Heart failure monitor最新文献

Diabetes mellitus is associated with an increased risk of cardiovascular disease (CVD), even in the presence of intensive glycemic control. Substantial clinical and experimental evidence suggests that both diabetes and insulin resistance cause a combination of endothelial dysfunctions, which may diminish the anti-atherogenic role of the vascular endothelium. Endothelial dysfunctions that have been described include decreased endothelium-dependent vasorelaxation, increased leukocyte-endothelial cell adhesion and vascular permeability, and the altered production of a variety of vasoactive substances, which affect coagulation, extracellular matrix homeostasis, and smooth muscle physiology. The primary mechanisms that contribute to these endothelial dysfunctions in diabetes appear to involve the activation of protein kinase C (PKC) pathways, increased non-enzymatic glycation, increased oxidant stress, and reduced endothelial insulin action. In addition, many of the adverse effects of these abnormalities associated with hyperglycemia and insulin resistance are mediated and amplified by potent vasoactive hormones including angiotensin II, transforming growth factor-beta, and vascular endothelial growth factor. Multiple interventions have been shown to improve endothelial dysfunction in diabetes, including PKC inhibition, infusion of soluble receptors for advanced glycation end-products, antioxidant and insulin supplementation, and angiotensin-converting enzyme inhibition. These findings are consistent with a model involving a combination of factors contributing to the etiology of the endothelial dysfunctions in diabetes. Further work is needed to determine whether endothelial function can be used as a therapeutic target to reduce CVD and improve clinical outcomes.

Clinical suspicion of congestive heart failure (CHF) always requires a careful diagnostic workup. This comprises the verification of the presence of CHF (in contrast to other conditions that cause nonspecific phenomena such as shortness of breath and edema), evaluation of the underlying cause of heart failure, and assessment of left ventricular (LV) systolic function. In addition to clinical examination, echocardiography is warranted in most cases. On the basis of this information, patients can be selected for further studies, such as exercise testing, cardiac catheterization and coronary angiography. In view of the serious prognosis of heart failure, especially systolic CHF, the threshold for specialist consultation should be low. Although the classification of CHF into systolic and diastolic forms is complex, clinically meaningful data can be derived simply by determining whether LV systolic function is impaired (predominantly systolic CHF) or not (probable diastolic CHF). In the latter case, treatment is mainly symptomatic in addition to the management of the underlying condition (e.g. hypertension). In systolic CHF, considerable therapeutic advances have recently been made and it is important that patients receive appropriate care to improve their prognosis. These measures include angiotensin-converting enzyme inhibitors, beta-blockers and spironolactone.

In patients with advanced chronic heart failure, characterized by prolonged QRS duration and by decreased cardiac contractility, decreasing dysynchrony by biventricular pacing seems to improve exercise tolerance (6-min walk distance), symptoms (New York Health Association class), and quality of-life scores. Although the results of several reports were consistent, the numbers of patients studied were small, and many of the changes were trends that did not reach statistical significance. The availability of a non-pharmacological treatment that improves exercise capacity and quality-of-life would be a major advance. However, further studies will need to address the question of mortality and morbidity benefits of such intervention.

Accumulating evidence indicates that inflammatory mediators are important in the pathogenesis of chronic heart failure. Several studies have shown raised levels of inflammatory cytokines in patients with congestive heart failure (CHF), in both plasma and circulating leukocytes, as well as in the failing myocardium itself. Importantly, many of the inflammatory cytokines (e.g. tumor necrosis factor-a and interleukin-6) have the potential to negatively influence heart contractility, induce hypertrophy, and promote apoptosis or fibrosis, thereby contributing to the continuous remodeling process in CHF. Traditional cardiovascular drugs seem to have little influence on the cytokine network in CHF patients, and immunomodulatory therapy, in addition to 'optimal' cardiovascular treatment regimens, has emerged as an option. Thus, several small studies with therapy targeted against inflammatory mediators have shown promising effects on functional capacity and myocardial performance. These studies suggest a potential for immunomodulating therapy, in addition to optimal conventional cardiovascular-treatment regimens in CHF patients. However, the results in these small studies will have to be confirmed in larger placebo-controlled mortality studies. More importantly, further research in this area will have to precisely identify the most important components in the immunopathogenesis of chronic heart failure, in order to develop more specific immunomodulating agents in this disorder.

Numerous prospective cohort studies have indicated that diabetes mellitus (DM), particularly type-2 DM (the type of diabetes associated with insulin resistance that usually strikes adults), is associated with a 3-4-fold increase in risk for coronary heart disease (CHD) [1-3]. The increase in risk is particularly evident in younger-age groups, and in women: females with type-2 DM appear to lose a great deal of the protection that characterizes non-diabetic females. Furthermore, patients with DM have a 50% greater in-hospital mortality, and a 2-fold increased rate of death within 2 years of surviving a myocardial infarction. Overall, CHD is the leading cause of death in individuals with DM who are >35 years old. Although a significant portion of this increased risk is associated with the presence of well-characterized risk factors for CHD, a significant proportion remains unexplained. Patients with DM, particularly those with type-2 DM, have abnormal plasma lipid and lipoprotein concentrations that are less commonly present in non-diabetics [4-6]. Patients with poorly controlled type-1 DM can also have a dyslipidemic pattern, but, in this review, we will focus on the dyslipidemia seen commonly in patients with type-2 DM. In particular, we will describe the pathophysiology underlying the increase in plasma very low-density lipoprotein triglyceride levels, the reductions in plasma high-density lipoprotein cholesterol levels, and the abnormal, small, dense low-density lipoproteins that are the central components of diabetic dyslipidemia. The dyslipidemia of DM clearly adds significantly to the high risk for CHD in this group, and must be treated aggressively with diet, weight loss and lipid-altering medications. Combinations of lipid-altering medications, particularly statins and fibrates, can markedly change plasma lipid levels, often bringing them all into the normal range.

Current thinking views the progression of heart failure as the result of sustained activation of vasoconstrictor neurohormones. In this model, the sustained synthesis of vasoconstrictor neurohormones leads to disease progression through alterations in cardiomyocyte structure and function, which affects myocardial contractility, cardiac metabolism, and cellular growth. Ultimately, these events induce irreversible adverse ventricular remodeling through myocyte cell loss and progressive myocardial fibrosis. In the past decade, several landmark clinical trials tested the neurohormonal hypothesis, by targeting the activation of both the beta-adrenergic and the renin-angiotensin-aldosterone systems. Although the observed decrease in mortality using this strategy in heart failure populations was encouraging, morbidity and mortality levels remained elevated, and it has now been shown that several other humoral interactions are at play and potentially deserve antagonizing, or in the case of vasodilator neurohormones, deserve stimulation. It is known a family of vasodilator neurohormones - the natriuretic peptides - that have natriuretic, vasodilatory, and antiproliferative effects, endogenously inhibit the renin-angiotensin system. These peptides are degraded primarily by a neutral endopeptidase (NEP), an endothelial cell-surface zinc metallopeptidase, which shares a similar structure and catalytic site with the angiotensin converting enzyme (ACE). NEPs have broad substrate specificity, encompassing atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide, but also bradykinin and adrenomedullin. The recognition that ACE and NEP enzymes had related structures, led to the design and development of a class of molecules with a dual inhibitory effect on ACE and NEP, referred to as vasopeptidase inhibitors. Preliminary clinical trials in heart failure with vasopeptidase inhibitors have become available and show promising results. Thus, the combined inhibition of ACE and NEP, by attenuating excessive vasoconstriction and enhancing vasodilator substances, holds promise as a valuable option in heart failure treatment for the near future.

Elevated levels of proinflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin-6 (IL-6), have been demonstrated in patients with chronic heart failure (CHF). Evidence suggests that cytokines such as these may play a central role in the pathogenesis of this syndrome. TNF has several properties that are particularly detrimental in CHF, such as negatively inotropic effects, the promotion of left ventricular remodelling, and the induction of dilated cardiomyopathy in humans. Furthermore, TNF can cause skeletal muscle wasting and apoptosis, and, therefore, may be important in the development of cardiac cachexia. Although the precise stimulus for immune activation in CHF is unknown, one hypothesis is that endotoxin may be a significant trigger for cytokine release. This is supported by the finding that decompensated CHF patients have elevated endotoxin levels that normalize on diuretic therapy. The factors that influence endotoxin responsiveness in patients with CHF, in particular the potential importance of serum lipoproteins, will be discussed in this review.

Augmented peripheral and central chemoreceptor sensitivity has recently been demonstrated in both experimental and clinical settings of chronic heart failure (CHF). As a result of the effects of chemoreflexes on the respiratory, circulatory and neurohormonal systems, changes in their activity may account for several pathophysiological features of CHF--predominantly augmented ventilation, abnormal cyclic respiratory pattern and sympathetic overactivity. Although the precise underlying mechanisms are not known, a heightened chemoreflex drive may constitute an ominous sign in CHF. Patients with abnormally elevated chemosensitivity demonstrate an augmented ventilatory response to exercise, a severely impaired autonomic regulation and suppression of baroreceptor function, and a higher prevalence of ventricular arrhythmias. All these factors may unfavorably influence the prognosis of CHF. In fact, we have recently confirmed in a group of patients with advanced CHF that high peripheral chemosensitivity is an independent predictor of death. New therapies are needed in CHF to improve prognosis and quality of life. Drugs, such as opiates, and oxygen administration have been shown to suppress chemosensitivity, which may further favorably influence exercise tolerance and modify periodic breathing in CHF patients. Treatment strategies targeted at peripheral and central chemoreceptors may be a promising option for further evaluation.

In epidemiological surveys and in large-scale therapeutic trials, the prognosis of patients with ischemic heart failure is worse than in patients with a non-ischemic etiology. Even heart transplant candidates may respond better to intensified therapy if they have non-ischemic heart failure. The term 'non-ischemic heart failure' includes various subgroups such as hypertensive heart disease, myocarditis, alcoholic cardiomyopathy and cardiac dysfunction due to rapid atrial fibrillation. Some of these causes are reversible. The therapeutic effect of essential drugs such as angiotensin-converting enzyme inhibitors, beta-blockers and diuretics does not, in general, significantly differ between ischemic and non-ischemic heart failure. However, in some trials, response to certain drugs (digoxin, tumor necrosis factor-alpha, inhibition with pentoxifylline, growth hormone and amiodarone) was found to be better in non-ischemic patients. Patients with ischemic heart failure and non-contracting ischemic viable myocardium may, on the other hand, considerably improve following revascularization. In view of prognostic and possible therapeutic differences, the etiology of heart failure should be determined routinely in all patients.