Changes in arterial function in a mouse model of human familial hypercholesterolaemia.

AIM: Atherosclerosis is the most common cause of cardiovascular disease. The ApoB mouse is a model for human familial hypercholesterolaemia and has a lipoprotein profile similar to that of humans with atherosclerosis. Therefore, it is a suitable model to investigate the changes in vasoreactivity during atherogenesis. This study investigates contractile and dilatative properties of arteries in this model in relation to age. METHODS: Male ApoB mice and B6, wild-type (WT), mice were examined at age four or 18 months. Isometric measurements of 2-mm ring preparations of the aorta thoracica were performed using a wire myograph. Histological and biochemical methods served to determine atherosclerosis, lipid status and endothelial markers respectively. RESULTS: Morphometric analysis showed that all old ApoB mice had severe atherosclerosis in the aorta. Atherosclerotic alteration of the aorta of the ApoB mice coincided with a diminished vasodilatation to acetylcholine. The phenylephrine response was significantly attenuated already to the same degree in the non-atherosclerotic aorta of the young ApoB mice as in the atherosclerotic aorta of the older ApoB mice. Serum parameters showed a rise in total cholesterol and triglycerides in the ApoB strain compared to WT mice. Soluble intercellular adhesion molecule (sICAM)-1 and soluble vascular adhesion molecule (sVCAM)-1 were increased in old compared to young ApoB mice. CONCLUSION: The study shows that reduced acetylcholine-induced dilatation is related to the presence of atherosclerosis in old ApoB mice. Remarkably, the impaired vessel reactivity to phenylephrine already in young ApoB mice indicates early changes in vascular function in this model.

Cardiovascular responses to angiotensin II in atherosclerosis.

Atherosclerosis is associated with increased angiotensin II AT1-receptor expression and vascular hyperresponsiveness to angiotensin II. Nevertheless, atherosclerosis is often not accompanied by hypertension. We studied if the hypertensive effect of angiotensin II is more pronounced in atherosclerosis. Rabbits were fed a high-cholesterol diet (n = 10) for 12 weeks, followed by a standard diet for another 6 weeks. Control animals received the standard diet (n = 8) for 18 weeks. After 18 weeks, haemodynamic measurements were performed during a baseline recording and during an intravenous infusion of angiotensin II (0.4 microg kg-1 min-1). Atherosclerosis in the high-cholesterol group was verified by histological and lipidchemical tissue examinations. During angiotensin II infusion, total peripheral resistance (TPR) increased more in the high-cholesterol group than in controls (+81.6 +/- 12.4 vs. +40.6 +/- 9.7 mmHg min L-1, P < 0.05). While cardiac output and stroke volume (SV) decreased more in the high-cholesterol group (P < 0.05), reflex bradycardia was stronger in the control group (P < 0.05), indicating a reduced baroreceptor reflex sensitivity in atherosclerosis. Despite the larger increase in TPR and the reduced baroreceptor reflex sensitivity in the high-cholesterol group, maximum blood pressure response to angiotensin II was similar in both groups. The lack of a greater blood pressure response to angiotensin II in the high-cholesterol group could be the result of the early stages of heart failure. Under resting conditions, heart failure seems to be fully compensated, as baseline haemodynamic parameters were similar in the high-cholesterol group and in controls. However, during angiotensin II infusion, the compensatory mechanisms do not prevent a stronger fall in cardiac output and SV. Therefore, the blood pressure response to angiotensin II is not exaggerated in atherosclerotic animals, as vascular hyperresponsiveness to angiotensin II is opposed by the stronger fall in cardiac output and SV.

Vascular response to angiotensin II in atherosclerosis: role of the baroreflex.

High-cholesterol alimentation is associated with an induction of angiotensin-converting enzyme and angiotensin II receptor expression within the vascular wall of the aorta. Despite an enhanced pressure response to angiotensin II in atherosclerotic conscious rabbits, angiotensin II-induced contraction was reduced in isolated vascular rings from the aorta and unchanged in those from the iliac artery. We, therefore, investigated whether cholesterol-induced atherosclerosis enhances overall vascular responsiveness to angiotensin II in intact animals and whether an altered arterial baroreflex sensitivity can explain the discrepancy between experiments in intact animals and isolated blood vessels. Rabbits were maintained on a high-cholesterol diet (2 g/d cholesterol plus 20 mL/d sunflower seed oil, n=11) or on a standard diet (n=12) for 12 weeks. Total serum lipids markedly increased (P<0.05). Tissue examinations 6 weeks after termination of the high-cholesterol diet revealed distinct atherosclerosis and elevated cholesterol content in the aorta (P<0.05). A high-cholesterol diet did not change baseline hemodynamic parameters. However, angiotensin II-induced increases in total peripheral resistance were larger in the atherosclerotic animals (86.3+/-13.0 versus 41.9+/-9.7 mm Hg. L(-1). min, P<0.05). In addition, the blood pressure pulse interval relationship was markedly reduced (slope: 0.80+/-0.14 versus 0. 49+/-0.06 ms/mm Hg, P<0.05), which suggested that the baroreflex blunted the angiotensin II response to a lesser extent in atherosclerotic animals. In conclusion, the overall vascular responsiveness to angiotensin II is increased in the atherosclerotic rabbit as indicated by the larger increase in total peripheral resistance. An attenuation of the arterial baroreflex sensitivity may contribute to this effect.

[Ultrastructural and functional changes of rabbit myocardium after cholesterol feeding]. / Ultrastrukturelle und funktionelle Veränderungen des Kaninchenmyokards nach Cholesterolfütterung.

The myocardium was ultrastructurally investigated immediately after 12 weeks of feeding in one part of the animals and in the remaining animals 27--30 months after termination of the feeding period. At the same time, parameters of the myocardial contraction were measured immediately after the feeding at isolated trabeculae of the left ventricle and 27--30 months after the termination of the feeding at the left ventricle in situ. After the 12 weeks of feeding the morphometrically estimated intracellular lipid content rises from 0.23% (normal) to 5.26%. The mitochondria decline from 36.98% (normal) to 29.08%. The sarcoplasmic reticulum (SR) changes in a vesicular or vacuolar manner respectively. The contractility index Vmax of isolated trabeculae decreases insignificantly. The resting potentiation and the diastolic stiffness are increased. 27--30 months after termination of feeding the lipid content and the mitochondria are normal in comparison to controls of the same age. The vacuolar changes of SR and its cellular portion are increased. The contractility index of the heart in situ max (dp/dt)/P is decreased insignificantly. The velocity of relaxation is enhanced in comparison with controls. By comparing ultrastructural and functional findings it can be seen that variations in the contraction performance are accompanied by stronger changes of the cellular structure immediately after the feeding than 27--30 months after the termination of the feeding. At this time continuing small alterations in the contraction performance of the heart in situ are observed in addition to the reversibility of various characteristics of damage together with an increase in the Ca++-transporting SR and its alterations.

[Systolic and diastolic load of right heart and right bundle block]. / Systolische und diastolische belastung des rechten Herzens und Rechtsschenkelblock

Analysing the Ecg and VCG of 818 subjects, healthy or with different congenital and acquired cardiopaties, the frequency of right bundle branch block (RBBB) is established to decrease with the increase in age of children, and is observed to be 8.9% in healthy adults. The right bundle block is observed in 82.5% of the patients with atrial septal defect and quite often in patients with right ventricle tension loading, gradually decreasing with the level of the left ventricle loading, as well as with the development of extreme right ventricle hypertrophy. Out of 50 experiments with dogs with acute and chronic right heart tension loading it is evident that the number of certain and marginal (uncertain) cases with RBBB steadily increases. At the same time this increase cannot be connected with the type of loading, in dogs in which dilatation of the right ventricle is presented as well as in others with light or marked hypertrophy. Besides, under the same conditions and durations of loading some hearts exhibit RBBB, while others do not. What has been stated before gives enough grounds to accept that RBBB in healthy subjects, as well as in patients with congenital and acquired cardiopaties manifests the electromotive tension (EMT) of persistent from foetal and children-age more pronounced physiological hypertrophy (as normal variant) of the basal part of the right ventricle. Whether the picture of RBBB is retained, pronounced or disappears is determined by the correlation between the quantity and the time-manifestation of EMT of the left ventricle and of the corps part of the right ventricle.

[Method for the immediate measurement of myocardial pressure velocity relationships in situ]. / Verfahren zur momentanen Erfassung von Druck-Geschwindigkeits-Beziehungen am Herzen in situ

A method for instantaneous measurements and representations of myocardial pressure-velocity relations permitting the analysis of various contractility parameters is described. Basing on a modified two-element model of cardiac muscle the measurement of the relative shortening velocity vce = dp/dt(p) of the contractile elements is carried out by a special analog computer, which calculates the quotient (dp/dt) to the simultaneous left ventricular pressure p. Electronic differentiation of the logarithm of pressure-proportional input voltages is used. The p-v-diagram can be displayed on x-y-oscilloscopes. Over an input voltage range of 20 mV---20V the quotient can be measured within the range of 20 sec-1---250 sec-1. Output voltages can be calibrated automatically. Between (dp/dt)p-1 determined by conventional methods and the dlnp/dt calcuated electronically there exists a correlation gamma = 0.995. An additional electronic circuit which permits the determination of a contractility parameter indicates the point of (dp/dt)max on the p-v-relation display. The application of the method in experimental studies under inotropic changes in the rabbit heart in situ following beta-receptor blockade is demonstrated.

A comparison between noninvasive and bloody methods for use in the continuous estimation of cardiac contractility.

Simultaneous measurements of the blood pressure in arteria carotis with a catheter device and a new noninvasive continuously recording method were carried out in 7 rabbits with a chronically isolated arteria carotis loop. Results show good correspondence between both methods for pulse curve and blood pressure over a long period and a wide range,as well as good reproducibility. An absolute calibration for the noninvasive method is impossible. The new method is quite suitable for studying the dynamics of pressure pulse and pressure behavior.