Naomi M. Hamburg

Arterial Stiffness and Cardiovascular Events The Framingham Heart Study

Background— Various measures of arterial stiffness and wave reflection have been proposed as cardiovascular risk markers. Prior studies have not assessed relations of a comprehensive panel of stiffness measures to prognosis in the community. Methods and Results— We used proportional hazards models to analyze first-onset major cardiovascular disease events (myocardial infarction, unstable angina, heart failure, or stroke) in relation to arterial stiffness (pulse wave velocity [PWV]), wave reflection (augmentation index, carotid-brachial pressure amplification), and central pulse pressure in 2232 participants (mean age, 63 years; 58% women) in the Framingham Heart Study. During median follow-up of 7.8 (range, 0.2 to 8.9) years, 151 of 2232 participants (6.8%) experienced an event. In multivariable models adjusted for age, sex, systolic blood pressure, use of antihypertensive therapy, total and high-density lipoprotein cholesterol concentrations, smoking, and presence of diabetes mellitus, higher aortic PWV was associated with a 48% increase in cardiovascular disease risk (95% confidence interval, 1.16 to 1.91 per SD; P=0.002). After PWV was added to a standard risk factor model, integrated discrimination improvement was 0.7% (95% confidence interval, 0.05% to 1.3%; P<0.05). In contrast, augmentation index, central pulse pressure, and pulse pressure amplification were not related to cardiovascular disease outcomes in multivariable models. Conclusions— Higher aortic stiffness assessed by PWV is associated with increased risk for a first cardiovascular event. Aortic PWV improves risk prediction when added to standard risk factors and may represent a valuable biomarker of cardiovascular disease risk in the community.

Cross-Sectional Relations of Digital Vascular Function to Cardiovascular Risk Factors in the Framingham Heart Study

Background— Digital pulse amplitude augmentation in response to hyperemia is a novel measure of peripheral vasodilator function that depends partially on endothelium-derived nitric oxide. Baseline digital pulse amplitude reflects local peripheral arterial tone. The relation of digital pulse amplitude and digital hyperemic response to cardiovascular risk factors in the community is unknown. Methods and Results— Using a fingertip peripheral arterial tonometry (PAT) device, we measured digital pulse amplitude in Framingham Third Generation Cohort participants (n=1957; mean age, 40±9 years; 49% women) at baseline and in 30-second intervals for 4 minutes during reactive hyperemia induced by 5-minute forearm cuff occlusion. To evaluate the vascular response in relation to baseline, adjusting for systemic effects and skewed data, we expressed the hyperemic response (called the PAT ratio) as the natural logarithm of the ratio of postdeflation to baseline pulse amplitude in the hyperemic finger divided by the same ratio in the contralateral finger that served as control. The relation of the PAT ratio to cardiovascular risk factors was strongest in the 90- to 120-second postdeflation interval (overall model R2=0.159). In stepwise multivariable linear regression models, male sex, body mass index, ratio of total to high-density lipoprotein cholesterol, diabetes mellitus, smoking, and lipid-lowering treatment were inversely related to PAT ratio, whereas increasing age was positively related to PAT ratio (all P<0.01). Conclusions— Reactive hyperemia produced a time-dependent increase in fingertip pulse amplitude. Digital vasodilator function is related to multiple traditional and metabolic cardiovascular risk factors. Our findings support further investigations to define the clinical utility and predictive value of digital pulse amplitude.

The Assessment of Endothelial Function From Research Into Clinical Practice

The discovery of nitric oxide (NO) as a crucial endothelium-derived molecule for vascular relaxation and the recognition of the endothelium as more than a passive interface between blood and the vessel wall led to substantial progress in the field of vascular research.1 Endothelial dysfunction is a pathological condition characterized mainly by an imbalance between substances with vasodilating, antimitogenic, and antithrombogenic properties (endothelium-derived relaxing factors)2 and substances with vasoconstricting, prothrombotic, and proliferative characteristics (endothelium-derived contracting factors).3 Among the most important vasodilator molecules, particularly in muscular arteries, is NO, which also inhibits other key events in the development of atherosclerosis such as platelet adhesion and aggregation, leukocyte adhesion and migration, and smooth muscle cell proliferation. Particularly in the microcirculation, prostacyclin and endothelium-derived hyperpolarization factors (an umbrella term for substances and signals hyperpolarizing vascular myocytes by opening voltage channels4) also play an important role. Generally, loss of NO bioavailability indicates a broadly dysfunctional phenotype across many properties of the endothelium. Thus, the assessment of its vasodilator properties resulting from NO and other molecules may provide information on the integrity and function of the endothelium. Interestingly, most, if not all, cardiovascular risk factors are associated with endothelial dysfunction,5 and risk factor modification leads to improvement in vascular function. Endothelial dysfunction has been detected in the coronary epicardial and resistance vasculature and in peripheral arteries, so endothelial dysfunction can be regarded as a systemic condition.6 Importantly, the process of atherosclerosis begins early in life, and endothelial dysfunction contributes to atherogenesis and precedes the development of morphological vascular changes.7 Over the past 25 years, many methodological approaches have been developed to measure the (patho)physiological function of the endothelium in humans.8 Although the ability to measure endothelial function has boosted clinical research in this field, its use as a …

Aortic Stiffness, Blood Pressure Progression, and Incident Hypertension

CONTEXT Vascular stiffness increases with advancing age and is a major risk factor for age-related morbidity and mortality. Vascular stiffness and blood pressure pulsatility are related; however, temporal relationships between vascular stiffening and blood pressure elevation have not been fully delineated. OBJECTIVE To examine temporal relationships among vascular stiffness, central hemodynamics, microvascular function, and blood pressure progression. DESIGN, SETTING, AND PARTICIPANTS Longitudinal community-based cohort study conducted in Framingham, Massachusetts. The present investigation is based on the 2 latest examination cycles (cycle 7: 1998-2001; cycle 8: 2005-2008 [last visit: January 25, 2008]) of the Framingham Offspring study (recruited: 1971-1975). Temporal relationships among blood pressure and 3 measures of vascular stiffness and pressure pulsatility derived from arterial tonometry (carotid-femoral pulse wave velocity [CFPWV], forward wave amplitude [FWA], and augmentation index) were examined over a 7-year period in 1759 participants (mean [SD] age: 60 [9] years; 974 women). MAIN OUTCOME MEASURES The primary outcomes were blood pressure and incident hypertension during examination cycle 8. The secondary outcomes were CFPWV, FWA, and augmentation index during examination cycle 8. RESULTS In a multivariable-adjusted regression model, higher FWA (β, 1.3 [95% CI, 0.5-2.1] mm Hg per 1 SD; P = .002) and higher CFPWV (β, 1.5 [95% CI, 0.5-2.6] mm Hg per 1 SD; P = .006) during examination cycle 7 were jointly associated with systolic blood pressure during examination cycle 8. Similarly, in a model that included systolic and diastolic blood pressure and additional risk factors during examination cycle 7, higher FWA (odds ratio [OR], 1.6 [95% CI, 1.3-2.0] per 1 SD; P < .001), augmentation index (OR, 1.7 [95% CI, 1.4-2.0] per 1 SD; P < .001), and CFPWV (OR, 1.3 [95% CI, 1.0-1.6] per 1 SD; P = .04) were associated with incident hypertension during examination cycle 8 (338 cases [32%] in 1048 participants without hypertension during examination cycle 7). Conversely, blood pressure during examination cycle 7 was not associated with CFPWV during examination cycle 8. Higher resting brachial artery flow (OR, 1.23 [95% CI, 1.04-1.46]) and lower flow-mediated dilation (OR, 0.80 [95% CI, 0.67-0.96]) during examination cycle 7 were associated with incident hypertension (in models that included blood pressure and tonometry measures collected during examination cycle 7). CONCLUSION In this cohort, higher aortic stiffness, FWA, and augmentation index were associated with higher risk of incident hypertension; however, initial blood pressure was not independently associated with risk of progressive aortic stiffening.

Physical Inactivity Rapidly Induces Insulin Resistance and Microvascular Dysfunction in Healthy Volunteers

Objectives—Sedentary lifestyle increases the risk of cardiovascular disease and diabetes. Vascular dysfunction contributes to atherogenesis and has been linked to insulin resistance. Methods and Results—We measured insulin sensitivity by glucose tolerance test and vascular function by ultrasound and venous occlusion plethysmography in 20 healthy subjects (14 men, 6 women) at baseline and during 5 days of bed rest. Bed rest led to a 67% increase in the insulin response to glucose loading (P<0.001) suggesting increased insulin resistance and produced increases in total cholesterol and triglycerides. Bed rest led to decreased reactive hyperemia in the forearm (1317±404 to 1112±260 mL/min, P=0.01) and the calf (28.5±7.0 to 22.2±8.7 mL/min/dL, P=0.003) indicating impaired microvascular function. Bed rest decreased brachial artery diameter and increased systolic blood pressure suggesting increased basal arterial tone. There were no changes in circulating inflammatory markers arguing against systemic inflammation as a mechanism for vascular dysfunction in this setting. Conclusions—Physical inactivity was associated with the development of insulin resistance, dyslipidemia, increased blood pressure, and impaired microvascular function in healthy volunteers. Our findings may provide insight into the pathogenesis of vascular disease in sedentary individuals and emphasize that even short-term physical inactivity may have adverse metabolic and vascular consequences.

2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines

Jonathan L. Halperin, MD, FACC, FAHA, Chair Glenn N. Levine, MD, FACC, FAHA, Chair-Elect Sana M. Al-Khatib, MD, MHS, FACC, FAHA Kim K. Birtcher, PharmD, MS, AACC Biykem Bozkurt, MD, PhD, FACC, FAHA Ralph G. Brindis, MD, MPH, MACC Joaquin E. Cigarroa, MD, FACC Lesley H. Curtis, PhD, FAHA

Relation of Brachial and Digital Measures of Vascular Function in the Community The Framingham Heart Study

Impaired vascular function contributes to the development of clinical cardiovascular disease. The relation between vasodilator function assessed noninvasively in the brachial and digital arteries remains incompletely defined. In the Framingham Offspring, Third Generation and Omni Cohorts, we measured flow-mediated dilation (FMD; n=7031; age 48±13 years; age range, 19 to 88 years; 54% women) and peripheral arterial tonometry (PAT) ratio (n=4352; 55±16 years; age range, 19 to 90 years; 51% women). Abnormal vascular function for each measure was defined by the sex-specific fifth percentile in a reference group free of conventional cardiovascular risk factors. The prevalence of abnormal FMD but not abnormal PAT ratio was higher with advancing age. In multivariable models, higher body mass index was associated with a higher prevalence of both abnormal FMD and PAT ratio. Additional correlates of abnormal FMD included increasing age and higher systolic blood pressure. In contrast, correlates of abnormal PAT ratio included lower systolic blood pressure, increasing total/high-density lipoprotein cholesterol ratio, diabetes, smoking, and lipid-lowering medication. Whereas women had higher FMD and PAT ratios compared with men, using sex-specific reference values, women had a higher prevalence of abnormal brachial and digital vascular function. In participants who had concurrent testing (n=1843), PAT ratio was not significantly associated with FMD in multivariable models. In this large, community-based cohort, brachial and digital measures of vascular function had differing relations with cardiovascular risk factors and were nearly uncorrelated with each other. These results suggest that FMD and PAT provide distinct information regarding vascular function in conduit versus smaller digital vessels.

Endothelial dysfunction in diabetes mellitus: molecular mechanisms and clinical implications.

Cardiovascular disease is a major complication of diabetes mellitus, and improved strategies for prevention and treatment are needed. Endothelial dysfunction contributes to the pathogenesis and clinical expression of atherosclerosis in diabetes mellitus. This article reviews the evidence linking endothelial dysfunction to human diabetes mellitus and experimental studies that investigated the responsible mechanisms. We then discuss the implications of these studies for current management and for new approaches for the prevention and treatment of cardiovascular disease in patients with diabetes mellitus.

Altered Mitochondrial Dynamics Contributes to Endothelial Dysfunction in Diabetes Mellitus

Background— Endothelial dysfunction contributes to the development of atherosclerosis in patients with diabetes mellitus, but the mechanisms of endothelial dysfunction in this setting are incompletely understood. Recent studies have shown altered mitochondrial dynamics in diabetes mellitus with increased mitochondrial fission and production of reactive oxygen species. We investigated the contribution of altered dynamics to endothelial dysfunction in diabetes mellitus. Methods and Results— We observed mitochondrial fragmentation (P=0.002) and increased expression of fission-1 protein (Fis1; P<0.0001) in venous endothelial cells freshly isolated from patients with diabetes mellitus (n=10) compared with healthy control subjects (n=9). In cultured human aortic endothelial cells exposed to 30 mmol/L glucose, we observed a similar loss of mitochondrial networks and increased expression of Fis1 and dynamin-related protein-1 (Drp1), proteins required for mitochondrial fission. Altered mitochondrial dynamics was associated with increased mitochondrial reactive oxygen species production and a marked impairment of agonist-stimulated activation of endothelial nitric oxide synthase and cGMP production. Silencing Fis1 or Drp1 expression with siRNA blunted high glucose–induced alterations in mitochondrial networks, reactive oxygen species production, endothelial nitric oxide synthase activation, and cGMP production. An intracellular reactive oxygen species scavenger provided no additional benefit, suggesting that increased mitochondrial fission may impair endothelial function via increased reactive oxygen species. Conclusion— These findings implicate increased mitochondrial fission as a contributing mechanism for endothelial dysfunction in diabetic states.

Hemodynamic Correlates of Blood Pressure Across the Adult Age Spectrum Noninvasive Evaluation in the Framingham Heart Study

Background— Systolic blood pressure and pulse pressure are substantially higher in older adults. The relative contributions of increased forward versus reflected pressure wave amplitude or earlier arrival of the reflected wave to elevated pulse pressure remain controversial. Methods and Results— We measured proximal aortic pressure and flow, forward pressure wave amplitude, global wave reflection, reflected wave timing, and pulse wave velocity noninvasively in 6417 (age range, 19 to 90 years; 53% women) Framingham Heart Study Third Generation and Offspring participants. Variation in forward wave amplitude paralleled pulse pressure throughout adulthood. In contrast, wave reflection and pulse pressure were divergent across adulthood: In younger participants, pulse pressure was lower and wave reflection was higher with advancing age, whereas in older participants, pulse pressure was higher and wave reflection was lower with age. Reflected wave timing differed modestly across age groups despite considerable differences in pulse wave velocity. Forward wave amplitude explained 80% (central) and 66% (peripheral) of the variance in pulse pressure in younger participants (<50 years) and 90% and 84% in the older participants (≥50 years; all P<0.0001). In a stepwise model that evaluated age–pulse pressure relations in the full sample, the late accelerated increases in central and peripheral pulse pressure were markedly attenuated when variation in forward wave amplitude was considered. Conclusions— Higher pulse pressure at any age and higher pulse pressure with advancing age is associated predominantly with a larger forward pressure wave. The influence of wave reflection on age-related differences in pulse pressure was minor.