Sympathetic activation in heart failure and its treatment with beta-blockade

Multiple models explaining the pathogenesis of heart failure have been put forth during the past 5 decades. These models were modified as clinical evidence supported or refuted their assumptions. During the past 2 decades, heart failure models emphasized the importance of neurohormonal systems in heart failure progression. The positive impact that angiotensin-converting enzyme inhibitors have had on mortality from heart failure has bolstered the neurohormonal theory. Attention recently has turned to the sympathetic nervous system and its potential deleterious effects on the cardiovascular system in heart failure. The sympathetic nervous system can negatively impact the cardiovascular system in heart failure in several ways, including down-regulating beta1-receptors, exerting direct toxic effects on the myocardium, and contributing to myocardial remodeling and life-threatening arrhythmias. Beta-adrenergic blockers have shown promise for reducing morbidity and mortality in heart failure, but definitive reductions in mortality remain to be shown by future investigations.     

Bioequivalence study of two capsule formulations of omeprazole

Congestive heart failure is associated with high morbidity and mortality. Modification of neurohormonal activation by use of angiotensin converting enzyme inhibitors has been shown to decrease symptoms and prolong survival. More recent evidence has suggested that beta-adrenoceptor blocking agent therapy may be also beneficial in patients with congestive heart failure, possibly by down-regulating the activation of the adrenergic system. A large number of randomized trials of beta-adrenoceptor blocking agents in heart failure have been performed. These studies demonstrated improvement in symptoms of congestive heart failure, functional classification, and reduction in the number of patients requiring cardiac transplantation. beta-adrenoceptor blocking agents have not been shown to decrease mortality, however, the current trials have been too small to be conclusive in this regard.     

Apoptosis in heart failure

A characteristic feature of heart failure is the progressive worsening of ventricular function over months or years despite the absence of clinically apparent intercurrent adverse events. The mechanism or mechanisms responsible for this hemodynamic deterioration are not known but may be related to progressive intrinsic contractile dysfunction of residual viable cardiac myocytes, or to ongoing degeneration and loss of myocytes, or both. This report will address the concept of ongoing cardiac myocyte loss that may occur during the course of evolving heart failure viewed from the perspective of apoptosis or "programmed cell death" as the potential mediator of cardiac muscle cell loss. In recent years, several studies have shown that constituent myocytes of failed explanted human hearts and hearts of animals with experimentally induced heart failure undergo apoptosis. Recent studies have shown that cardiac myocyte apoptosis also occurs after acute myocardial infarction, as well as in the hypertrophied heart and the aging heart, conditions frequently associated with the development of heart failure. Considerable work has also been conducted and novel concepts advanced to explain potential molecular triggers of cardiac myocyte apoptosis in heart failure. Although available data support the existence of myocyte apoptosis in the failing heart, questions essential to our understanding of the importance of myocyte apoptosis in this disease process remain unanswered. Lacking are studies aimed at identifying physiological factors inherent to heart failure that trigger myocyte apoptosis. Also lacking are studies that address the importance of myocyte apoptosis in the progression of left ventricular dysfunction. If loss of cardiac myocytes through apoptosis can be shown to be an important contributor to the progression of heart failure, and if factors that trigger apoptosis in the heart can be identified, such knowledge can potentially lead to the development of novel therapeutic modalities aimed at preventing, or at the very least retarding, the process of progressive ventricular dysfunction and the ultimate transition toward end-stage, intractable heart failure.     

Myocardial alpha1-adrenoceptor: inotropic effect and physiologic and pathologic implications

Alpha1-adrenergic receptors have been found in myocardium of all mammalian species. Although the exact underlying mechanisms have not been conclusively determined, it would appear that the myocardial effects of alpha1-adrenoceptors may vary in importance according to the pathophysiologic process involved. In physiological conditions, this receptor system plays a role in cardiac growth, cardiac contraction, and has both an antiarrhythmic function as well as a role in cardiac adaptation to various situations. This system is also involved in some pathological processes such as ischemia/reperfusion, ischemic preconditioning, and cardiac hypertrophy. The role of alpha1-adrenoceptors in heart failure is somewhat controversial. Experimental evidence suggests that myocardial alpha1-adrenoceptors can have either beneficial or deleterious effects on the heart. It thus seems possible that the development of agents specific to certain subtypes of alpha1-adrenoceptor and a better understanding of their role in pathophysiologic states could be clinically relevant.     

Mechanisms of cardiac failure]

Heart failure is defined as the inability of the heart to deliver a cardiac output sufficient for the needs of the periphery. The mechanisms responsible for ventricular failure always correspond for changes in ventricular filling that may have 2 origins: decrease in ventricular systolic function, leading the ventricle to operate on the vertical part of its pressure volume relationship; primary decrease in ventricular distensibility. An increase neurohormonal stimulation participates in sodium retention and in the preservation of blood pressure. The mechanisms leading to the progressive alteration of the haemodynamic status are not perfectly known, but a progressive increase in wall stress and myocyte loss are likely to occur.     

Digitalis, diuretic and vasodilator treatment of cardiac failure

Angiotensin-converting-enzyme inhibitors increase life expectancy in congestive heart failure, and they have thus changed the therapeutic strategy. The well tolerated highest daily dosage has to be used. Diuretics are often associated with vasodilators; however, they have to be administered at a minimal chronic daily dosage, in order to avoid deleterious neurohormonal effects. Digoxin keeps a great interest, as the unique positive inotropic agent without surmortality. Nitrates associated or not with hydralazine may show an additional interesting benefit. The role of other vasodilators, namely amlodipine and losartan, in the treatment of chronic heart failure remains to be defined. New vasodilators are in development and might further increase our therapeutic possibilities against congestive heart failure.     

Molecular pathobiology in heart failure

Heart failure is a pathophysiological state resulting from disturbed cardiac function. It is based on complex molecular processes, many of which are not fully understood. During heart failure adaptive mechanisms, that reinstall altered cardiac function, are activated. The main mechanisms are: a) Alteration of the structure and composition of myocytes by myocardial hypertrophy, reexpression of fetal and neo-natal proteins and the expression of certain proto-oncogenes; b) Activation of the neuroendocrinal system, specifically the sympathetic nervous system, renin-angiotensin-aldosterone system and vasopressin release; c) Activation of autocrine and paracrine systems. However, when these systems are activated beyond a certain limit they contribute to heart failure aggravation. This can also be promoted by alteration of the calcium metabolism inherent in heart failure. The synthesis of the counterregulator atrial natriuretic factor is also increased.     

In vivo assessment of neurotransmitter system in cardiovascular diseases. Clinical issues

Cardiac neurotransmitter systems, especially the adrenergic receptor pathway, are impaired in heart diseases. In patients with heart failure, these abnormalities contribute to arrhythmogenesis and to progression of cardiac dysfunction. The use of MIBG with single photon imaging has provided useful information on the mechanisms of ventricular arrhythmias, and on the causes of death in patients with heart failure or hypertrophic cardiomyopathy. It has been suggested as a prognostic indicator in patients with heart failure. Positron Emission Tomography (PET) now allows us to obtain noninvasively the quantitative determination of regional receptor density and affinity in humans as well as innervation integrity and functioning. These measurements are based upon the synthesis of a radioligand, usually either a selective receptor antagonist or a false neurotransmitter labeled with a positron-emitting radioisotope. Mathematical compartmental models are fitted to activity-versus-time curves obtained during saturation or displacement experiments in order to calculate the rate constants and the receptor density in the myocardium. PET has only recently begun to be applied to the study of cardiac physiology and disease. PET and SPECT cardiac neuroimaging techniques are able to demonstrate the physiological regulation of receptors, and to provide the possibility of studying regional abnormalities of cardiac neurotransmission, especially in arrhythmogenic cardiomyopathy. Furthermore these non invasive techniques could be useful in exploring the alteration of neurotransmission in the early stage of heart disease and could allow repeated scintigraphic examinations in order to evaluate the effects of cardiac medications.     

Prevention of heart failure]

Heart failure is a major problem of public health, associated with poor outcome in the advanced stage, thus justifying its prevention. Primary prevention is based on the prevention and treatment of its principal etiologic factors, hypertension and coronary artery disease. Broad use of echocardiography or dosage of neurohormonal markers improve detection of asymptomatic left ventricular dysfunction. In ischemic heart disease, coronary recanalisation prevents or limits left ventricular remodeling and dysfunction, even if the "open artery" theory has not been entirely proved. Understanding the deleterous role of neurohormonal stimulation results in a large use of ACE-inhibitors, which beneficial effect has been demonstrated also in case of asymptomatic left ventricular dysfunction. Betablockers, already largely used after myocardial infarction, seem to have also a beneficial effect in heart failure: the same is probably also true for angiotensin II-antagonists. Double blocking of both the sympathetic nervous system and the angiotensin-aldosterone system seems to be recommended. More precisely understanding the pathways signaling the processes of ventricular remodeling and dysfunction points to new potential targets for a preventive treatment: endothelin receptors, apoptosis, oxidative stress, cytokines or even angiogenesis.     

Circulatory support with pneumatic paracorporeal ventricular assist device in infants and children

BACKGROUND: Mechanical circulatory support in intractable heart failure in children has been limited to centrifugal pumps and extracorporeal membrane oxygenation: Since 1990 small adult-size pulsatile air-driven ventricular assist devices "Berlin Heart" (VAD) and, since 1992 miniaturized pediatric VAD (12, 15, 25, 30 mL pumps), have been used in our institution. Since 1994 the blood-contacting surfaces of the device system have been heparin-coated. In this report the experiences with VAD support in 28 children are presented. METHODS: In 28 children-ages between 6 days and 16 years-the Berlin Heart VAD has been applied for periods of between 12 hours and 98 days (mean, 16.9 days) aiming at keeping the patient alive and allowing for recovery from shock sequelae until later transplantation or myocardial recovery. There were three groups. Group I: with primary intention of "bridge-to-transplantation" in various forms of cardiomyopathy (n = 13) or chronic stages of congenital heart disease (n = 5). Group II: "Rescue" in intractable heart failure early after corrective surgery for congenital heart disease (n = 4) or in early graft failure after a heart transplantation (n = 1). Group III: "Acute myocarditis" (n = 5) aiming at either myocardial recovery or transplantation. Twelve were brought to the operating room under cardiac massage and 25 had been on the respirator for more than 24 hours. RESULTS: Twelve patients died on the system from sequelae of profound shock-multiorgan failure, sepsis, loss of peripheral circulatory resistance-or from hemorrhagic complications (n = 4) or brain death (n = 1). Thirteen patients (groups I and III) were transplanted after support periods of between 3 and 98 days with 7 long-term survivors living now up to 7.5 years (mean, 4.4 years). Three patients (groups II and III) were weaned from the system with two long-term survivors (both in group III). There were no patients in group II who survived and the "rescue" indication has been discarded for VAD since 1992. Such patients are since treated by extracorporeal membrane oxygenation (ECMO) in our institution. Out of the 8 patients placed on VAD during 1996 and 1997, 7 were successfully supported until transplantation or weaning. Thirteen patients were extubated and mobilized on the system. Whereas with the earlier systems thrombi in the blood pumps were seen in 15 instances and 2 patients suffered from thromboembolic complications, no thrombotic events occurred with the heparin-coated systems. CONCLUSIONS: After accumulating clinical experience and several technical improvements since 1990 the use of the pediatric Berlin Heart VAD has matured into a reliable and safe system to keep patients with otherwise intractable heart failure alive until complete myocardial recovery is reached or transplantation becomes feasible. Whereas heart failure early after cardiac operation is now primarily treated by ECMO, acute myocarditis appears to be a promising precondition for complete cardiac recovery during VAD support.     

Increased endogenous nitric oxide synthase inhibitor in patients with congestive heart failure

Nitric oxide (NO) plays a role in controlling vascular tone and regulates the contractile properties of cardiac myocytes. Patients with heart failure exhibit high plasma levels of nitrite/nitrate (NOx), a stable metabolite of NO, and of cytokines such as tumor necrosis factor-alpha, a potent inducer of NO synthase. An increase in inducible NO synthase activity has been found in cardiac tissue from patients with dilated cardiomyopathy. These findings raise the possibility that local or systemic overproduction of NO induced by cytokines exerts a chronic negative inotropic effect on the myocardium and may have detrimental effects on systemic hemodynamics in patients with heart failure. Plasma levels of NG,NG-dimethylarginine (asymmetric dimethylarginine; ADMA), a circulating endogenous NO synthase inhibitor, were measured in control subjects and patients with valvular, hypertensive, or ischemic heart diseases or idiopathic cardiomyopathy. The plasma levels of NOx and ADMA were assessed by high performance liquid chromatography. The plasma levels of NOx and ADMA were significantly elevated in patients with heart failure. Both NOx and ADMA were positively correlated with New York Heart Association functional class. There was a significant inverse correlation between plasma NOx and ejection fraction, as estimated by echocardiography. A significant relationship between plasma NOx and ADMA was found only in patients with moderate to severe heart failure (r=0.41, p=0.01). Findings suggest a compensatory role of a circulating endogenous NO synthase inhibitor against induced NO synthase activity in patients with heart failure.     

Alterations in reflex function contributing to syncope: orthostatic hypotension, carotid sinus hypersensitivity and drug-induced dysfunction

Orthostatic hypotension and related neurologic symptoms are frequently encountered in clinical practice. The maintenance of appropriate blood pressure and heart rate responses upon assuming the upright posture are dependent upon: 1. intact mechanical (venous valves) mechanisms, 2. functioning arterial and cardiopulmonary baroreceptors, 3. normal peripheral neural pathways, 4. normal central neural integration, and 5. appropriate neurohormonal secretion. Dysfunction at one or more of these loci may facilitate the occurrence of orthostatic hypotension and syncope. In general, the mechanisms of orthostatic hypotension may be divided into three categories. In the first category, processes interfere with normal compensatory responses to upright posture. Examples of this mechanism include age related autonomic changes, diabetic neuropathy and central nervous system disease such as Shy-Drager syndrome. The second principal mechanism involves overwhelming otherwise normal reflexes by an intense orthostatic stimulus. An obvious example of this mechanism is syncope related to hemorrhage. A final category of orthostatic hypotension relates to interference with reflex responses by drugs that may limit vasoconstriction, heart rate or cardiac output adjustments or exaggerate venous pooling. These are commonly used medications such as vasodilators, beta-adrenergic blockers and nitrates. The treatment of orthostatic hypotension revolves around the recognition of underlying causes or contributing factors amenable to correction or avoidance. Other helpful treatment options include nocturnal head-up tilting and mineralocorticoids, both of which help to expand blood volume. Many other therapeutic agents have been tried in small and selected patient populations, often with disappointing results. While many of the drugs available (phenylephrine, ephedrine, tyramine, dihydroergotamine) can improve upright blood pressure, side effects are common, and supine hypertension is problematic in many patients. Interventions of this type should be carefully initiated in a monitored setting. The carotid sinus is an important component of a neural control system responsible for heart rate and blood pressure homeostasis. Excessive heart rate and blood pressure responses to distortion of the carotid sinus are the basis for the carotid sinus syndrome (CSS). Patients with CSS tend to be elderly males and local pathology in the neck is frequently involved. Atherosclerotic coronary artery disease and hypertension are important clinical correlates. Two major categories of carotid sinus hypersensitivity (CSH) are recognized: cardioinhibitory and vasodepressor. Cardioinhibitory CSH is the most common, and in its purest form consists of sinus bradycardia or arrest, asystole or AV block during carotid sinus massage. This vagally-mediated response is eliminated by atropine. Cardiac pacing is nearly universally successful in preventing severe symptoms.(ABSTRACT TRUNCATED AT 400 WORDS)     

Haemodynamic effects of beta-adrenergic blockade in hyperthyroid patients with and without heart failure

Haemodynamic studies were performed in 10 patients with uncomplicated thyrotoxicosis and seven with thyrotoxic cardiac failure. The cardiac output of those with uncomplicated hyperthyroidism was higher than normal at rest. After 2 mg of intravenous propranolol there was a 13% fall but the level was still higher than normal. In patients with thyrotoxic cardiac failure the resting cardiac output was normal, but it fell after propranolol by 30% to subnormal levels. In both groups there was an increase in right heart pressures and fall in the rate of increase in arterial pressure, which indicated a decrease in myocardial contractility. These results indicate that increased autonomic activity is a compensatory phenomenon in hyperthyroid heart failure and that its abolition by beta-blocking drugs has a deleterious effect on cardiac function. They are therefore contraindicated in patients with thyrotoxic heart failure.     

Treatment of heart failure

Heart failure is a disease which involves not only the heart but the entire circulatory system. Progression is directly related to interactions between myocardial disorders and neurohormonal and circulatory phenomena. Advances in treatment have resulted more from the development of vasodilator drugs with neurohormonal effects than from drugs with a direct effect on the myocardium. Diuretics are essential due to their rapid functional effect and the reduction in pressure on the ventricle wall. The effectiveness of digitalics is recognized not only in patients with atrial fibrillation, but also in those in sinus rhythm with ischemic heart disease. Conversion enzyme inhibitors are useful in all stages of heart failure, improving both quality of life and life expectancy as well as limiting myocardial and vascular remodeling and retarding progression of ventricular dysfunction. As current progress in the treatment of heart failure has not greatly reduced mortality, prevention is the major challenge facing all physicians. Treatment of asymptomatic ventricular function is one rational approach.     

Extracorporeal membrane oxygenation for cardiac support in children

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) support for cardiac failure has been used in children since 1981 at the Children's Hospital in Pittsburgh. Most children required support after cardiac operations. Recently, however, a larger number of patients with decompensated cardiomyopathy or myocarditis have been supported with ECMO, which was used as a bridge to transplantation in most. METHODS: From 1981 to 1994, 68 children were placed on ECMO for cardiac support. RESULTS: The overall survival for the entire time period was 38%, with the more recent experience survival increased to 47%. In 14 children, ECMO was used as a bridge to transplantation, with 9 children receiving a heart transplant and 7 long-term survivors. Extracorporeal membrane oxygenation has also been used to resuscitate 11 children after sudden cardiac arrest, with a long-term survival of 53%. CONCLUSIONS: We conclude that ECMO support for severe cardiac failure is effective. Patient selection and the use of heart transplantation for intractable heart failure have improved the overall survival.     

Effects of eprosartan on renal function and cardiac hypertrophy in rats with experimental heart failure

Activation of the renin-angiotensin system may contribute to the derangement in renal and cardiac function in congestive heart failure. The present study evaluated the effects of eprosartan, a selective angiotensin II receptor antagonist, on renal hemodynamic and excretory parameters and on the development of cardiac hypertrophy in rats with aortocaval fistula, an experimental model of congestive heart failure. Infusion of eprosartan (1.0 mg/kg) in rats with aortocaval fistula produced a significant increase (+34%) in total renal blood flow and a sustained decrease (-33%) in the calculated renal vascular resistance. These effects on renal hemodynamics were more pronounced than those observed in sham-operated control rats and occurred despite a significant fall (-12%) in mean arterial blood pressure. Moreover, eprosartan caused a preferential increase in renal cortical blood perfusion and significantly increased glomerular filtration in rats with congestive heart failure. Chronic administration of eprosartan (5.0 mg/kg per day for 7 days through osmotic minipumps inserted intraperitoneally on the day of operation) resulted in a significant enhancement of urinary sodium excretion compared with nontreated rats with heart failure. Moreover, administration of eprosartan to salt-retaining rats with congestive heart failure resulted in a progressive increase and ultimate recovery in urinary sodium excretion. Finally, early treatment with eprosartan blocked the development of cardiac hypertrophy in rats with aortocaval fistula to a larger extent than the angiotensin-converting enzyme inhibitor enalapril. These findings emphasize the importance of angiotensin II in mediating the impairment in renal function and induction of cardiac hypertrophy in heart failure and further suggest that angiotensin II receptor blockade may be a useful treatment of these consequences in severe cardiac failure.     

The clinical diagnosis of heart failure in older patients

OBJECTIVE: To review the differences in presentation and clinical manifestation of heart failure in older and younger patients and to determine if these differences influence the ability to diagnose the disorder clinically. Based on this information, an approach to diagnosing heart failure in older patients is provided. DATA SOURCE: Scientific reports regarding heart failure in both the general population and the geriatric population were identified from repeated searches of MEDLINE data base and citations from appropriate articles. DATA EXTRACTION AND SYNTHESIS: Relevant data were obtained from articles, with special importance placed on studies designed to examine older patients exclusively or as a subgroup in a larger study. Review of data pertaining to clinical characteristics and presentation of heart failure was performed, with emphasis on comparing the characteristics between age groups. Specific cardiac diseases that cause ventricular impairment in older patients were assessed, and the importance of systolic versus diastolic dysfunction in this age group was analyzed. CONCLUSION: Clinical diagnosis of heart failure in older patients may be difficult because of the absence of typical symptoms and physical findings. When present, the symptoms and signs may be mistakenly diagnosed as caused by concomitant disorders or aging changes. In other older patients, the symptoms and signs will be obscured by the presence of aging changes or the presence of other diseases. As a result of these difficulties, the initial diagnosis of heart failure in older patients is made later in the course of the cardiac disease process; older patients will be more unstable, and secondary preventive therapies may be of less benefit than in younger patients with the disorder. Though clinically difficult, the differentiation between systolic and diastolic ventricular dysfunction is mandatory in all older patients with heart failure.     

Alexithymia and attachment representation in idiopathic spasmodic torticollis

In the last years there has been an appreciation of the importance of left ventricular geometry. After a period, in the sixties and seventies, that the interest was focused on cardiac physiology and the left ventricular geometry role about this subject, new studies are available on clinical significance of normal or distorted left ventricular shape. New assessment methods of ventricular geometry have been described. The use of simple measurements to assess ventricular geometry has allowed to know the clinical value of the shape distortion in patients with heart failure. The suspicion that left ventricular shape change to sphericity has prognosis value, has raised the interest about this subject. Whether distortion of left ventricular shape is an even better parameter than cardiac function indices normally used is under consideration. Moreover, new surgical therapies have been developed in an attempt to improve the ventricular geometry and to get better clinical prognosis in patients with heart failure.