versus 0.2% [4.8%], P=0.3). Low-density lipoprotein cholesterol was not associated with changes in augmentation index at any time point. Conclusions Statin therapy led to a short-term reduction in augmentation index after 12 months, but this effect did not persist after 18 months despite continued reduction in low-density lipoprotein cholesterol levels. These findings suggest that statins may have a transient effect on aortic stiffness. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00939822.

Carotid artery displacement and cardiovascular disease risk in the Multi-Ethnic Study of Atherosclerosis.

Novel technology permits quantification of common carotid artery (CCA) displacement, which is traditionally ignored. We evaluated associations with CCA displacement and cardiovascular disease (CVD) risk and events in a large, multi-ethnic cohort. Right CCA longitudinal displacement (LD), transverse displacement (TD), and grayscale median (GSM) were evaluated using ultrasound speckle-tracking and texture analysis software in 2050 participants. Regression analyses were used to define relationships between CCA LD, TD, GSM, and CVD risk factors. Cox proportional hazards models were used to assess relationships between LD, TD, and incident CVD events. Participants were mean (SD) 64 (10) years old. There were 791 cases with a CVD event over a 12-year median follow-up. The mean LD was 0.29 (0.20) mm. In multivariable models including age, sex, race/ethnicity, heart rate, and CVD risk factors, LD was associated positively with active smoking (ß = 0.08, p < 0.001) and inversely with black (ß = -0.08, p < 0.001), Chinese (ß = -0.05, p < 0.001), and Hispanic (ß = -0.04, p < 0.05) race/ethnicities relative to white individuals, heart rate (ß = -0.03/10 beats/min, p < 0.001), and diastolic blood pressure (ß = -0.01/5 mmHg, p < 0.05). In fully adjusted models, LD and TD were associated with GSM (p < 0.01), but neither predicted incident CVD events (LD: hazard ratio (HR) 0.77 [0.48 to 1.24], p = 0.3; TD: HR 1.12 [0.8 to 1.57], p = 0.5). CCA LD and TD are associated with race/ethnicity and CVD risk factors but not incident CVD events. LD and TD are not measures of arterial stiffness but their association with GSM suggests that lower LD and TD may be related to structural changes within the carotid arterial wall.

Carotid Artery Echolucency, Texture Features, and Incident Cardiovascular Disease Events: The MESA Study.

Background We hypothesized that measures of common carotid artery echolucency and grayscale texture features were associated with cardiovascular disease ( CVD ) risk factors and could predict CVD events. Methods and Results Using a case-cohort design, we measured common carotid artery ultrasound images from 1788 participants in Exam 1 of the MESA study (Multi-Ethnic Study of Atherosclerosis) to derive 4 grayscale features: grayscale median, entropy, gray level difference statistic-contrast, and spatial gray level dependence matrices-angular second moment. CVD risk factor associations were determined by linear regression. Cox proportional hazard models with inverse selection probability weighting and adjustments for age, sex, race/ethnicity, CVD risk factors, and C-reactive protein were used to determine if standardized values for grayscale median, entropy, gray level difference statistic-contrast, and spatial gray level dependence matrices-angular second moment could predict incident coronary heart disease, stroke, and total CVD events over a median 13 years follow-up. Participants were mean ( SD ) 63.1 (10.3) years of age, 52.6% female, 32.1% white, 27.8% black, 23.3% Hispanic, and 16.8% Chinese. There were 283 coronary heart disease, 120 stroke, and 416 CVD events. Several associations of grayscale features with CVD risk factors were identified. In fully adjusted models, higher gray level difference statistic-contrast was associated with a lower risk of incident coronary heart disease (hazard ratio 0.82, 95% CI 0.71-0.94, padj=0.005) and CVD events (hazard ratio 0.87, 95% CI 0.77-0.98, padj=0.018); higher spatial gray level dependence matrices-angular second moment was associated with a higher risk of CVD events (hazard ratio 1.09, 95% CI 1.00-1.19, padj=0.044). Conclusions Gray level difference statistic-contrast and spatial gray level dependence matrices-angular second moment predicted CVD events independent of risk factors, indicating their potential use as biomarkers to assess future CVD risk.

Ultrasound carotid plaque features, cardiovascular disease risk factors and events: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: It is not known if ultrasound carotid plaque features are associated with cardiovascular disease (CVD) risk factors or if they predict future CVD events. METHODS: We measured total carotid plaque area (TPA) and grayscale plaque features (grayscale median, black areas, and discrete white areas) by B-mode carotid ultrasound among 2205 participants who participated in the first (baseline) visit of the Multi-Ethnic Study of Atherosclerosis. Multivariable linear regression was used to examine relationships between ultrasound plaque features and CVD risk factors at baseline. Cox proportional hazards models were used to assess if TPA, grayscale features, and carotid plaque score (number of arterial segments with a plaque) could predict incident coronary heart disease and cerebrovascular disease events over a mean follow-up of 13.3 years. RESULTS: Participants were mean (standard deviation [SD]) 65.4 (9.6) years, 49% male, 39% White, 11% Chinese, 28% Black, and 22% Hispanic. Mean TPA 27.7 (24.7) mm2, but no grayscale plaque features, was associated with CVD risk factors. In fully adjusted models, TPA but no grayscale features predicted incident coronary heart disease (CHD) events (HR 1.23; 95%CI 1.11-1.36; p<0.001), however, C-statistics for CHD were similar to carotid plaque score but less than for coronary artery calcium (CAC) scoring. Neither TPA nor grayscale features independently predicted cerebrovascular events. CONCLUSIONS: In middle-aged adults free of known cardiovascular disease, TPA but not grayscale plaque features was associated with CVD risk factors and predicted incident CHD events. For CHD, prediction indices for TPA were similar to carotid plaque score but less than for CAC.

Effect of Vitamin D Supplementation on Markers of Vascular Function: A Systematic Review and Individual Participant Meta-Analysis.

BACKGROUND: Low 25-hydroxyvitamin D levels are associated with an increased risk of cardiovascular events, but the effect of vitamin D supplementation on markers of vascular function associated with major adverse cardiovascular events is unclear. METHODS AND RESULTS: We conducted a systematic review and individual participant meta-analysis to examine the effect of vitamin D supplementation on flow-mediated dilatation of the brachial artery, pulse wave velocity, augmentation index, central blood pressure, microvascular function, and reactive hyperemia index. MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.gov were searched until the end of 2016 without language restrictions. Placebo-controlled randomized trials of at least 4 weeks duration were included. Individual participant data were sought from investigators on included trials. Trial-level meta-analysis was performed using random-effects models; individual participant meta-analyses used a 2-stage analytic strategy, examining effects in prespecified subgroups. 31 trials (2751 participants) were included; 29 trials (2641 participants) contributed data to trial-level meta-analysis, and 24 trials (2051 participants) contributed to individual-participant analyses. Vitamin D3 daily dose equivalents ranged from 900 to 5000 IU; duration was 4 weeks to 12 months. Trial-level meta-analysis showed no significant effect of supplementation on macrovascular measures (flow-mediated dilatation, 0.37% [95% confidence interval, -0.23 to 0.97]; carotid-femoral pulse wave velocity, 0.00 m/s [95% confidence interval, -0.36 to 0.37]); similar results were obtained from individual participant data. Microvascular function showed a modest improvement in trial-level data only. No consistent benefit was observed in subgroup analyses or between different vitamin D analogues. CONCLUSIONS: Vitamin D supplementation had no significant effect on most markers of vascular function in this analysis.