In most patients, cardiac tamponade should be diagnosed by a clinical examination that shows elevated systemic venous pressure, tachycardia, dyspnea, and paradoxical arterial pulse. Systemic blood pressure may be normal, decreased, or even elevated. The diagnosis is confirmed by echocardiographic demonstration of moderately large or large circumferential pericardial effusion and in most instances, of right atrial compression, abnormal respiratory variation in right and left ventricular dimensions, and in tricuspid and mitral valve flow velocities. Pulsus paradoxus may be absent with left ventricular dysfunction, atrial septal defect, regional tamponade, and positive-pressure breathing. Systemic venous pressure may be normal with localized tamponade of the left atrium or ventricle. Patients with moderately large or large pericardial effusions may have echocardiographic evidence of right atrial compression without clinical signs of elevated venous pressure or pulsus paradoxus. The majority of these patients have mild or moderate tamponade and if not subjected to pericardial drainage, should be observed closely. In some of these patients, when the etiology is known and the disease can be treated effectively with medication, e.g., nonsteroidal anti-inflammatory agents or adrenal corticosteroids in Dressler's syndrome or relapsing pericarditis, pericardial drainage may not be necessary.

The nitrovasodilators are a diverse group of pharmacological agents that produce vascular relaxation by releasing nitric oxide. The mechanisms by which these compounds release nitric oxide vary, depending on their chemical structure. Compounds with lower oxidation states of nitrogen such as nitroprusside, nitrosamines, and nitrosothiols release nitric oxide nonenzymatically. In the case of nitroprusside, this involves a one-electron reduction that may occur upon exposure to a variety of reducing agents and tissues such as vascular smooth muscle membranes. In the case of the organic nitrates, which have higher oxidation states of nitrogen, the release of nitric oxide in vascular tissue occurs predominantly by a poorly understood enzymatic process. This interesting property of nitroglycerin is important because it "targets" its effect to vascular tissues that are capable of this enzymatic process. In the case of the coronary circulation, nitroglycerin predominantly dilates the larger coronary arteries while having a minimal effect on coronary resistance vessels < 100 microns in diameter. This prevents the development of coronary steal, which is often encountered with agents that produce intense vasodilation of the coronary resistance vessels. In this review, the mechanisms by which the nitrovasodilators (particularly nitroglycerin) release nitric oxide will be considered, and recent studies of nitroglycerin bioconversion in various-sized coronary vessels will be discussed in detail.

Advances in our knowledge of the regulation of cardiac myosin isoforms made possible by molecular cloning of the alpha- and beta-MHCs genes are reviewed. Expression of these genes in heart does not seem to require MyoD or related proteins of the skeletal muscle myogenic program. Cardiac MHC genes are under the control of T3, which stimulates transcription of the alpha-MHC gene and inhibits beta-MHC mRNA production both in vivo and in cultured heart cells. The responsiveness of the genes to T3 varies in different mammals, however. The genes are most responsive in rat and rabbit, intermediate in sensitivity in calf and subhuman primate (baboon), and very resistant in the dog. The human alpha-MHC gene is T3-inducible in ventricle, but the degree of response has not been quantified. Introduction of chimeric plasmids containing 5' flanking sequences of cardiac MHC genes fused to the CAT gene into cultured heart cells and transgenic animals has permitted identification of regulatory elements. Although the genes are closely linked in genomic DNA, they are controlled independently. The element within the alpha-MHC promoter responsible for induction by T3 is located approximately 160 base pairs from the transcription initiation site. Additional transcriptional activators located 5' upstream amplify the response to T3, probably by looping out intervening DNA sequences. The proximal region of the beta-MHC gene contains important regulatory elements, including those required for repression by T3, muscle-specific expression, a MyoD-independent positive element, and a hormone-independent repressor.(ABSTRACT TRUNCATED AT 250 WORDS)

Epidemiological studies have identified associations between time of day and risk of sudden cardiac death. The marked peak in the occurrence of sudden cardiac death after awakening suggests that the disease is triggered by changes that occur during this time period. Increased sympathetic stimulation is a likely cause of such triggering. In the light of the circadian variation of sudden cardiac death and the evidence linking physical activity or mental stress (both associated with activation of the sympathetic nervous system) to the disease, the role of potential triggering events should be investigated. Controlled studies are needed to determine the relative risk of activities that may trigger sudden cardiac death. Since such studies must rely on witnesses (or resuscitated patients), data quality must be closely scrutinized, and studies using case-control and case-crossover designs are needed. The epidemiological and pathophysiological data reviewed in the present article suggest a number of pathways through which activities may trigger sudden cardiac death. Different extrinsic stimuli may cause similar physiological changes that subsequently lead to acute pathological events, a decrease in the ventricular fibrillation threshold through a direct myocardial effect, or a harmful effect on the conduction system. Myocardial ischemia induced by plaque rupture and thrombosis may lead directly to myocardial electric instability. The presence of chronic structural abnormalities of the myocardial tissue or the conduction system may further lower the threshold for electric instability and ventricular fibrillation.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular manifestations are a frequent finding in hyperthyroid and hypothyroid states. In this review, potential mechanisms by which thyroid hormones may exert their cardiovascular effects and pathophysiological consequences of such effects are briefly discussed. Two major concepts have emerged about how thyroid hormones exert their cardiovascular effects. First, there is increasing evidence that thyroid hormones exert direct effects on the myocardium, which are mediated by stimulation of specific nuclear receptors, which in turn leads to specific mRNAs production. Furthermore, there is some evidence that thyroid hormones may also activate extranuclear sites and may directly alter plasma membrane function. Second, thyroid hormones interact with the sympathetic nervous system by altering responsiveness to sympathetic stimulation presumably by modulating adrenergic receptor function and/or density. Pathophysiological consequences of such direct and indirect thyroid hormone effects include increased myocardial contractility and relaxation that may be related to stimulation by T3 of specific myocardial enzymes. However, when left ventricular hypertrophy occurs in association with hyperthyroidism, it may be related to either direct thyroid hormone-induced stimulation of myocardial protein synthesis or to thyrotoxicosis-induced increases in cardiac work load. Although hyperthyroidism generally has little or no effect on mean arterial blood pressure, hypothyroidism is often associated with increases in diastolic blood pressure that are reversible after hormone substitution and may be mediated in part by sympathetic activation. Moreover, there is increasing evidence that thyroid hormones have direct chronotropic effect on the heart that are independent of the sympathetic nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)

Diastolic dysfunction is characterized by an increased resistance to filling with increased diastolic filling pressures. A variety of disorders are associated with diastolic dysfunction, such as hypertrophy, structural alterations of the myocardium with increased fibrosis, myocardial scarring, or infiltrative processes. In addition to these changes, physiological abnormalities of the left ventricle with impaired relaxation, decreased diastolic filling, and increased stiffness of the myocardium can be observed. In patients with aortic stenosis, the most common cause for diastolic dysfunction is left ventricular hypertrophy. Diastolic dysfunction is found in approximately 50% of the patients with normal systolic ejection performance and in 100% of the patients with depressed function. Diastolic function appears either to be more sensitive for detection of abnormal left ventricular function in patients with aortic stenosis or to precede systolic dysfunction or both. Treatment of diastolic dysfunction is usually achieved by aortic valve replacement with regression of left ventricular hypertrophy, but in patients with decompensated aortic stenosis, a reduction of circulating blood volume to reduce diastolic filling pressures, and thus dyspnea, is often indicated. Prognosis of patients with diastolic dysfunction is usually better than that of patients with systolic dysfunction but is clearly worse than that of normal patients.

The identification of the components of the renin-angiotensin system (RAS) in various extrarenal tissues suggested the existence of local renin-angiotensin systems with organ-specific functions that may act independently from the plasma RAS. These findings have led to the hypothesis of paracrine-autocrine functions of the RAS, which implies that locally generated angiotensin II mediates effects within one tissue or within one cell. Whereas the circulating endocrine RAS appears to be responsible for acute effects, the tissue RAS seems to participate in more chronic processes such as secondary structural changes and therefore may contribute to the pathogenesis of hypertension as well as other cardiovascular disorders such as cardiac hypertrophy, coronary artery disease, and atherosclerosis.

Arterial hypertension leads to left ventricular hypertrophy. In proportion to increased left ventricular systolic pressure, left ventricular hypertrophy is considered to be of adaptive nature from the point of view of wall stress regulation. In the beginning, left ventricular function is normal, whereas diastolic filling is already compromised by the process of hypertrophy and altered ventricular geometry. In case of ventricular dilation and wall thinning, wall stress increases and leads to an increment in myocardial oxygen demand and a decrease of left ventricular ejection fraction. This is followed by a further decline in intrinsic myocardial contractility and a decrease in the elastic material properties of the myocardium. The structure of the myocardium is characterized by myocyte hypertrophy, a process of reactive and reparative fibrosis and alterations of the coronary microcirculation. Coronary vasodilator reserve is markedly impaired and is likely to initiate a process of malperfusion and malnutrition under increased metabolic demands. Particularly, the combined involvement of myocytes, interstitium, and intramyocardial vasculature appears to predispose to late heart failure after prolonged exposure to chronic pressure overload in arterial hypertension.

The purpose of the study was to characterize the functional and metabolic adjustments of a myocardial region subjected to low-flow ischemia. In addition, studies tested whether such myocardium retains an inotropic reserve.

During times of physiological stress, the human heart is able to markedly increase contractility. This response is facilitated by the release of norepinephrine from postganglionic sympathetic nerves and epinephrine from the adrenal gland. These neurotransmitters effect a contractile response by interacting with a transmembrane signaling system within the myocyte sarcolemma consisting of beta 1- and beta 2-adrenergic receptors, the guanine nucleotide-binding regulatory proteins Gs and Gi, and the effector enzyme adenylyl cyclase. Activation of this beta-receptor-G-protein-adenylyl cyclase signal transduction complex results in production of the second messenger, cAMP, activation of protein kinase A, and phosphorylation of a group of cellular proteins that are important in excitation-contraction coupling. In contrast to normal human myocardium, the failing human heart is insensitive to adrenergic stimulation. This insensitivity is a result of alterations in the function of this signal transduction pathway, including selective downregulation of the beta 1-adrenergic receptor, uncoupling of beta 2-adrenergic receptors from adenylyl cyclase, and an increase in the functional activity of the inhibitory G-protein. Subtle yet important differences exist between beta-adrenergic neuroeffector mechanisms in idiopathic dilated cardiomyopathy and cardiomyopathy secondary to ischemic heart disease. Most notably, beta-receptors are downregulated to a lesser degree in patients with ischemic heart disease. Therefore, various types of end-stage heart muscle disease may exhibit important pathophysiological differences despite common clinical features and an understanding of the regulatory mechanisms that modulate cardiac signal transduction may have therapeutic implications.

Cardiac hypertrophy is the physiological adaptation of the heart to chronic mechanical overload. Cardiac failure indicates the limits of the process. Cardiac hypertrophy is only one example of biological adaptation and results from the induction of several changes in gene expression, mostly of the fetal type, including those coding for the myosin heavy chain or the alpha-subunit of the Na+,K(+)-ATPase. From a thermodynamic point of view, the decrease in Vmax allows the heart to produce a normal tension at a lower cost. This process results from changes both in the sarcomere and in the expression of certain membrane proteins. The decrease in calcium transient is determined by several changes in membrane proteins that result in a rather fragile equilibrium in terms of calcium homeostasis. Any abnormal input in calcium will have exaggerated detrimental consequences on a hypertrophied myocyte and may cause automaticity and arrhythmias or an exaggerated response to anoxia in terms of compliance.

Mortality in congestive heart failure remains high. In analysis of heart failure in the perspective of pathophysiological mechanisms, some approaches to treatment to improve survival become particularly interesting. The concept of unloading myocardial performance by reducing systemic vascular resistance has received general acceptance. This approach was associated with improved survival with nitrates and hydralazine in the V-HeFT I study. Stimulation of the myocardium in excess of what is achieved by endogenous stimulation might be dangerous. Long-term therapy with positive inotropic agents, therefore, is not an appropriate approach at present. However, addition of beta-blockers may protect the myocardium from the intense endogenous sympathetic stimulation in congestive heart failure. There are favorable trends with this approach in several small trials. An ongoing trial in idiopathic dilated cardiomyopathy may help to clarify this question. Counteraction of neuroendocrine activation may also be obtained by the addition of an angiotensin converting enzyme inhibitor. The CONSENSUS I study demonstrated a clear improvement in survival among very compromised patients by addition of enalapril. A positive effect was significantly associated with the degree of neuroendocrine activation at baseline. Two recent large-scale trials have emphasized the importance of adding an angiotensin converting enzyme inhibitor to other treatments in patients with mild to moderate symptoms and left ventricular dysfunction. These trials also support the importance of myocardial protection from neuroendocrine stimulation with symptomatic or asymptomatic myocardial failure. Antiarrhythmic agents have not been documented to improve survival. On the contrary, class I agents are deleterious in some patients with left ventricular dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Ischemic heart disease is the major etiology for the development of congestive heart failure. Patients with acute myocardial infarction have a greatly increased risk for mortality and for manifesting symptomatic heart failure. This risk is not a uniform one but is greatly augmented in patients with a more extensive infarction and, consequently, a more depressed global ventricular function. An important concept that was derived from studies in rats with myocardial infarction and has been confirmed in patients is that ventricular enlargement, which has been shown to be a marker for an adverse outcome, can be a progressive process that leads to further deterioration of ventricular performance. Both experimental and early clinical studies have indicated that chronic therapy with an angiotensin converting enzyme inhibitor may attenuate this progressive ventricular enlargement. More definitive clinical trials are currently under way to determine whether this form of therapy, which may diminish the extent of ventricular enlargement over time, will result in an improvement in survival and in the prevention of the development of congestive heart failure. The addition of this pharmacological therapy to that of the primary prevention of atherosclerosis and that of the limitation of infarct size should make a substantial impact on the reduction of the incidence of congestive heart failure.

Chronic blockade of the renin-angiotensin system by angiotensin converting enzyme (ACE) inhibitors in patients with mild to moderate heart failure as a second-line therapy has been shown to exert beneficial effects on exercise tolerance and symptomatology.

Chronic (CRF) and acute renal failure (ARF) are accompanied by cardiac dysfunction, particularly if ARF is complicated by sepsis. Intermyocardiocytic fibrosis is described in CRF, but there is also evidence for functional cardiomyopathy. Acetate ion (present in the dialysate) and secondary hyperparathyroidism do not appear to be clinically relevant myocardial depressant factors in uremia. The role of carnitine deficiency is not clarified, because most of the data are evaluated in poorly controlled study trials. Multiple effects of serum fractions and ultrafiltrates obtained from CRF and ARF patients during dialysis suggest the existence of myocardial depressant factor(s). Beneficial effects of continuous hemofiltration in multiorgan failure give evidence for the pathogenetic role of this substance(s). One group of experiments suggests a molecular weight between 500 and 5,000 d; other experiments suggest activity at > 10,000 d. It is currently believed that myocardial depressant substance is a water-soluble molecule weighing 10,000-30,000 d. The data confirm the existence of "specific cardiomyopathy" caused by a functional defect related to filterable toxins. There are different myocardial depressant factors in CRF, ARF, and sepsis.

Intracellular signaling systems that are involved in growth of cardiac myocytes and that are modified in congestive heart failure include the alpha 1- and beta-adrenergic systems and angiotensin II. These systems include G-protein-linked hormone receptors and their membrane enzyme including adenylyl cyclase and phospholipase C. In addition, membrane enzymes, and adenylyl cyclase in particular, respond directly to stretch of the cell membrane with an increase in cAMP formation. Furthermore, interactions between stretch and hormonal stimuli can potentiate each other and result in enhanced signal generation.

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)