Wilmer W. Nichols

Effects of age on ventricular-vascular coupling

The effects of age on the interrelation between the physical properties of the arterial tree (aortic input impedance) and left ventricular performance (cardiac output) were studied in 45 subjects, aged 19 to 62 years, without apparent cardiovascular disease. Ascending aortic pulsatile pressure and blood flow velocity were measured with a multisensor catheter and cardiac output by green dye or the Fick method. Heart rate and end-diastolic aortic pressure remained unchanged with age, whereas aortic systolic, mean and pulse pressures and aortic radius increased. In subjects younger than 30 years, early systolic pressure usually exceeded late systolic pressure (type C beat); in subjects older than 50 years, late systolic pressure usually exceeded early systolic pressure (type A beat). In 55% of subjects aged 30 to 50 years, early and late systolic pressures were essentially equal (type B beat). The impedance spectra from all subjects showed fluctuations about the characteristic impedance (index of elastance) that were greater in the older subjects. Peripheral resistance increased 37% (r = 0.47, p less than 0.001) over the age range of 20 to 60 years, whereas characteristic impedance increased 137% (r = 0.66, p less than 0.001). The fundamental impedance modulus increased, and the impedance modulus minimum shifted to a higher frequency. These changes in the impedance spectral pattern indicate that the ascending aorta becomes stiffer and the cross section of the peripheral vascular bed decreases with age, causing increased pulse wave velocity and wave reflection.(ABSTRACT TRUNCATED AT 250 WORDS)

Recommendations for Improving and Standardizing Vascular Research on Arterial Stiffness: A Scientific Statement From the American Heart Association.

Much has been published in the past 20 years on the use of measurements of arterial stiffness in animal and human research studies. This summary statement was commissioned by the American Heart Association to address issues concerning the nomenclature, methodologies, utility, limitations, and gaps in knowledge in this rapidly evolving field. The following represents an executive version of the larger online-only Data Supplement and is intended to give the reader a sense of why arterial stiffness is important, how it is measured, the situations in which it has been useful, its limitations, and questions that remain to be addressed in this field. Throughout the document, pulse-wave velocity (PWV; measured in meters per second) and variations such as carotid-femoral PWV (cfPWV; measured in meters per second) are used. PWV without modification is used in the general sense of arterial stiffness. The addition of lowercase modifiers such as “cf” is used when speaking of specific segments of the arterial circulation. The ability to measure arterial stiffness has been present for many years, but the measurement was invasive in the early times. The improvement in technologies to enable repeated, minimal-risk, reproducible measures of this aspect of circulatory physiology led to its incorporation into longitudinal cohort studies spanning a variety of clinical populations, including those at extreme cardiovascular risk (patients on dialysis), those with comorbidities such as diabetes mellitus (DM) and hypertension, healthy elders, and general populations. In the ≈3 decades of clinical use of PWV measures in humans, we have learned much about the importance of this parameter. PWV has proven to have independent predictive utility when evaluated in conjunction with standard risk factors for death and cardiovascular disease (CVD). However, the field of arterial stiffness investigation, which has exploded over the past 20 years, has proliferated without logistical guidance for clinical and …

Input impedance of the systemic circulation in man.

To determine the systemic input impedance, pulsatile pressure and flow were measured in the ascending aorta in 16 human subjects who were undergoing diagnostic cardiac catheterization. Blood flow was measured with a catheter-tip electromagnetic velocity meter, and pressure with an external transducer connected with the fluid-filled lumen of the catheter. Five subjects were found to have no evidence of cardiovascular disease (group A, mean age 32 ± 2 years, mean aortic pressure 97 ± 4 mm Hg). Seven had clinical and angiographic signs of coronary arterial disease, and mean pressures less than 100 mm Hg (group B, mean age 48 ± 2 years). Four subjects had signs of coronary disease and mean pressures greater than 100 mm Hg (group C, mean age 48 ± 3 years). The frequency spectra of impedance were qualitatively similar in all three groups and resembled those previously observed in the canine aorta. Characteristic impedance was lower in the normal subjects (group A, average 53 dyn sec cm−5) than in the subjects with coronary artery disease (groups B and C, average 129 dyn sec cm−5). Among the subjects with coronary disease, characteristic impedance was higher in the hypertensive subjects (group C, average 202 dyn sec cm−5) than in those with lower mean pressures (group B, average 95 dyn sec cm−5). External left ventricular work per unit time (hydraulic power) averaged 1715 milliwatts (mW) in group A, 1120 mW in group B, and 2372 mW in group C. Cardiac outputs were within normal limits in all subjects, but tended to be lower in group B than in group C. These results suggest that the subjects of group C were better able to meet the increased energy demands imposed by an abnormally high aortic input impedance. Further investigation is needed to learn whether the high impedances in subjects with coronary disease represent an increase with age and transmural pressure alone, or whether some additional factor is involved. The data on relatively normal subjects permit a tentative definition of the normal limits for aortic input impedance in man: 26-80 dyn sec cm−5.

In vivo validation of a thermodilution method to determine regional left ventricular blood flow in patients with coronary disease.

SUMMARY Several methods have been used to measure left ventricular regional blood flow in humans. However, limitations and lack of validation in patients are major problems. A continuous thermodilution technique to measure regional left ventricular blood flow in patients with coronary disease was validated in vivo. This technique permits simultaneous assessment of venous blood flow draining predominantly from the anterior wall and of the total left ventricular effluent. Thermodilution measurements with simultaneous electromagnetic flowmeter recordings from anterior descending vein grafts were compared in patients with occluded or subtotally occluded anterior descending coronary arteries. The thermodilution method yielded values for both absolute anterior regional blood flow and changes in anterior regional flow that compared closely to anterior descending bypass graft flow measured independently. The multithermistor technique may be useful in monitoring flow effects of regional coronary disease over time, as well as in studies of agents purported to alter regional blood flow.

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

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 < 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 < 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.

Arterial elastance and wave reflection augmentation of systolic blood pressure : deleterious effects and implications for therapy

Systolic and pulse blood pressures are stronger predictors of stroke, coronary heart disease, myocardial infarction, heart failure, end-stage renal disease, and cardiovascular mortality than diastolic pressure. Furthermore, diastolic pressure is inversely related to coronary heart disease and cardiovascular mortality. Increased elastance (or stiffness, inverse of compliance) of the central elastic arteries is the primary cause of increased systolic and pulse pressure with advancing age and in patients with cardiovascular disease, including hypertension, and is due to degeneration and hyperplasia of the arterial wall; diastolic pressure decreases as arterial elastance increases. As elastance increases, transmission velocity of both forward and backward (or reflected) traveling waves increases, which causes the reflected wave to arrive earlier in the central aorta and augments pressure in late systole. These changes in arterial wall properties cause an increase in left ventricular afterload and myocardial oxygen consumption and a decrease in myocardial perfusion pressure, which may induce an imbalance in the supply-demand ratio, especially in hypertrophied hearts with coronary artery disease. Also, an increase in systolic pressure increases arterial wall circumferential stress, which promotes fatigue and development of athersclerosis. Vasodilator drugs have little direct active effect on large elastic arteries but can markedly reduce wave reflection amplitude and augmentation index by decreasing elastance of the muscular arteries and reducing pulse wave velocity of the reflected wave from the periphery to the heart. This decrease in intensity (or amplitude) and increase in travel time (or delay) of the reflected wave causes a generalized decrease in systolic pressure and arterial wall stress and an increase in ascending aortic flow during the deceleration phase. The decrease in systolic pressure brought about by this mechanism is grossly underestimated when systolic pressure is measured in the brachial artery.

Aortic input impedance in heart failure.

SUMMARY 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 pressureand 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.

Effects of Arterial Stiffness, Pulse Wave Velocity, and Wave Reflections on the Central Aortic Pressure Waveform

Brachial systolic and pulse blood pressures (BPs) are better predictors of adverse cardiovascular (CV) events than diastolic BP in individuals older than 50 years. The principal cause of increased systolic and pulse BP is increased stiffness of the elastic arteries as a result of degeneration and hyperplasia of the arterial wall. Recent studies have shown that central BP, the pressure exerted on the heart, brain, and kidneys, is a better predictor of CV risk than brachial BP. As stiffness increases, reflected wave amplitude increases and augments pressure in late systole, producing an increase in left ventricular afterload and myocardial oxygen demand. Vasoactive drugs have little direct effect on large human elastic arteries but can markedly modify wave reflection by altering stiffness of the muscular arteries and changing pulse wave velocity of the reflected wave from the periphery to the heart. Vasodilators decrease the amplitude and increase the travel time (or delay) of the reflected wave, causing a generalized decrease in systolic BP. The decrease in systolic BP brought about by this mechanism is grossly underestimated when systolic BP is measured in the brachial artery.

Inhibition of Arterial Thrombus Formation by ApoA1 Milano

The mutant form of human apoA1, known as apoA1 Milano, is formed as a result of arginine 173 to cysteine substitution and inhibits experimental atherosclerosis in cholesterol-fed animals. This study was designed to determine if apoA1 Milano would modify arterial thrombogenesis. Sprague Dawley rats were intravenously administered the carrier alone (n=8) or apoA1 Milano (20 mg. kg-1. d-1 for 4 to 10 days, n=17). The abdominal cavity was opened, and the abdominal aorta was isolated. Whatman paper impregnated with 35% FeCl3 was wrapped around the surface of the aorta, and aortic flow was recorded continuously. In carrier-treated rats, an occlusive platelet-fibrin-rich thrombus was formed in 21.2+/-4.1 (mean+/-SD) minutes. Treatment of rats with apoA1 Milano markedly delayed time to thrombus formation (38.8+/-11.9 versus 21.2+/-4.1 minutes, P<0. 01), inhibited platelet aggregation (25+/-7% versus 50+/-11%, P<0. 01), and reduced weight of the thrombus (18.5+/-1.8 versus 23.7+/-2. 3 mg/cm, P<0.01). Total cholesterol and HDL levels remained similar in both groups of rats, but plasma apoA1 Milano levels were elevated in apoA1 Milano-treated rats. In in vitro studies, incubation of platelets with apoA1 Milano reduced ADP-induced platelet aggregation by about 50%, but apoA1 Milano had no direct effect on vasoreactivity. This study provides further evidence for critical role of platelets in thrombosis. Use of apoA1 Milano offers a novel approach to inhibit arterial thrombosis.

Coronary and systemic hemodynamic effects of nicardipine

Systemic and coronary hemodynamic effects of a new dihydropyridine calcium antagonist, nicardipine, were studied in 15 patients. Nicardipine was administered as a 2-mg bolus intravenously followed by an infusion titrated to maintain a 10 to 20-mm Hg decrease in systolic pressure. Nicardipine increased both heart rate from 69 +/- 3 to 81 +/- 3 beats/min and cardiac output from 7.3 +/- 0.5 to 9.9 +/- 0.5 liters/min (both p less than 0.001) as systemic vascular resistance decreased from 1,183 +/- 70 to 733 +/- 33 dynes s cm-5 (p less than 0.001). Left ventricular end-diastolic pressure remained constant, at 14 +/- 1 vs 14 +/- 1 mm Hg as stroke volume increased from 108 +/- 6 to 123 +/- 6 ml/m2 (p less than 0.001). Coronary blood flow increased from 102 +/- 9 to 147 +/- 13 ml/min, while coronary resistance decreased from 1.17 +/- 0.1 to 0.7 +/- 0.1 mm Hg/ml/min (both p less than 0.001). Heart rate-systolic blood pressure product did not change (104 +/- 5 vs 106 +/- 5 beats/min mm Hg X 10(-2), difference not significant) with drug administration. At the same heart rate before and during nicardipine administration (using atrial pacing in 6 patients), significant augmentation of coronary flow was still observed. Thirteen of 14 patients showed a greater percent decrease in coronary resistance than systemic vascular resistance. Nicardipine differs from other calcium antagonists with respect to consistent augmentation of coronary blood flow. This effect appears to be the result, in part, of increased potency in the coronary bed compared with the systemic vascular bed.