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PubMed2006

[Pathophysiology of chronic heart failure].

Heart failure is a progressive and often fatal disease process. In general, the pathophysiologic mechanisms responsible for progressive myocyte dysfunction and cell loss, cardiac remodeling and arrhythmias involve signaling mechanisms that alter myocardial gene expression. These changes in gene expression are complex and involve contractile proteins, ion channels, Ca(++) handling, apoptosis, cell metabolism, the extracellular matrix, signal transduction pathways and growth factors. In the failing heart, several changes occur in cardiac adrenergic receptor-signal transduction pathways. The most striking of these changes occur in beta-adrenergic receptors, and of the changes in beta-adrenergic receptors beta1-receptor down-regulation is the most prominent. Other changes include uncoupling of beta2-adrenergic receptors and increased activity of the inhibitory G-protein. Most of these changes appear to be related to increased activity of the adrenergic nervous system, i.e. increased exposure to norepinephrine. Antagonists of the adrenergic nervous system may improve left ventricular function and outcome in patients with heart failure. This fact supports the notion that activation of these neurohormonal systems exerts a net long-term detrimental effect on the natural history of chronic heart failure and that myocardial adrenergic desensitization phenomena are at least partially maladaptive in the setting of left ventricular dysfunction. In addition to functional alterations structural remodeling plays a major role in the progression of various heart diseases to congestive heart failure. Major contributors to this remodeling process in the heart include alterations in myocyte shape, myocyte number and extracellular matrix. However, it is unclear as to which of these changes is most critical in the development of congestive heart failure, and this may vary by etiology.

Chronic Disease↗
PubMed2005

Caring for patients with heart failure.

Heart failure affects more: 350,000 Canadians and accounts for more than dollar 1 billion of Canada's health budget. It is the most common condition requiring re-hospitalization and carries with it a mortality rate of between 25% and 40% (Liu et al., 2003) In British Columbia, approximately 70,000 people (1.5% of the B.C. population) were diagnosed with heart failure in 2003 and it is estimated that a further 70,000 people may be living undiagnosed with the condition (British Columbia Ministry of Health Services, 2003). The vast majority of people with heart failure are over 70 years of age. As our population ages, it is reasonable to expect that the burden of heart failure on our health system will continue to increase. Heart failure is usually a chronic condition marked by frequent exacerbations. It is these exacerbations that bring patients to hospital emergency departments and medical wards.

Adrenergic beta-Antagonists↗
PubMed2000

Cellular and functional defects in a mouse model of heart failure.

Heart failure and dilated cardiomyopathy develop in mice that lack the muscle LIM protein (MLP) gene (MLP(-/-)). The character and extent of the heart failure that occurs in MLP(-/-) mice were investigated using echocardiography and in vivo pressure-volume (P-V) loop measurements. P-V loop data were obtained with a new method for mice (sonomicrometry) using two pairs of orthogonal piezoelectric crystals implanted in the endocardial wall. Sonomicrometry revealed right-shifted P-V loops in MLP(-/-) mice, depressed systolic contractility, and additional evidence of heart failure. Cellular changes in MLP(-/-) mice were examined in isolated single cells using patch-clamp and confocal Ca(2+) concentration ([Ca(2+)]) imaging techniques. This cellular investigation revealed unchanged Ca(2+) currents and Ca(2+) spark characteristics but decreased intracellular [Ca(2+)] transients and contractile responses and a defect in excitation-contraction coupling. Normal cellular and whole heart function was restored in MLP(-/-) mice that express a cardiac-targeted transgene, which blocks the function of beta-adrenergic receptor (beta-AR) kinase-1 (betaARK1). These data suggest that, despite the persistent stimulus to develop heart failure in MLP(-/-) mice (i.e., loss of the structural protein MLP), downregulation and desensitization of the beta-ARs may play a pivotal role in the pathogenesis. Furthermore, this work suggests that the inhibition of betaARK1 action may prove an effective therapy for heart failure.

Animals↗
PubMed2003

Therapies for Preventing Heart Failure.

Heart failure is an increasingly common syndrome. Despite numerous advances in the treatment of patients with established heart failure, the prevalence and economic burden of the disease will continue to escalate as long as the number of patients with heart failure continues to increase. Much effort has been directed at developing and refining expensive therapies for the small number of patients with advanced heart failure; these efforts will offer little benefit to public health. Simple preventive strategies have been shown to reduce the likelihood of heart failure. Widespread use of these strategies would result in substantial improvement in community health and reduction in societal cost for a disease that will otherwise prove increasingly burdensome.

Journal Article↗
PubMed2004

Cytokines are not upregulated in adriamycin-induced cardiomyopathy and heart failure.

Heart failure due to a variety of causes is accompanied by an upregulation of cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6). Adriamycin-induced cardiomyopathy (AIC) and heart failure is an important clinical problem. The current study investigated the expression of these cytokines in AIC and heart failure in rats. Both early and late stages of AIC was produced in rats. Myocardial gene expressions for TNF-alpha, IL-1beta and IL-6 were examined with DNA microarrays and RT-PCR. Protein levels of these cytokines in both the plasma and the myocardium were also examined by ELISA. In the early stage, myocardial mRNA expression of IL-1beta showed significant increase at 4 and 24 h, peaking at 4 h, while TNF-alpha did not change and IL-6 was undetectable. The protein levels of these three genes did not show any upregulation in the plasma or the heart. In the late stage, heart failure was confirmed by clinical signs as well as homodynamic changes. In this stage, plasma protein levels for TNF-alpha, IL-1beta and IL-6 were not changed. However, myocardial TNF-alpha mRNA expression and protein levels were significantly decreased, while both IL-1beta mRNA and protein levels were not different compared to the control group. IL-6 mRNA expression was undetectable in both normal and adriamycin-treated hearts while its protein level was not changed by adriamycin. Positive control using lipopolysaccharides (LPS) treatment (0.5 mg/kg body weight) for 2 h resulted in a significant increase in these three cytokines in the heart and plasma. These data suggest that an upregulation of cytokines may not be involved in AIC. Heart failure may in fact be accentuated by a downregulation of myocardial TNF-alpha.

Animals↗
PubMed2001

New epidemiologic perspectives concerning mild-to-moderate heart failure.

Heart failure is emerging as a major component of the public health problem of cardiovascular disease as we move into the twenty-first century. Current statistics indicate 4.9 million US citizens are afflicted with direct treatment costs estimated to be $18.8 billion per year. These figures are expected to worsen substantially as the prevalence of heart failure continues to increase. Epidemiologic studies also point to important increases in morbidity and have identified risk factors that aid in prognosis and that may contribute to our mechanistic understanding of heart failure pathophysiology. In addition, epidemiologic results indicate that many patients with mild-to-moderate clinical heart failure are still at substantial risk for morbidity and mortality during follow-up periods of only a few years. These data highlight the importance of enhancing physician and public awareness of heart failure. New methods of molecular epidemiology will point toward better and earlier detection of this common and frequently fatal condition.

Age Distribution↗
PubMed1989

Arrhythmias and their treatment in patients with heart failure.

Heart failure is almost without exception associated with arrhythmias, which may be either supraventricular or ventricular. Supraventricular arrhythmias include frequent supraventricular extrasystoles, and episodic or chronic atrial fibrillation. The absence of atrial contraction may further reduce cardiac output, as may impaired control of QRS frequency. Therefore, supraventricular arrhythmias may be markers of the degree of heart failure and these arrhythmias will respond to heart failure therapy including diuretics, nitrates and, possibly, angiotensin-converting enzyme (ACE) inhibitors. Ventricular rate will be controlled by cardiac glycosides and further rate reduction obtained by verapamil or diltiazem. The rationale for this therapy is to optimize heart rate without compromising contractility. Severe heart failure is generally accompanied by severe ventricular arrhythmias including repetitive forms. Improving left ventricular function by ACE inhibition is accompanied by a reduction in the number of ventricular premature complexes and also a reduction in the rate of ventricular tachycardia. ACE inhibition reduces mortality but does not seem to influence sudden death rate, and sudden death patients may have different neurohormonal responses compared with patients destined to die of progressive heart failure. Uncontrolled trials with class IA or class III antiarrhythmic drugs have suggested that prognosis may be improved, but other studies have pointed out the increased risk of proarrhythmic responses in patients with low ejection fraction.

Anti-Arrhythmia Agents↗
PubMedDate not supplied

Angiotensin II receptor blockers in the treatment of heart failure.

Heart failure treatment centers on antagonism of the renin-angiotensin-aldosterone system and adrenergic nervous system. Angiotensin-converting enzyme (ACE) inhibitors have been shown to benefit patients with left ventricular systolic dysfunction irrespective of symptoms. Despite ACE inhibitor use, left ventricular dysfunction continues to progress in most patients. In addition, ACE inhibitors are substantially underused in patients who would benefit, in large part due to physician concern over potential adverse effects. Angiotensin receptor blockers (ARBs) have been proposed as either potential substitutes for ACE inhibitors or as additive therapy for heart failure patients. The authors will review the importance of the renin-angiotensin-aldosterone system in the progression of heart failure, as well as the mechanisms by which ACE inhibitors and ARBs counteract this effect. The clinical evidence to date supporting the use of ARBs in heart failure also will be reviewed. Based on current trials, ARBs are suitable substitutes for ACE inhibitors in patients who have true ACE inhibitor intolerance, but ACE inhibitors should still be considered first-line therapy in the treatment of left ventricular systolic dysfunction and heart failure. ARBs are a reasonable additive therapy in patients on maximal ACE inhibitor therapy who remain symptomatic, especially in patients unable to tolerate beta blockade.

Angiotensin II↗
PubMed1998

Surgical alternatives in the treatment of heart failure.

Heart failure continues to plague a large population worldwide, and its incidence is increasing annually as a result of an aging population. It is associated with lengthy hospital stays, multiple hospital readmissions, and decreased quality of life because of its clinical manifestations. Although cardiac transplantation has become the therapy of choice for patients with heart failure, scarcity of donor hearts and age limitations prohibit its widespread use. Despite major advances in medical management, researchers continue to explore alternative surgical therapies to help augment cardiac function. This article explores surgical interventions in the management of heart failure, many of which are still experimental or in clinical trials. Coronary artery bypass surgery, dynamic cardiomyoplasty, and partial left ventriculectomy for the management of heart failure are discussed in detail. Descriptions of each surgical procedure, special care needs, and clinical outcomes are presented. However, because readers are familiar with the coronary artery bypass procedure and postoperative patient care, the discussion will focus on issues related to coronary artery bypass grafting in the presence of ischemic cardiomyopathy.

Cardiomyoplasty↗
PubMed2004

Levosimendan: first in a new class of inodilator for acute and chronic severe heart failure.

Heart failure is the most common malignant disease in the developed world. Levosimendan (Simdax) is a novel intravenous agent that exerts inotropic effects through sensitization of myofilaments to calcium and vasodilator effects by opening ATP-dependent potassium channels on vascular smooth muscle. Infusion of levosimendan increases cardiac output due to an increase in stroke volume and heart rate, with a fall in pulmonary capillary wedge pressure. It has an active metabolite with a half-life of about 80 h, therefore infusions of 6 to 24 h result in hemodynamic effects that persist for 7 to 10 days. Preliminary observations suggest that a single infusion of levosimendan lasting 6 to 24 h in patients with severe heart failure due to left ventricular systolic dysfunction results in hemodynamic changes, symptomatic benefit and a reduction in morbidity and mortality over the following 2 to 4 weeks compared with placebo in one study and with dobutamine in another. Long-term follow-up suggests no loss of this early benefit over 6 months. Levosimendan is licensed for the treatment of decompensated heart failure in many countries but not in North America. Further large trials are being conducted comparing levosimendan with placebo and with dobutamine in patients with severe heart failure and left ventricular systolic dysfunction. If these studies confirm the benefits of levosimendan, then it may become routine therapy for the management of severe heart failure.

Cardiotonic Agents↗
PubMed2000

Prospects for gene therapy for heart failure.

Heart failure represents an enormous clinical challenge in need of effective therapeutic approaches. The possibility of gene therapy for heart failure merits consideration at this time because of improvements in vector technology; cardiac gene delivery; and, most importantly, our understanding of the molecular pathogenesis of heart failure. We will first review recent advances in cardiac gene delivery in animal models and then examine several targets being considered for therapeutic intervention. In this context, gene transfer provides not only a potential therapeutic modality but also an important tool to help validate specific targets. Several interventions, particularly those enhancing sarcoplasmic calcium transport, show promise in animal models of heart failure and in myopathic cardiomyocytes derived from patients. However, bridging the gap between these basic investigative studies and clinical gene therapy remains a formidable task. Early experiments in rodents will need to be extended to large-animal models with clinical-grade vectors and delivery systems to assess both efficacy and safety. On the basis of a foundation of rigorous science and a growing understanding of heart failure pathogenesis, there is reason for cautious optimism for the future.

Animals↗
PubMedDate not supplied

Pathophysiology of heart failure.

Heart failure, a major contributor to cardiovascular disease morbidity and mortality, is newly diagnosed in approximately 400,000 patients each year, and is particularly prevalent in individuals over age 65 years. Average mortality rates 5 years after diagnosis are 45-60%, and may be as high as 50% after 1 year for those with New York Heart Association class IV heart disease. Heart failure occurs when myocardial muscle dysfunction prevents the heart from pumping enough blood at normal cardiac pressures to meet the metabolic needs of the body, especially during exercise, and compensatory hemodynamic and neurohormonal mechanisms are overwhelmed or maladaptive. Pathologic classifications are broadly based on the presence of systolic (dilated cardiomyopathy) or diastolic (hypertrophic or restrictive cardiomyopathies) dysfunction. The etiologies of heart failure may include inadequate coronary blood flow, pressure or volume overload, cardiomyopathy, or pericardial disease. Coronary artery disease, idiopathic dilated cardiomyopathy, and hypertension are the most frequent causes, and certain drugs may also worsen myocardial function. When contractility is reduced, stroke volume and cardiac output are decreased, and alterations in the kidneys may induce fluid retention to compensate for the perceived low output and reduced circulating blood volume. Fluid retention in turn causes preload or filling pressure to increase and symptoms of pulmonary congestion to emerge. Depressed contractility also results in a reduction in blood pressure, leading to compensatory neurohormonal activation and vasoconstriction, which significantly elevate afterload and further reduce stroke volume. The overall approach to heart failure includes defining the etiology, identifying precipitant factors, and assessing the severity of myocardial dysfunction and clinical symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed2004

Aldosterone Receptor Blockers in the Treatment of Heart Failure.

Heart failure is associated with neurohormonal activation, including activation of the renin-angiotensin-aldosterone system. Plasma aldosterone levels are elevated in patients with heart failure in spite of the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers because of angiotensin-independent stimuli for aldosterone production. In addition to its long recognized role in sodium retention, aldosterone has a number of other deleterious effects, including the increase in myocardial and vascular fibrosis and myocardial remodeling in patients with heart failure. Based on strong clinical trial data, low-dose aldosterone receptor blockers are recommended to improve morbidity and mortality in patients with severe chronic heart failure due to left ventricular systolic dysfunction and in patients with heart failure associated with left ventricular systolic dysfunction after acute myocardial infarction, and in patients already on standard therapy including ACE inhibitors (or angiotensin receptor blockers) and beta blockers. In view of the potential for serious hyperkalemia with the use of aldosterone receptor blockers, it is essential to monitor serum potassium closely and to adjust the dose of aldosterone antagonists based on serum potassium levels. Close adherence to the dosing regimens used in the clinical trials (RALES and EPHESUS ) is recommended. These agents should not be initiated in patients with severe renal insufficiency and closer monitoring is warranted in those with mild to moderate renal insufficiency or diabetes.

Journal Article↗
PubMed2004

Recent advances in the diagnosis of heart failure.

Heart failure has reached epidemic proportions and the prevalence is increasing. The accurate and efficient diagnosis of heart failure remains problematic, as signs and symptoms are neither sensitive nor specific. Recent advances in the diagnosis of this condition include a conceptual change in what constitutes heart failure, a greater understanding of heart failure with preserved systolic function, and an abundance of data supporting the use of neurohormonal assays, particularly brain-type natriuretic peptide. These factors will help facilitate earlier diagnosis and targeted treatment of patients with this malady.

Biomarkers↗
PubMed1999

Diastolic dysfunction and collagen structure in canine pacing-induced heart failure.

Heart failure is characterized not only by systolic, but also by diastolic dysfunction. The present study tested whether or not diastolic dysfunction is associated with changes in tissue properties and collagen network structure. Heart failure was induced in seven chronically instrumented, conscious dogs by rapid left ventricular pacing (2 50 min(-1)). After 2-5 [mean: 4+/-1 (S.D.)] weeks pacing, heart failure was apparent from clinical symptoms (ascites, cachexia, edema, exercise intolerance) and hemodynamic parameters (significant increases of heart rate and left ventricular end-diastolic pressure and decreases of left ventricular maximal pressure, dP/dtmax and systolic wall thickening). The left ventricle was dilated, as indicated by a decrease of end-diastolic wall thickness (6.3+/-2.0 v 7.2+/-2.1 mm; P<0.05; sonomicrometry). The left ventricular end-diastolic pressure-strain relation (strain: relative change of end-diastolic wall thickness) was obtained during alterations of loading conditions by inferior caval vein and descending thoracic aortic occlusion. The slope of this relation increased from 85+/-20 to 428+/-188 in heart failure, indicating an increase of left ventricular stiffness. Collagen was stained with picrosirius red and analyzed using polarized light microscopy. In heart failure, the collagen volume fraction remained unchanged (1.9+/-1.2 v 2.3+/-1.3%; N.S.), while the nonuniformity of collagen orientation, as reflected by its standard deviation, was increased (11.1+/-1.8 v 6.1+/-0.4 o; P<0.05). The nonuniformity of collagen fiber orientation correlated with left ventricular stiffness [r=0.75].

Animals↗
PubMed2006

Beyond the basics: right vs. left heart failure.

Heart failure is a pathophysiologic cascade that, if improperly identified and managed, may lead to death. If heart failure is identified early enough, development of irreversible end-stage heart failure may be avoided. The goal of the prehospital care provider in managing heart failure is directed at maintenance of adequate cellular oxygenation, reduction of preload and afterload to improve forward blood flow, and, ultimately, improve cardiac output.

Education, Continuing↗
PubMed2004

Mitral Valve Repair in the Treatment of Heart Failure.

Heart failure continues to be one of the leading causes of hospitalizations and mortality in the United States. Mitral valve regurgitation in patients with heart failure is most often a functional abnormality and as such represents a different disease entity from other more common causes of regurgitation. In general, in patients with heart failure the mitral valve structure is normal; however, regurgitation is secondary to changes in left ventricular (LV) structure and function, including mitral annular dilatation and changes in LV geometry. Mitral regurgitation affects almost all patients with heart failure as a preterminal or terminal event, and carries a high morbidity and mortality. Medical management is limited to treatment with diuretics and afterload reduction. Unfortunately, once significant amounts of mitral regurgitation are manifest, medical treatment alone is generally associated with poor long-term survival and outcome. Surgical treatment by means of undersized annuloplasty type repairs has shown great promise, for preventing worsening heart failure and improving overall LV function.

Journal Article↗