Robert S. Reneman

Concentration and Velocity Profiles of Blood Cells in the Microcirculation

Although this chapter basically deals with the concentration and velocity profiles of blood cells in general, most of the data presented concern blood platelets. These small blood cells, with a density close to that of blood plasma, can be nicely used as natural markers of flow by fluorescently labeling them in vivo allowing their localization and the assessment of blood flow velocities at various sites in microvessels. Because of their role in hemostasis, thrombosis, and maintaining endothelial cell integrity, blood platelets can be expected to come in contact with the vessel wall. Recent in vivo studies have shown that blood platelets indeed do come close to the wall in arterioles(1,2), but less so in venules. In the latter microvessels a relatively large zone near the vessel wall from which blood platelets seem to be expelled, has to be appreciated(2).

Serum-myocardium gradients of non-esterified fatty acids in dog, rat and man

In the three species under investigation (dog, rat and man) a gradient from serum to heart tissue for total non-esterified fatty acids was assessed. The ratios serum/left ventricular tissue in dogs, serum/right auricular appendage in dogs, serum/whole heart tissue in rats and serum/right auricular appendage in man were found to be 6.4, 2.5, 5.6 and 2.8, respectively. The highest gradient was found for oleic acid, whereas no significant gradient for arachidonic acid could be detected. In the dog the arterio:local venous differences of non-esterified fatty acids across the left ventricular tissue correlated better with the serum/tissue ratio of non-esterified fatty acids than with the arterial non-esterified fatty acid level. Since the correlation coefficient (0.74) was still far from excellent, more factors than the non-esterified fatty acid serum/tissue gradient are likely to be involved in determining the extent to which non-esterified fatty acids are extracted by myocardial tissue.

Wall Shear Rate in Arterioles: Least Estimates from in Vivo Recorded Velocity Profiles

In this chapter velocity profiles, as recorded in mesenteric arterioles of the rabbit with the use of fluorescently labeled platelets as natural flow markers, are described. These velocity profiles are flattened parabolas with maximal and mean velocity ratios varying between 1.39 and 1.54 (median; 1.50). The wall shear rate values estimated from these velocity profiles, considering a two phase model, range from 472 to 4712 s−1 (median: 1700 s−1) for centerline red blood cell velocities varying between 1.3 and 14.4 mm.s−1. These wall shear rate values are at least 1.46 to 3.94 (median 2.12) times higher than those expected on the basis of a parabolic velocity profile, but with the same volume flow in the vessel.

Regional Electromechanical Coupling During Ventricular Pacing

Cardiac pacing can modulate heart rate, atrial filling and the sequence of electrical activation. The first pacemakers were mainly meant to normalise heart rate. More recently dual-chamber pacing enabled optimisation of the atrioventricular interval and, hence, ventricular filling. However, the effects of asynchronous electrical activation of the ventricular wall, caused by impulse conduction via muscle fibres rather than via the Purkinje system, has received little attention.

Alterations in Membrane Phospholipids During Ischemia and Reperfusion

Loss of cellular integrity in the cardiomyocyte is most probably caused by overt rupture of cellular membranes, in particular the sarcolemma enclosing the cytoplasmic space. A variety of mechanisms may underlie the process of destabilization of the sarcolemma, which occurs prior to irreversible disintegration of the semipermeable barrier between the extra- and intracellular environment. The factors thought to provoke membrane instability are chemical (hydrolysis and synthesis of membrane phospholipids), physicochemical (including loss of phospholipid asymmetry, phase transition of membrane phospholipids, and extrusion of lipid material from the membrane), and ultrastructural (detachment of cytoskeleton and sarcolemma, and impaired anchoring of basement membrane to sarcolemma). During the acute phase of reperfusion, production of oxygen free-radicals, enhanced cytoplasmic levels of Ca2+, osmotic load, and resumption of contractile activity may cause directly or indirectly overt rupture of the cellular membrane, weakened during the preceding ischemic insult.

Integrity of Myocardial Fiber Structure Maintained by Fiber Load Induced Local Growth

In a mathematical simulation of left ventricular wall mechanics, it is hypothesized that the process of left ventricular hypertrophy is controlled by the feedback signals: fiber stress, end-diastolic sarcomere length, and sarcomere shortening during ejection. In this simulation, a stable final solution is found for the transmural course of fiber orientation, in which cardiac muscle is loaded homogeneously within ± 2%. The solution is self-correcting for deviations in the anatomical structure. The transmural course of fiber orientation thus found is not significantly different from anatomical findings reported in many species. Thus, according to the simulation, the global, complicated cardiac structure can be maintained by control signals on the cellular level.

Adaptation of the Left Ventricular Wall Under Pathological Circumstances

As a reaction to hormonal and mechanical stimuli, the ventricular wall adapts to enhanced workload through hypertrophy of individual myocytes. In the hypertrophic process, the growth of cardiac cells results from an increase in protein content per myocardial cell. The most important cellular features of the myocardial hypertrophic response are an increase in the content of contractile proteins, such as myosin heavy chain, myosin light chain-2, β-tropomyosin, and α-skeletal and α-cardiac actin, the induction of contractile protein isoforms—at least in some species—and the expression of embryonic markers. The expression of proto-oncogenes, genes related to growth, is an early phenomenon in the hypertrophic response. In pressure-overload hypertrophy, the sarcoplasmic reticular (SR)-Ca2+ ATPase content, and hence activity, is decreased. In cardiac hypertrophy, the extracellular content (mg) of both collagen and fibronectin increases, mainly in the interstitial space. The collagen concentration (mg/g), however, does not necessarily change and there is increasing evidence that the functional consequences of the changes in extracellular matrix collagen have to be ascribed to the type of collagen expressed and/or cross-linking of collagen. These changes combined with the decrease in SR-Ca2+ ATPase activity, enhancing cytoplasmic Ca2+ content, probably explain the increased diastolic stiffness of the left ventricle observed during pressure- and volume-overload hypertrophy. Although the molecular changes occurring during a hypertrophic response have been well documented, the way in which myocardial cells sense the change in loading, and the mechanisms through which forces are converted to biomechanical signals regulating cardiac genes during growth, are still incompletely understood. Both stretching of cardiomyocytes and contraction of myofibrils induce the expression of protooncogenes followed by protein translation. Although the signal responsible for the induction of the hypertrophic response is not precisely known, there is increasing evidence that protein kinases, especially protein kinase C, play an important role. Most of the data obtained on the hypertrophic response are derived from studies using pressure- or volume-overload as a stimulus. One should realize, however, that the molecular changes observed under these circumstances do not necessarily hold for other forms of hypertrophy. For example, differences between pressure-overload hypertrophy and hypertrophy induced by thyroid hormone have been described. Even so, species differences have to be appreciated. Most of the information about the molecular changes in the hypertrophic response of the heart has been obtained in studies performed on cardiomyocytes in culture. Although the set-ups used seem to mimic the pathophysiological situation rather well, it remains to be seen whether the results obtained in these models can be extrapolated to the in vivo situation.

Degradation of Membrane Phospholipids in the Ischemic and Reperfused Heart

Under normal circumstances cardiac cells provide sufficient amounts of energy by oxidative degradation of substrates such as fatty acids, glucose and lactate to fulfil their energy requirements. Contraction and relaxation of the myofibrils consume over 70 of ATP produced by mitochondrial activity, the remaining part is used for transport of ions across membranes, and maintenance of cellular integrity. The plasmalemma, the membrane enclosing the content of living cells, plays a crucial role in the complex process of maintenance of integrity. As soon as the plasmalemma is no longer capable of maintaining a barrier between the extracellular and intracellular compartments, the cell will die (1). Loss of semi-permeable properties of the plasmalemma results in release of metabolites and cytoplasmic proteins, required for enzymatic or transport processes, and influx of extracellular macromolecules and calcium ions into the interior of the injured cell (1). This condition, usually designated as cell death, will be followed by degenerative changes such as lysis of the cellular remnants by lysosomal enzymes and by macrofages invading the damaged area of the heart. A variety of pathophysiological derangements may lead to death of cardiac cells. The most common cause of cellular injury and cell death is ischemia (insufficient blood supply to the heart). Restoration of flow to previously ischemic areas may inflict additional damage upon the injured cells.

Diminished Tolerance to Ischemia of Hypertrophied Hearts

The findings presented in this survey indicate that old, not fully compensated, hypertrophied hearts are more vulnerable to ischemia than non-hypertrophied hearts of comparable age. Also, young fully compensated hypertrophied hearts have a similar susceptibility to ischemia as non-hypertrophied hearts of comparable age, provided that they are perfused at a relatively high pressure, leading to a similar coronary flow rate per gram tissue.

Nonesterified Fatty Acid Metabolism and Membrane Disorders in Myocardial Ischemia and Reperfusion

Under normal circumstances, 40%–60% of the circulatory non esterified fatty acids (NEFAs) are extracted from the heart in a single transit time [1]. The majority of NEFAs are oxidized in the mitochondria for energy delivery. Such NEF As as arachidonic acid, linoleic acid, and docosahexaenoic acid are mainly incorporated into phospholipids, a major constituent of cell membranes. In this respect, species differences and the effect of nutrition have to be appreciated. For example, in the dog, myocyte membranes mainly consist of arachidonic acid and linoleic acid, while membrane lipids of rat myocytes mainly consist of arachidonic acid and docosahexaenoic acid.