Congestive heart failure occurs when myocardial dysfunction is advanced. Although clinical manifestations and diminished functional capacity can be traced back to the poor cardiac contractile state, there are major modifying influences from a complex series of compensatory responses. These particularly involve the heart, vessels, kidneys, sympathetic nervous system, the renin-angiotensin system, and other hormone systems. Functional capacity is, therefore, determined by the sum of the effects of the original cardiac insult and the effects, beneficial and adverse, of the secondary events. Functional capacity relates closely to prognosis only in the most severely disabled patients. The latter is mainly related to the extent of ventricular dysfunction, and there can be independent contributions from arrhythmias and sympathetic activity. Measures of resting parameters of cardiac contractility, hemodynamics, or neurohumoral responses are, therefore, of no value in predicting functional capacity but can be useful in examining outlook or examining mechanisms of disease and therapy. Exercise measurements are necessary because adequate resting performance can disguise major limitations in cardiac reserve. Measurement of functional capacity can be used to quantify the effects of therapy on daily living and to give an indication of the overall response of the body to major cardiac inadequacy. Limitation of exercise capacity, the earliest symptom of heart failure, can be quantified during a graded exercise test. Measurements of cardiac output and hemodynamic variables during exercise quantify the extent to which the cardiovascular system can increase performance to meet the demands of exercise. Work capacity and maximum oxygen capacity indicate the limits of physical performance, whereas determination of the anaerobic threshold indicates the highest level of exercise at which cardiorespiratory mechanisms are able to provide adequate oxygen supply to maintain aerobic metabolism in working skeletal muscle.

The physiological requirements of performing exercise above the anaerobic threshold are considerably more demanding than for lower work rates. Lactic acidosis develops at a metabolic rate that is specific to the individual and the task being performed. Although numerous pyruvate-dependent mechanisms can lead to an elevated blood lactate, the increase in lactate during muscular exercise is accompanied by an increase in lactate/pyruvate ratio (i.e., increased NADH/NAD ratio). This is typically caused by an inadequate O2 supply to the mitochondria. Thus, the anaerobic threshold can be considered to be an important assessment of the ability of the cardiovascular system to supply O2 at a rate adequate to prevent muscle anaerobiosis during exercise testing. In this paper, we demonstrate, with statistical justification, that the pattern of arterial lactate and lactate/pyruvate ratio increase during exercise evidences threshold dynamics rather than the continuous exponential increase proposed by some investigators. The pattern of change in arterial bicarbonate (HCO3-) and pulmonary gas exchange supports this threshold concept. To estimate the anaerobic threshold by gas exchange methods, we measure CO2 output (VCO2) as a continuous function of O2 uptake (VO2) (V-slope analysis) as work rate is increased. The break-point in this plot reflects the obligate buffering of increasing lactic acid production by HCO3-. The anaerobic threshold measured by the V-slope analysis appears to be a sensitive index of the development of metabolic acidosis even in subjects in whom other gas exchange indexes are insensitive, owing to irregular breathing, reduced chemoreceptor sensitivity, impaired respiratory mechanics, or all of these occurrences.

Platelet adhesion to blood vessel walls and subsequent aggregation require binding of von Willebrand factor to glycoprotein receptors on the platelet cell membrane. Consequently, inhibition of binding to these glycoproteins by monoclonal antibodies or synthetic peptides could provide a useful approach to the treatment of thrombotic conditions. Most of the studies that have used this approach have focused on glycoprotein IIb/IIIa, which is a multispecific receptor that binds von Willebrand factor, fibrinogen, fibronectin, and vitronectin, all of which are involved in cell adhesion. In animal studies, monoclonal antibodies raised against glycoprotein IIb/IIIa cause an increase in bleeding time, indicative of impaired platelet function, and there is some evidence that these antibodies are more effective at reducing platelet adhesion than anticoagulants or thromboxane synthase inhibitors. Furthermore, as glycoprotein IIb/IIIa binds several proteins involved in cell adhesion, many of which bear the amino acid sequence Arg-Gly-Asp, it may be possible to prevent thrombus formation by the use of synthetic peptides containing this sequence.

Vessel wall injury and lipid deposition in the walls of arteries can contribute to the development of atherosclerotic lesions. The mitogen (platelet-derived growth factor) for smooth muscle cells that is released from platelets that adhere to the sites of injury contributes to vessel wall thickening, as does the organization of mural thrombi. Although many arterial thrombi result from fissure or rupture of the fibrous cap of lipid-rich atherosclerotic plaques, thrombi that result from shear-induced platelet aggregation and disturbed blood flow at stenotic lesions also contribute to the thromboembolic clinical complications of atherosclerosis. Prevention of thrombus initiation requires a better understanding of platelet interaction with injured vessel walls and of the ways in which this process may be inhibited. A crucial factor in the management of thrombus formation in severely injured vessels is restoration of a normal pattern of blood flow. Theoretically, it may be possible to use angioplasty (to remove atherosclerotic lesions and to dilate stenosed vessels) and to use new therapeutic interventions (to prevent the accumulation of an initial layer of platelets on the acutely injured surface) to reduce the probability of restenosis and thrombosis at these sites.

This review of the clinical studies of thromboxane synthase inhibitors (TXSIs) and thromboxane receptor blocking drugs (TXRBs) covers the years 1981 to the present. Clinical studies on TXSIs include those in normal volunteers as well as those in patients with angina, peripheral vascular disease and Raynaud's syndrome, pulmonary hypertension, cerebral vasospasm, hepatorenal syndrome, adult respiratory distress syndrome, and those on cardiopulmonary bypass and hemodialysis. The compounds studied include dazoxiben, dazmagrel, CGS 13080, CV 4151, OKY 1581, OKY 046, and U 63557A. In volunteers, single-dose studies have demonstrated inhibition of thromboxane A2 (TXA2) formation, with some small increases in bleeding time but no marked effect on platelet aggregation. In general, the compounds tested were ineffective in both chronic stable angina and vasospastic angina but caused symptomatic improvement in patients with unstable angina. The TXSIs studied were found to produce no consistent effects in any of the other clinical conditions. Since none of the compounds tested produced a sustained inhibition of TXA2 synthesis, the disappointing clinical results with this class of drugs may be due to an incomplete blockade of thromboxane synthase with the dosage regimens used. Possible alternative or additional reasons for the general lack of success with TXSIs could be that some of the diseases studied do not involve TXA2 or that accumulating prostaglandin endoperoxides in the presence of thromboxane synthase inhibition substitute for TXA2 in causing platelet aggregation. TXRBs rely for their efficacy only on blockade of the TXA2 receptor and antagonize the deleterious effects of both TXA2 and prostaglandin H2 equally, so they represent a simpler pharmacological approach than TXSIs. Such drugs include AH 23848, GR 32191, BM 13.177, BM 13.505, and SQ 28668. All of these compounds are inhibitors of platelet aggregation induced by TXA2 or by its stable mimetic, U-46619. AH 23848 was ineffective in patients with stable angina but did benefit patients with peripheral vascular disease. BM 13.177 has also proven effective in preventing restenosis after angioplasty, occlusion of coronary artery bypass grafts, and the deleterious effects of TXA2 in renal disease. From these preliminary studies, it would appear that TXRBs may offer greater clinical potential than TXSIs. Further studies currently underway with TXRBs to resolve this question include those in unstable angina, angioplasty, peripheral vascular disease, renovascular hypertension, and cyclosporine nephrotoxicity.

The interaction between blood factors and the vessel wall is important in the development of common cardiovascular diseases. Clinical markers of these interactions should be sought to help in the understanding of the processes involved, and such markers should ideally be available to identify people at risk from the disease, screen relatives, help identify appropriate treatment, and monitor the outcome of the therapy. Various aspects of platelet interaction with the vessel wall can be used, as can some changes in levels of coagulation factors, fibrinolytic proteins, and natural anticoagulants. All have their advantages and disadvantages in terms of having the attributes of the ideal marker that would identify the pathophysiological processes and be reproducible, inexpensive, and easy to perform. This review will consider the value of various clinical markers, taking account of their advantages and disadvantages.

Thromboxane (TXA2), a potent proaggregatory and vasoconstricting eicosanoid, is produced at a very low rate and is cleared rapidly from the human circulation. Its chemically stable hydration product, TXB2, is extensively metabolized through dehydrogenation of the hemiacetal alcohol group at C-11 and beta-oxidation, resulting in the formation of two main enzymatic derivatives (i.e., 11-dehydro-TXB2 and 2,3-dinor-TXB2). A large discrepancy exists between the platelet biosynthetic capacity and actual TXA2 production in vivo. This has both methodological and pathophysiological relevance. Platelet synthesis of TXA2 can be reduced by cyclooxygenase and thromboxane-synthase inhibitors. Furthermore, the platelet and vascular actions of TXA2 can be antagonized by prostaglandin H2/TXA2-receptor antagonists. The combined administration of a thromboxane-synthase inhibitor and a TXA2-receptor antagonist gives stronger inhibition of platelet aggregation and prolongs bleeding time more than either drug alone or acetylsalicylic acid. Finally, TXA2-dependent glomerular damage, as seen in lupus nephritis, might represent a unique therapeutic target for receptor antagonists and/or tissue-selective synthase inhibitors.

alpha-Adrenoceptor-mediated effects of sympathetic activation on the heart and coronary circulation are reviewed with emphasis on the pathophysiology of myocardial ischemia. A classification of alpha-adrenoceptor subtypes is presented, and the effects of alpha-adrenoceptor activation on presynaptic sympathetic nerve terminals, cardiomyocytes, endothelium, platelets, and coronary smooth muscle cells are discussed. alpha-Adrenergic coronary vasoconstriction at rest and during situations of sympathetic activation such as exercise and excitement is analyzed for the segmental, transmural, and regional distribution of coronary blood flow. Evidence for a significant contribution of alpha-adrenergic coronary vasoconstriction to experimental and clinical myocardial ischemia is provided. Cardiomyocyte alpha-adrenoceptor activation may be involved in ischemic and reperfusion arrhythmias. The participation of presynaptic and postsynaptic alpha-adrenoceptors, as well as of alpha 1- and alpha 2-adrenoceptors, in experimental and clinical myocardial ischemia will require further investigation.

Calcium entry blockers can decrease myocardial ischemia and coronary spasm in association with percutaneous transluminal coronary artery angioplasty (PTCA). Restenosis after PTCA has not been shown to be statistically decreased by nifedipine or diltiazem in patients who clinically did not have coronary spasm. Patients who have evidence of coronary spasm before or at PTCA have a higher incidence of restenosis after PTCA, but this is decreased by treatment with calcium entry blockers. Most patients at Emory receive a calcium entry blocker before and after PTCA while in the hospital. After discharge, long-term therapy is given to select patients, especially those with any evidence of coronary vasospasm or patients with incompletely revascularized, multivessel disease. All patients receive aspirin before and long-term after PTCA. Some physicians give calcium entry blockers to all patients after PTCA. There is a need for larger, controlled clinical trials to evaluate the current use of calcium entry blockers before, during, and after PTCA as well as other therapeutic agents to prevent acute and chronic restenosis.

Accumulating data indicate that silent ischemia is a common accompaniment of coronary artery disease. In the population at large, studies estimate that 2-4% of middle-aged men have asymptomatic coronary artery disease and silent ischemia on treadmill testing. In patients with known coronary artery disease, positive treadmill tests are unaccompanied by pain about 34% of the time. In patients with stable angina pectoris, silent ischemia comprises about 70% of total ischemic events. This frequency approaches 80% in patients with unstable angina. About 20-30% of all myocardial infarctions are silent. Of patients who survive myocardial infarction, about 5% have silent ischemia on early treadmill testing, which signals an adverse prognosis. Overall, the presence of ischemia increases the risk for any subset of patients with coronary disease. Furthermore, the risk is the same whether the ischemia is silent or symptomatic. In summary, silent ischemia is common in patients with coronary disease and adversely affects prognosis, especially in high-risk patients.

Although the vasodilator and anti-ischemic actions of calcium channel blocking drugs might be expected to produce hemodynamic benefits in chronic heart failure, none of these agents has been shown to exert favorable clinical effects in these patients. Furthermore, when left ventricular function is markedly impaired, short- and long-term therapy with calcium channel blockers can increase cardiovascular morbidity and mortality. Previous investigators have attributed these unfavorable results to the established negative inotropic effects of calcium channel blockers on the failing heart. Yet, this cardiodepressant action seems to account for only the deleterious responses seen during short-term therapy with these drugs, whereas the detrimental effects of long-term treatment can be more readily explained by the capacity of calcium channel blockers to activate endogenous neurohormonal systems, especially the renin-angiotensin system. According to this hypothesis, a number of cardioactive drugs (including calcium channel blockers, beta-blockers, and converting enzyme inhibitors) can depress myocardial contractility, but only calcium channel blockers, which activate neurohormonal systems, adversely affect patients with left ventricular dysfunction, whereas beta-blockers and converting enzyme inhibitors, which interfere with neurohormonal activity, can favorably modify the long-term outcome of these high-risk patients. If confirmed by future studies, these observations suggest that the effect of antianginal drugs on neurohormonal systems, as well as on cardiac contractility, should be an important consideration in the selection of a therapeutic agent in patients with coronary artery disease and chronic heart failure.

There is increasing evidence that the clinically available calcium entry blockers (i.e., diltiazem, nifedipine, and verapamil) improve noninvasively determined indexes of diastolic filling in patients with chronic coronary artery disease, hypertensive heart disease, and hypertrophic cardiomyopathy. These favorable alterations in diastolic function are often associated with clinical improvement. Current information suggests that salutary indirect actions of these agents on ventricular loading, sympathetic reflexes, and myocardial supply-demand relations, rather than direct effects on transsarcolemmal myocyte calcium influx, underlie these beneficial effects.

Once initiated, chronic renal disease inexorably progresses to end stage. Recent studies of various experimental renal disorders have shown that normalization of glomerular capillary flow and pressure, either by restricting protein intake or by administering converting enzyme inhibitors, slows this progression. Because the hemodynamic actions of Ca2+ channel blockers modify the angiotensin II-induced renal changes, these drugs have the potential for altering the course of renal disorders. These agents also protect the kidney from ischemic injury and nephrocalcinosis and reduce platelet aggregation, which can further contribute to the preservation of renal function. The published studies regarding the role of Ca2+ channel blockers in chronic renal disease, however, do not allow drawing firm conclusions. The effect of these agents might depend on the nature of renal disease and the drug and dose used. Controlled trials are needed before these drugs can be recommended for preservation of renal function.

In clinical arrhythmias, the main therapeutic role of calcium channel entry blockers is related to their effect on the sinus and atrioventricular (AV) node. Consequently, in cardiac arrhythmias where the AV node is part of the reentry circuit, a beneficial effect of diltiazem and verapamil can be demonstrated. These include AV nodal reentry and orthodromic tachycardia in patients with Wolff-Parkinson-White syndrome. In addition, the ventricular response by the AV node during atrial tachycardias can also be controlled with these agents. A specific type of ventricular tachycardia seen in the absence of structural heart disease has also been reported to respond to intravenous and oral verapamil. Calcium channel blockers have no proven depressant effect on accessory pathway conduction. Similarly, the value of these agents in the treatment of ventricular tachycardia in association with chronic coronary artery disease and idiopathic dilated cardiomyopathy is rather limited. The use of calcium entry blockers in patients with wide QRS tachycardia, therefore, is to be discouraged unless it can be proved that supraventricular tachycardia with aberrant conduction is the underlying basis.

Cardiac arrhythmias are generated as the result of disorders of automaticity or impulse conduction. Regardless of the mechanism, however, calcium is likely to be involved. The rate of Ca2+ flux across the membrane of automatic cells alters their firing rate. Myocardial cells that do not ordinarily initiate action potentials can do so when they are partially depolarized. Low extracellular Ca2+ concentrations or Ca2+ channel-blocking drugs can reduce or abolish such ectopic firing. Early afterdepolarizations are also induced in cardiac cells by partial depolarization, whereas delayed afterdepolarizations are induced by Ca2+ overloading. Early afterdepolarizations and delayed afterdepolarizations can both be suppressed by low external Ca2+ concentrations or by Ca2+ channel blockers. With respect to arrhythmias ascribable to disorders of conduction, Ca2+ channel blockers can aggravate conduction disturbances in the sinoatrial node or atrioventricular junction. Furthermore, these drugs can abolish those reentrant arrhythmias in which a cardiac impulse rotates around a loop in which nodal tissue is an integral element. Ca2+ channel blockers can also reduce the susceptibility for ventricular fibrillation to supervene in ischemic hearts, especially when the sympathetic nervous system is overactive.

Despite decreasing cardiac mortality rates in the elderly since 1968, rates of health care service use by persons over age 65 years have progressively increased. The growing availability of potent and effective cardiovascular drugs, together with the high prevalence of untoward side effects in the elderly, make it important that we consider the influence of age on cardiovascular response to the calcium entry blockers. The age-related structural, functional, pharmacokinetic, and pharmacodynamic changes that occur in elderly patients suggest that careful monitoring, adjustment, and frequent reassessment of the medical regimen should be performed to minimize untoward effects. Nifedipine, diltiazem, and verapamil are all well absorbed orally, are extensively protein bound, and are metabolized by the liver. The age-associated attenuation in rates of hepatic metabolism and hepatic blood flow contribute to the decreased clearance and prolonged elimination half-lives of these drugs in the elderly. Advanced age can be associated with increased susceptibility to sinoatrial depression, fatigue, constipation, hypotension, and peripheral edema after calcium entry blockade, even at modest doses. It would be prudent, therefore, to administer these agents at lower doses and at less frequent intervals.

The mosaic of essential hypertension seems to be gaining new tiles at an accelerating rate. Of the many pathophysiological factors and markers for the factors that can be considered as possible elements of a profiling algorithm, there are relatively few with solid data to support their use. Use of plasma renin activity for prospective profiling does not appear to be valid for individual patients. It remains useful for diagnosis of renal artery stenosis and primary aldosteronism. The black race does have some well-documented pathophysiological differences from the white race regarding hypertension, and there are some useful data bits for selecting specific therapy. The elderly, obese patients, and young patients with hyperdynamic circulation appear to have enough group characteristics to enable selection of drugs more targeted to their needs. Anxious patients who often display symptoms that mimic pheochromocytoma symptoms comprise a unique group. One of the largest groups is patients with hypertension plus one or more concomitant diseases. Finally, drug selection decisions must also consider the effect of drugs on serum lipoproteins, left ventricular hypertrophy and vascular compliance, sexual function and other quality of life issues, and cost.

Treatment of patients with mild to moderate essential hypertension is now commonly undertaken. Clinical trials have shown a marked decrease in strokes in treated hypertensive patients. But despite reports of decreases in coronary deaths in some trials, the overall incidence of coronary events has been largely unaffected. This disappointing outcome has raised interesting issues. The patients in comparative placebo groups often do better than expected in formal trials; apart from the benefits of lifestyle changes, many of these patients appear to normalize their blood pressures during the trial. This latter effect can be due to erroneous diagnoses of hypertension at the start of the study, and this partially dilutes the likelihood of differences in outcome between the placebo- and actively treated patients. Optimal control of blood pressure is difficult to define, and controversies exist concerning whether pressures have been decreased insufficiently or excessively in clinical trials; it has been argued, too, that systolic as well as diastolic hypertension should be the target of treatment. Inadvertent treatment-induced metabolic abnormalities, especially in blood lipids, glucose, and electrolytes can weaken the antihypertensive benefits. Failure to deal with concurrent risk factors including smoking and left ventricular hypertrophy also could explain the absence of a decrease in coronary events. Newer classes of antihypertensive agents offer the potential to address these concerns and improve the cardiovascular prognosis of treated hypertensive patients.