In recent years, great emphasis has been placed on the role of arterial stiffness in the development of cardiovascular diseases. Indeed, the assessment of arterial stiffness is increasingly used in the clinical assessment of patients. Although several papers have previously addressed the methodological issues concerning the various indices of arterial stiffness currently available, and their clinical applications, clinicians and researchers still report difficulties in selecting the most appropriate methodology for their specific use. This paper summarizes the proceedings of several meetings of the European Network for Non-invasive Investigation of Large Arteries and is aimed at providing an updated and practical overview of the most relevant methodological aspects and clinical applications in this area.

Expert consensus document on arterial stiffness: methodological issues and clinical applications

A b s t r ac t Background Whether the treatment of patients with hypertension who are 80 years of age or older is beneficial is unclear. It has been suggested that antihypertensive therapy may reduce the risk of stroke, despite possibly increasing the risk of death. Methods We randomly assigned 3845 patients from Europe, China, Australasia, and Tunisia who were 80 years of age or older and had a sustained systolic blood pressure of 160 mm Hg or more to receive either the diuretic indapamide (sustained release, 1.5 mg) or matching placebo. The angiotensin-converting-enzyme inhibitor perindopril (2 or 4 mg), or matching placebo, was added if necessary to achieve the target blood pressure of 150/80 mm Hg. The primary end point was fatal or nonfatal stroke. Results The active-treatment group (1933 patients) and the placebo group (1912 patients) were well matched (mean age, 83.6 years; mean blood pressure while sitting, 173.0/90.8 mm Hg); 11.8% had a history of cardiovascular disease. Median follow-up was 1.8 years. At 2 years, the mean blood pressure while sitting was 15.0/6.1 mm Hg lower in the active-treatment group than in the placebo group. In an intention-to- treat analysis, active treatment was associated with a 30% reduction in the rate of fatal or nonfatal stroke (95% confidence interval (CI), −1 to 51; P = 0.06), a 39% reduc- tion in the rate of death from stroke (95% CI, 1 to 62; P = 0.05), a 21% reduction in the rate of death from any cause (95% CI, 4 to 35; P = 0.02), a 23% reduction in the rate of death from cardiovascular causes (95% CI, −1 to 40; P = 0.06), and a 64% re- duction in the rate of heart failure (95% CI, 42 to 78; P<0.001). Fewer serious adverse events were reported in the active-treatment group (358, vs. 448 in the placebo group; P = 0.001). Conclusions The results provide evidence that antihypertensive treatment with indapamide (sus- tained release), with or without perindopril, in persons 80 years of age or older is beneficial. (ClinicalTrials.gov number, NCT00122811.)

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Treatment of Hypertension in Patients 80 Years of Age or Older

Background—Current definitions of hypertension are based on levels of systolic blood pressure (SBP) and diastolic blood pressure (DBP), but not on pulse pressure (PP). We examined whether PP adds useful information for predicting coronary heart disease (CHD) in the population-based Framingham Heart Study. Methods and Results—We studied 1924 men and women between 50 and 79 years of age at baseline with no clinical evidence of CHD and not taking antihypertensive drug therapy. Cox regression, adjusted for age, sex, and other risk factors, was used to assess the relations between blood pressure components and CHD risk over a 20-year follow-up. The association with CHD risk was positive for SBP, DBP, and PP, considering each pressure individually; of the 3, PP yielded the largest χ2 statistic. When SBP and DBP were jointly entered into the multivariable model, the association with CHD risk was positive for SBP (HR, 1.22; 95% CI, 1.15 to 1.30) and negative for DBP (HR, 0.86; 95% CI, 0.75 to 0.98). Four subgroup...

Is Pulse Pressure Useful in Predicting Risk for Coronary Heart Disease? The Framingham Heart Study

Arterial stiffness is a growing epidemic associated with increased risk of cardiovascular events, dementia, and death. Decreased compliance of the central vasculature alters arterial pressure and flow dynamics and impacts cardiac performance and coronary perfusion. This article reviews the structural, cellular, and genetic contributors to arterial stiffness, including the roles of the scaffolding proteins, extracellular matrix, inflammatory molecules, endothelial cell function, and reactive oxidant species. Additional influences of atherosclerosis, glucose regulation, chronic renal disease, salt, and changes in neurohormonal regulation are discussed. A review of the hemodynamic impact of arterial stiffness follows. A number of lifestyle changes and therapies that reduce arterial stiffness are presented, including weight loss, exercise, salt reduction, alcohol consumption, and neuroendocrine-directed therapies, such as those targeting the renin-angiotensin aldosterone system, natriuretic peptides, insulin modulators, as well as novel therapies that target advanced glycation end products.

Mechanisms, Pathophysiology, and Therapy of Arterial Stiffness

Arterial pressure waves were recorded noninvasively from the carotid, radial, femoral, or all three of these arteries of 1,005 normal subjects, aged 2-91 years, using a new transcutaneous tonometer containing a high fidelity Millar micromanometer. Waves were ensemble-averaged into age-decade groups. Characteristic changes were noted with increasing age. In all sites, pulse amplitude increased with advancing age (carotid, 91.3%; radial 67.5%; femoral, 50.1% from first to eighth decade), diastolic decay steepened, and diastolic waves became less prominent. In the carotid pulse, there was, in youth, a second peak on the downstroke of the waves in late systole. After the third decade, this second peak rose with age to merge with and dominate the initial rise. In the radial pulse, a late systolic wave was also apparent, but this occurred later; with age, this second peak rose but not above the initial rise in early systole, even at the eighth decade. In the femoral artery, there was a single systolic wave at all ages. Aging changes in the arterial pulse are explicable on the basis of both an increase in arterial stiffness with increased pulse-wave velocity and progressively earlier wave reflection. These two factors may be separated and effects of the latter measured from pressure wave-contour analysis using an "augmentation index," determined by a computer algorithm developed from invasive pressure and flow data. Changes in peak pressure in the central (carotid) artery show increasing cardiac afterload with increasing age in a normal population; this can account for the cardiac hypertrophy that occurs with advancing age (even as other organs atrophy) and the predisposition to cardiac failure in the elderly. Identification of mechanisms responsible offers a new approach to reduction of left ventricular afterload.

Noninvasive determination of age-related changes in the human arterial pulse.

Effects of sublingual glyceryl trinitrate (GTN) were studied in ten patients without heart failure during diagnostic cardiac catheterisation following angiography. GTN caused substantial reduction in peak left ventricular and aortic pressure (19 mmHg) with lesser reduction in mean aortic pressure (9 mmHg) and no change in diastolic aortic pressure. Reduction in stroke volume (by 15%), associated with fall in left ventricular end diastolic pressure (by 4 mmHg) was insufficient to explain the marked (17 mmHg - 34%) reduction in pulse pressure. Decrease in pulse pressure was associated with loss of the late systolic peak on both the aortic and left ventricular pressure wave. This peak is caused by pulse wave reflection. GTN caused no change in peripheral resistance or in indices of aortic compliance (characteristic impedance, total arterial compliance) but was associated with reduction in fluctuations of both modulus and phase of aortic impedance. All these changes in pressure waves and in impedance spectra are explicable on the basis of decreased peripheral wave reflection. This can be attributed to the known vasodilatory effect of GTN on the peripheral arteries. Simulation of arterial vasodilatation in a multi-branched model of the systemic arterial system confirmed this interpretation. Dilatation of peripheral arteries explains in part the beneficial effects of GTN in adult man.

Effect of glyceryl trinitrate on peripheral arteries alters left ventricular hydraulic load in man

The input impedance of the systemic circulation was calculated from recordings of pulsatile pressure and flow in the ascending aorta of 20 patients. Ten patients had clinical and hemodynamic evidence of heart failure. The other 10 subjects had no clinical evidence of heart failure and were used as a control group. In the heart failure patients, both input resistance and characteristic impedance (index of aortic distensibility) were significantly increased compared to pressure- and age-matched control subjects. Oscillations of impedance moduli, represented by the difference between maximum and minimum moduli, were also significantly increased in the heart failure patients compared with the control subjects. The increased characteristic input impedance in these heart failure patients suggests that the human aorta is stiffer in heart failure, and the larger oscillations in the impedance spectrum indicate an increase in pressure and flow wave reflections. From reflected wave theory in elastic tubes, reflected pressure waves add to the amplitude of incident pressure waves at the entrance of the system, whereas reflected flow waves subtract from the magnitude of the forward flow. Thus, changes in aortic distensibility could have an important influence on the pulsatile function of the failing left ventricle.

Aortic input impedance in heart failure.

The acute coronary hemodynamic and metabolic effects of intravenous dipyridamole were studied in 13 patients. Total left ventricular (LV), anterior (supplied by the left anterior descending coronary artery) and inferior (supplied by circumflex and right coronary arteries) regional flows and metabolic responses were assessed from the coronary sinus and great cardiac vein. Perfusion to LV regions was classified as potentially "normal" or "abnormal," based on coronary angiographic findings. Before dipyridamole, coronary flow, LV oxygen delivery and lactate extraction in both the normal and abnormal regions were similar. Within 1 minute after injection of 20 mg of dipyridamole by i.v. bolus, total coronary flow increased 51% (p less than 0.05). Fifteen minutes after injection the flow increase persisted. Flow decreased to approximately control level by 20 minutes. The major component of this increased total coronary flow resulted from increased flow in normal regions (75% at 1 minute, p less than 0.05). Mean regional LV oxygen delivery and lactate extraction were not changed significantly in either normal or abnormal regions. However, lactate production occurred more often after dipyridamole in abnormal regions. These results suggest that during dipyridamole-induced hyperemia, regional coronary flow and metabolic responses depend upon the status of the arteries supplying the LV region. Regional differences in flow and metabolism occur independent of major changes in heart rate and aortic and LV pressures.

Acute effect of intravenous dipyridamole on regional coronary hemodynamics and metabolism.

Total left ventricular external power and aortic input impedance spectra were calculated from recordings of pulsatile pressure and flow in the ascending aorta of 22 human subjects undergoing cardiac catheterization. Eleven subjects had increased aortic pressure (systolic 153 +/- 3.8[SEM] mm Hg, p less than .001; diastolic 91 +/- 2.4 mm Hg, p less than .03; mean 118 +/- 2.4 mm Hg, p less than .001) and constituted the group with mild hypertension (average age 50 +/- 1.9 years). The other 11 (age-matched) subjects had normal arterial pressures and constituted the control group. Cardiac output in the hypertensive group was abnormally high (6.9 +/- 0.3 liters/min, p less than .04) compared with that in control subjects (6.1 +/- 0.2 liters/min), so that peripheral resistance was similar. Characteristic aortic impedance (index of aortic elastance) was increased in the hypertensive group (142 +/- 19 vs 72 +/- 4.5 dyne-sec-cm-5, p less than .002), as was the fluctuation of impedance moduli and phase. These elevated pulsatile components of arterial load were associated with a significant (p less than .002) increase in pulsatile left ventricular external power (89%), and the increased cardiac output was associated with a significant (p less than .001) increase in steady flow power (31%). The ratio of pulsatile to total power was also increased (38%) in the hypertensive group (p less than .001). Increased characteristic aortic impedance in the hypertensive group suggests that the human aorta is stiffer, and fluctuations in the impedance spectra suggest increased or less dispersed wave reflections.(ABSTRACT TRUNCATED AT 250 WORDS)

Wilmer W. Nichols

Papers

Effect of glyceryl trinitrate on peripheral arteries alters left ventricular hydraulic load in man

Aortic input impedance in heart failure.

Acute effect of intravenous dipyridamole on regional coronary hemodynamics and metabolism.

Ventricular/vascular interaction in patients with mild systemic hypertension and normal peripheral resistance.

Pulse waveform analysis and arterial stiffness: realism can replace evangelism and scepticism.