Stephen E. Greenwald

Ageing of the conduit arteries.

Conduit arteries become stiffer with age due to alterations in their morphology and the composition of the their major structural proteins, elastin and collagen. The elastic lamellae undergo fragmentation and thinning, leading to ectasia and a gradual transfer of mechanical load to collagen, which is 100–1000 times stiffer than elastin. Possible causes of this fragmentation are mechanical (fatigue failure) or enzymatic (driven by matrix metallo proteinases (MMP) activity), both of which may have genetic or environmental origins (fetal programming). Furthermore, the remaining elastin itself becomes stiffer, owing to calcification and the formation of cross‐links due to advanced glycation end‐products (AGEs), a process that affects collagen even more strongly. These changes are accelerated in the presence of disease such as hypertension, diabetes and uraemia and may be exacerbated locally by atherosclerosis. Raised MMP activity, calcification and impaired endothelial function are also associated with a high level of plasma homocysteine, which itself increases with age. Impaired endothelial function leads to increased resting vascular smooth muscle tone and further increases in vascular stiffness and mean and/or pulse pressure. The effect of increased stiffness, whatever its underlying causes, is to reduce the reservoir/buffering function of the conduit arteries near the heart and to increase pulse wave velocity, both of which increase systolic and pulse pressure. These determine the peak load on the heart and the vascular system as a whole, the breakdown of which, like that of any machine, depends more on the maximum loads they must bear than on their average. Reversing or stabilising the increased arterial stiffness associated with age and disease by targeting any or all of its causes provides a number of promising new approaches to the treatment of systolic hypertension and its sequelae, the main causes of mortality and morbidity in the developed world. Copyright

Impaired synthesis of elastin in walls of aorta and large conduit arteries during early development as an initiating event in pathogenesis of systemic hypertension

There is much evidence that people who had low birthweight tend to have higher blood pressure in later life. However, the mechanisms that mediate this relation are unknown. We argue that, in fetuses whose growth is impaired, synthesis of elastin in the walls of the aorta and large arteries may be deficient, and that this deficiency would lead to permanent changes in the mechanical properties of these vessels. Over a lifetime, such changes could predispose an individual to higher blood pressure, increased left-ventricular mass, and cardiovascular disease.

Improving vascular grafts: the importance of mechanical and haemodynamic properties

In the last 40 years, as techniques and materials have improved, the success rate of vascular prostheses with a diameter greater than 6mm has risen steadily, 5‐year survival rates exceeding 95% in most centres. With smaller grafts no comparable improvement has occurred, the majority failing within 5 years, usually as a result of intimal hyperplasia and, ultimately atherosclerosis, in and around the downstream anastomosis. Clinical evidence suggests that the patency rates of small grafts are improved by matching the elastic properties of the graft to that of the artery into which it is placed. Although there is little reliable evidence that ‘elastic mismatch’ per se is the cause of intimal hyperplasia, it is generally accepted that mechanical factors are important in its genesis. These include disturbed flow at the anastomosis leading to fluctuations in shear stress at the endothelium (a known cause of intimal hyperplasia in normal arteries), injury due to suturing and stress concentration at the anastomosis. Few suitable materials or techniques have yet been developed to improve the long‐term survival rates of small grafts. Recent advances in tissue engineering in which prostheses are manufactured by culturing vascular smooth muscle cells on a tubular scaffold of biodegradable polymer may ultimately make it possible to manufacture biologically and haemodynamically compatible grafts with diameters as small as 1mm. Copyright

Experimental investigation of the distribution of residual strains in the artery wall

Arterial wall stresses are thought to be a major determinant of vascular remodeling both during normal growth and throughout the development of occlusive vascular disease. A completely physiologic mechanical model of the arterial wall should account not only for its residual strains but also for its structural nonhomogeneity. It is known that each layer of the artery wall possesses different mechanical properties, but the distribution of residual strain among the different mechanical components, and thus the true zero stress state, remain unknown. In this study, two different sets of experiments were carried out in order to determine the distribution of residual strains in artery walls, and thus the true zero stress state. In the first, collagen and elastin were selectively eliminated by chemical methods and smooth muscle cells were destroyed by freezing. Dissolving elastin provoked a decrease in the opening angle, while dissolving collagen and destroying smooth muscle cells had no effect. In the second, different wall layers of bovine carotid arteries were removed from the exterior or luminal surfaces by lathing or drilling frozen specimens, and then allowing the frozen material to thaw before measuring residual strain. Lathing material away from the outer surface caused the opening angle of the remaining inner layers to increase. Drilling material from the inside caused the opening angle of the remaining outer layers to decrease. Mechanical nonhomogeneity, including the distribution of residual strains, should thus be considered as an important factor in determining the distribution of stress in the artery wall and the configuration of the true zero stress state.

Validation of a device to measure arterial pulse wave velocity by a photoplethysmographic method

We aimed to validate a new method for measuring arterial pulsewave transit time and pulsewave velocity (a measure of arterial elasticity), based on the principle of photoplethysmography (PPG), and to compare transcutaneous values with those obtained by intra-arterial measurements. Three validation experiments are described. (a) PPG pulse wave delay times (defined as the time interval between the ECG R wave and the foot of the arterial pulse wave measured at the wrist or ankle) were compared to values obtained simultaneously from an established methodology (Doppler ultrasound). (b) Aortic pulsewave delay times in 17 subjects obtained non-invasively by the PPG method were compared with those obtained from the intra-arterial pressure wave. (c) Repeatability measurements of PWV on the same subjects were carried out over two timescales (minutes and hours) in the arm, the leg and the trunk. The Doppler and PPG delay times correlated well, as did intra-arterial and transcutaneous values. Repeatability at short timescales was good (coefficients of variation (CV) < 6% for all measurement sites) and, at the longer timescale, was satisfactory (CVs in the aorta, the arm and leg were 6.3, 13.1 and 16.0, respectively). The PWV values agreed well with others in the literature. We conclude that the PPG technique provides a complement to existing methods for the non-invasive measurement of arterial compliance. Its simplicity and ease of use make it suitable for large-scale epidemiological studies.

Motion-compensated noncontact imaging photoplethysmography to monitor cardiorespiratory status during exercise

With the advance of computer and photonics technology, imaging photoplethysmography [(PPG), iPPG] can provide comfortable and comprehensive assessment over a wide range of anatomical locations. However, motion artifact is a major drawback in current iPPG systems, particularly in the context of clinical assessment. To overcome this issue, a new artifact-reduction method consisting of planar motion compensation and blind source separation is introduced in this study. The performance of the iPPG system was evaluated through the measurement of cardiac pulse in the hand from 12 subjects before and after 5 min of cycling exercise. Also, a 12-min continuous recording protocol consisting of repeated exercises was taken from a single volunteer. The physiological parameters (i.e., heart rate, respiration rate), derived from the images captured by the iPPG system, exhibit functional characteristics comparable to conventional contact PPG sensors. Continuous recordings from the iPPG system reveal that heart and respiration rates can be successfully tracked with the artifact reduction method even in high-intensity physical exercise situations. The outcome from this study thereby leads to a new avenue for noncontact sensing of vital signs and remote physiological assessment, with clear applications in triage and sports training.

Residual strains in conduit arteries

Residual strains and stresses are those that exist in a body when all external loads are removed. Residual strains in arteries can be characterized by the opening angle of the sector-like cross-section which arises when an unloaded ring segment is radially cut. A review of experimental methods for measuring residual strains and the main results about the variation of the opening angle with arterial localization, age, smooth muscle activity, mechanical environment and certain vascular pathologies are presented and discussed. It is shown that, in addition to their well-established ability to homogenize the stress field in the arterial wall, residual strains make arteries more compliant and thereby improve their performance as elastic reservoirs and ensure more effective local control of the arterial lumen by smooth muscle cells. Finally, evidence that, in some cases, residual strains remain in arteries even after they have been cut radially is discussed.

Morbid anatomy in neonates with Ebstein's anomaly of the tricuspid valve: Pathophysiologic and clinical implications

The hearts of six neonates with Ebsteins anomaly of the tricuspid valve who died in the 1st month of life were compared with hearts of six age- and size-matched control neonates. All six hearts had morphologically severe disease with gross right atrial dilation and marked apical displacement of the tricuspid valve. All had a secundum atrial septal defect and four had additional cardiac lesions (pulmonary atresia in two, ventricular septal defect in two). There was significant thinning of the right ventricular free wall distal to the tricuspid valve (3 +/- 0.2 mm vs. control 4.2 +/- 0.2, p less than 0.01) and right ventricular fiber diameter was reduced (7.2 +/- 0.3 microns vs. control 11.4 +/- 0.6, p less than 0.001). The fibrous tissue content of both right and left ventricular free walls was increased (right, 29.3 +/- 2.6% vs. control 8.7 +/- 1.1, p less than 0.001; left, 23.2 +/- 1.5% vs. control 8.5 +/- 0.7%, p less than 0.001). Although the right ventricular abnormalities might be explained by hemodynamic stress in utero, abnormalities of the left ventricular free wall suggest that either genetic or nonhemodynamic environmental factors are involved in the morphogenesis of this condition. Increased right and left ventricular fibrosis may contribute to the poor early outcome in this group and may predispose to late complications, such as subnormal exercise performance, hemodynamic deterioration or late sudden death that may occur in patients with Ebsteins anomaly who survive the neonatal period.

The effects of maternal protein deprivation on the fetal rat pancreas: major structural changes and their recuperation

There is evidence that low birth weight and poor growth in early life cause a long‐term predisposition to non‐insulin‐dependent diabetes. Morphological changes were assessed in fetal rat pancreas subjected to both pre‐ and post‐natal maternal protein deprivation (LP). Further groups were subjected to purely prenatal maternal protein deprivation (preLP) and purely postnatal maternal protein deprivation (postLP), as well as a control group. The results show that the LP and postLP groups had fewer but larger islets than the control group, while the preLP group had more numerous, smaller islets. All three low protein groups had more irregularly shaped islets than the control group. There was a reduction in the amount of beta cells within each islet in all three protein‐deprived groups. The LP and postLP groups showed a reduction in the percentage of islet tissue and beta cells per pancreas, but the percentage of islet tissue expressed per unit body weight was similar in all four groups. These results show that in maternal protein deprivation, homeostatic mechanisms ensure a constant amount of pancreatic endocrine tissue per unit of body weight. However, there remain major structural changes in the size, shape, and composition of the islets. These results support the theory that early development profoundly affects the structure of the pancreas and may play a role in the later development of adult diseases, such as non‐insulin‐dependent diabetes mellitus.

Twin-twin transfusion syndrome: the influence of intrauterine laser photocoagulation on arterial distensibility in childhood.

Background—In twin-twin transfusion syndrome (TTTS), the donor and recipient fetus are exposed to differing volume loads and show discordant intertwin vascular compliance in childhood despite identical genotype. We hypothesized that discordance is prevented by intrauterine endoscopic laser ablation of placental anastomoses, which abolishes intertwin transfusion. We tested this by examining pulse wave velocity (PWV) in brachial arteries of twin survivors of TTTS treated with and without laser therapy. Methods and Results—One hundred children (50 twin pairs, 27 with TTTS) were studied. Group 1 comprised 14 monochorionic (MC) twin pairs with TTTS treated symptomatically; group 2 comprised 13 MC twin pairs with TTTS treated by laser. The control groups comprised 12 MC twin pairs without TTTS (group 3) and 11 dichorionic twin pairs (group 4). Fetal cardiovascular data, predictive factors for, and duration of TTTS and cord blood were collected prospectively. We measured blood pressure and PWV photoplethysmographically at a median corrected postnatal age of 11 months (range, 1 week to 66 months). Both TTTS groups showed marked intertwin PWV discordance, unlike MCDA control subjects. The PWV discordance seen in laser treated twin pairs resembled that of dichorionic control subjects (heavier individual with higher PWV), whereas group 1 showed the opposite (negative) intertwin discordance (ANOVA F (1,45)=4.5, P =0.04). No significant differences in blood pressure or intrauterine growth were observed between TTTS groups. Conclusions—Vascular programming is evident in monozygotic twins with intertwin transfusion and is altered but not abolished by intrauterine therapy to resemble that seen in dichorionic twins.