Inodilation, i.e., the combination of positive inotropic and vasodilating therapy, conceptually should be an ideal form of heart failure treatment. However, available orally active inodilator drugs, such as beta-agonists, dopaminergic compounds, and agents with phosphodiesterase (PDE)-inhibiting properties, have not been generally accepted for the treatment of heart failure. In contrast, there is serious concern that agents that act predominantly through PDE inhibition and thereby increase cellular cyclic AMP (cAMP) content, e.g., amrinone, milrinone, and enoximone, not only are ineffective in heart failure but also may lead to serious adverse events, i.e., arrhythmogenicity, and may increase mortality rate in advanced heart failure. Similarly, combined beta 1- and beta 2-agonists do not afford long-term clinical efficacy and also may lead to serious ventricular arrhythmias. Moreover, dopaminergic compounds that, besides dopamine-1 and dopamine-2 activation, act through beta-receptor stimulation do not consistently improve the patient's clinical condition. Thus, inodilation by way of increasing cAMP may not be the right approach, at least not in advanced heart failure, in which cAMP-dependent inotropic activity is significantly diminished. In contrast, clinical efficacy may be present when partial PDE inhibitors that also act through calcium sensitization, such as pimobendan, are administered to patients with mild to moderate or moderately severe heart failure. Moreover, adverse events may be less at the lower dose level at which, consequently, the degree of PDE inhibition is reduced. Calcium-sensitizing properties may afford an alternative, more economical way to improve contractile force in failing hearts. Hence, agents that combine calcium sensitization with a relatively low degree of PDE inhibition may well be the inodilators of choice, in particular in mild to moderate failure. Whether they improve the condition of such patients without affecting relaxation and whether they do not lead to adverse events and an increase in mortality rate have as yet to be evaluated. Furthermore, the potential beneficial effect of additional neurohumoral modulation by dopaminergic inodilator compounds and of heart rate-reducing properties of inodilators, such as OPC-8212 and DPI 201-106, needs to be clarified to assess the place, if any, of inodilator therapy in heart failure.

Congestive heart failure is often preceded by a latent or preclinical phase in which patients are relatively asymptomatic. During this period, there is neuroendocrine activation, left ventricular dysfunction, and remodeling of the heart. The extent to which these activities are interrelated is unclear, but it appears from experimental studies that myocardial damage is associated with chronic sympathetic nervous system activation, left ventricular hypertrophy, and a subsequent increase in left ventricular volume. The nondamaged myocardial tissue demonstrates enhanced messenger RNA for angiotensinogen and angiotensin converting enzyme activity. Angiotensin II along with other trophic signals may prime the cell for "growth." Alteration of left ventricular function may produce unusual loading conditions on the myocardium. Stretch of membrane-bound ion channels may impart mechanical signals that may be transduced and expressed as cellular hypertrophy. Interstitial collagenase may be activated, leading to disruption of the collagen-supporting network. Elongated cells (eccentric hypertrophy), cell slippage, and cell dropout may contribute to the dilatative process. The end product is cardiac dilatation, inefficient left ventricular performance, and congestive heart failure. We have observed that an increase in left ventricular mass is the initial morphological response to acute myocardial damage in a canine model. This occurs at 1 week and is followed by progressive activation of the sympathetic nervous system, left ventricular dilatation, and modest left ventricular dysfunction, a condition that mimics preclinical heart failure in patients. The remodeling process in the canine model, including the increase in mass and volume, may be blocked by angiotensin converting enzyme inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)

Disorders associated with the overproduction or delayed clearance of beta-very low density lipoprotein and low density lipoprotein (LDL) are strikingly related to premature coronary artery disease. There are five recognized classes of LDL-lowering drugs, each acting through different basic mechanisms. The increased predictability, safety, and efficacy of newer lipid-lowering agents have allowed controlled clinical trials to demonstrate conclusively that reducing LDL leads to a reduction in coronary artery disease. Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is almost completely absorbed, actively targeted to the liver, and secreted in the bile. It has no active circulating metabolites. The safety and efficacy of fluvastatin have been demonstrated in more than 2,500 subjects treated in the United States, Canada, and Europe, and more than 1,000 have been treated for more than 1 year. Combination of fluvastatin with cholestyramine results in additional cholesterol lowering. The Lipoprotein and Coronary Atherosclerosis Study, a randomized, double-blind trial of fluvastatin using quantitative coronary angiography to measure atherosclerotic plaque change and positron emission tomography to evaluate myocardial perfusion (myocardial flow reserve), illustrates the further exploration of lipoproteins and atherogenesis made possible by the availability of this new generation of cholesterol-lowering agents.

The reverse cholesterol transport model is most widely used to explain both the role of high density lipoproteins (HDL) in lipid metabolism and the inverse association between HDL cholesterol plasma concentration and the risk for coronary artery disease (CAD). As familial HDL cholesterol deficiency is frequently paralleled with a family history of premature CAD, much interest has been directed toward the molecular defects in apolipoproteins and lipid-transfer enzymes involved in the formation and metabolism of HDL. Knowledge of the basic defects in rare HDL-deficiency syndromes and apolipoprotein variants provides genetic markers of whether the presence of these molecular defects accounts for low HDL cholesterol levels and the accompanying coronary risk.

Human high density lipoprotein (HDL) contains at least two types of lipoprotein-containing A-I particles: one contains both apolipoproteins (apo) A-I and A-II (Lp A-I:A-II) as main protein components, whereas in the other, apo A-II is absent (Lp A-I). The two subpopulations have different metabolisms and physiological roles. Studies indicate that apo A-II is an antagonist of cholesterol efflux. Lp A-I but not Lp A-I:A-II is increased in women compared with men. The lower apo A-I levels in patients with coronary artery disease reflect a decrease in Lp A-I. Lp A-I also is decreased in children with a family history of coronary artery disease, and increased in elderly subjects. Despite cholesterol intake remaining constant, a high polyunsaturated:saturated fat diet leads to a decrease in Lp A-I but not Lp A-I:A-II. Chronic alcohol consumption induces an increase in Lp A-I:A-II and a decrease in Lp A-I, although short bouts of drinking produce increases in both Lp A-I and Lp A-I:A-II. Hypolipidemic drugs have specific effects on discrete apo A-I particles.

Lipoproteins are circulating complexes of lipids and proteins, the transport and metabolism of which are directly controlled by apolipoproteins A-I, A-II, A-IV, B, C-I, C-II, C-III, D, E, and (a); lipoprotein-processing proteins lipoprotein lipase, hepatic lipase, lecithin-cholesterol acyltransferase, and cholesteryl ester-transfer protein; and lipoprotein receptors, low density lipoprotein (LDL) receptor, chylomicron remnant receptor, and scavenger receptors. Studies have shown a close association between lipoprotein abnormalities and coronary artery disease susceptibility. Four types of abnormalities are frequently seen: increased LDL cholesterol levels; decreased high density lipoprotein cholesterol levels, usually accompanied by increased triglyceride or very low density lipoprotein levels; increased concentrations of chylomicron remnants and intermediate density lipoproteins; and increased concentrations of an abnormal lipoprotein, lipoprotein (a). One or more of these abnormalities is present in 50-80% of myocardial infarction survivors. The exact pathogenic process whereby each of these abnormalities causes coronary artery disease is a subject of active investigation but beyond the scope of this brief presentation. However, the genetic contribution to each of these abnormal lipoprotein phenotypes is coming into focus and is discussed.

The association between coronary heart disease and lesions of the coronary arteries has led to investigations of different interventions on atherosclerotic change. Currently, B-mode ultrasound of the peripheral arterial vessels, rather than arteriography of the coronary arteries, provides the most accurate evaluation of atherosclerotic disease extent in the patient.

Investigations of the progression of atherosclerosis in human arteries suggest that changes in the thickness of the arterial intima-media complex, observable with B-mode ultrasonography, may precede development of atherosclerotic lesions. For epidemiological studies and clinical trials, B-mode ultrasound has the advantage that it is noninvasive, can be used in nonsymptomatic subjects, and can be carried out repeatedly, thus reducing the necessary sample size. In the Kuopio Ischaemic Heart Disease Risk Factor Study, we have assessed the reliability of B-mode ultrasound through studying intraobserver and interobserver variability. We have also investigated its predictive value by associating ultrasound observations with clinical end points, risk factors for common carotid and femoral atherosclerosis, and predictors of progression of common carotid atherosclerosis.

Associations of risk factors with atherosclerosis may be assessed by either invasive methods for measuring the arterial disease, such as angiography, or noninvasive methods; these methods differ in their potential for bias. Biases associated with coronary angiography may be difficult to control in statistical analysis, either because they are unrecognized or because they are amenable to neither stratification nor multivariate analysis. Problems in control selection include the likelihood that angiography controls overrepresent related ischemic or noncoronary cardiac conditions with their own risk factor associations. Differential misclassification is more likely in the clinical setting when invasive studies are used than in a research setting involving ultrasound imaging of carotid arteries. Nondifferential misclassification, however, affects both types of studies and clouds interpretation of the comparative strength of risk factor associations with atherosclerosis assessed by the two methods. Recent angiographic studies have generally provided insufficient information to evaluate these biases. However, with proper attention to such biases, one may be able to learn much about early and late stages of atherosclerosis by comparing risk factor associations with disease measured by both coronary angiography and carotid ultrasound.

Clinical trials with angiographic end points have been used to assess whether interventions influence the evolution of coronary atherosclerosis because sample size requirements are much smaller than for trials with hard clinical end points. Further studies of the variability of the computer-assisted quantitative measurement techniques used in such studies would be useful to establish better standardized criteria for defining significant change.

Several of the theories on the pathogenesis of atherosclerosis may be integrated into a single multifactorial one. According to this theory, the most likely sequence of events involved in early atherosclerosis is vascular dysfunction and/or injury, monocyte recruitment and macrophage formation, lipid deposition, vascular smooth muscle cell proliferation (mitogenic factor mediated), and synthesis of extracellular matrix. The interaction of all these factors will configurate the typical characteristic of the atherosclerotic plaque.

Methods for imaging arterial disease manifest by compromise of the lumen or thickening of the walls are undergoing continuing development and refinement. Methods used for many years to image arterial lumens (e.g., angiography, Doppler ultrasound) are of greatest utility for assessing the relation of arterial disease to clinical outcome. Newer methods (B-mode ultrasound) visualize arterial walls and thus provide qualitatively different information that has not previously been available to investigators and that is particularly suitable for studies of the relation of risk factors to arterial disease.

The endothelium possesses the ability to modulate vascular tone by the release of vasodilator and vasoconstrictor substances, among them endothelium-derived relaxing factor (EDRF) and endothelin. Abnormalities in EDRF generation were demonstrated in various cardiovascular pathophysiological states, specifically atherosclerotic vascular disease, congestive heart failure, and essential and pulmonary hypertension. Moreover, increases in plasma endothelin concentration have been reported as well in these disease states. When these observations are taken together, these states may be characterized by an attenuated release of EDRF, whereas the release of endothelin is augmented. An imbalance between EDRF and endothelin may contribute to the alteration in vascular tone characteristic of cardiovascular disease. The following review summarizes the present knowledge of the role of EDRF and endothelin in such disease processes.

Many have proposed a relation between presence of a patent foramen ovale, with or without atrial septal aneurysm, and cryptogenic stroke. The effect of foramen ovale closure on the risk for subsequent strokes is unknown.