Role of autophagy in heart failure associated with aging

Heart failure is a progressive disease, leading to reduced quality of life and premature death. Adverse ventricular remodeling involves changes in the balance between cardiomyocyte protein synthesis and degradation, forcing these myocytes in equilibrium between life and death. In this context, autophagy has been recognized to play a role in the pathophysiology of heart failure. At basal levels, autophagy performs housekeeping functions, maintaining cardiomyocyte function and ventricular mass. Autophagy also occurs in the failing human heart, and upregulation has been reported in animal models of pressure overload–induced heart failure. Although the factors that determine whether autophagy will be protective or detrimental are not well known, the level and duration of autophagy seem important. Autophagy may antagonize ventricular hypertrophy by increasing protein degradation, which decreases tissue mass. However, the rate of protective autophagy declines with age. The inability to remove damaged structures results in the progressive accumulation of ‘garbage’, including abnormal intracellular proteins aggregates and undigested materials such as lipofuscin. Eventually, the progress of these changes results in enhanced oxidative stress, decreased ATP production, collapse of the cellular catabolic machinery, and cell death. By contrast, in load-induced heart failure, the extent of autophagic flux can rise to maladaptive levels. Excessive autophagy induction leads to autophagic cell death and loss of cardiomyocytes and may contribute to the worsening of heart failure. Accordingly, the development of therapies that up-regulate the repair qualities of the autophagic process and down-regulate the cell death aspects would be of great value in the treatment of heart failure.     

骨桥蛋白在心力衰竭中的作用

近期相关研究提示,骨桥蛋白与心功能不全严重程度相关,其机制与介导细胞外基质表达,肾素-血管紧张素-醛固酮系统调控相关,有望作为心力衰竭患者临床评估的新的生物化学指标。本文就骨桥蛋白的结构、功能及其与心力衰竭相关的机制和意义进行综述。     

The role of inflammatory and fibrogenic pathways in heart failure associated with aging

Heart failure is strongly associated with aging. Elderly patients with heart failure often have preserved systolic function exhibiting left ventricular hypertrophy accompanied by a decline in diastolic function. Experimental studies have demonstrated that age-related cardiac fibrosis plays an important role in the pathogenesis of diastolic heart failure in senescent hearts. Reactive oxygen species and angiotensin II are critically involved in fibrotic remodeling of the aging ventricle; their fibrogenic actions may be mediated, at least in part, through transforming growth factor (TGF)-β. The increased prevalence of heart failure in the elderly is also due to impaired responses of the senescent heart to cardiac injury. Aging is associated with suppressed inflammation, delayed phagocytosis of dead cardiomyocytes, and markedly diminished collagen deposition following myocardial infarction, due to a blunted response of fibroblasts to fibrogenic growth factors. Thus, in addition to a baseline activation of fibrogenic pathways, senescent hearts exhibit an impaired reparative reserve due to decreased responses of mesenchymal cells to stimulatory signals. Impaired scar formation in senescent hearts is associated with accentuated dilative remodeling and worse systolic dysfunction. Understanding the pathogenesis of interstitial fibrosis in the aging heart and dissecting the mechanisms responsible for age-associated healing defects following cardiac injury are critical in order to design new strategies for prevention of adverse remodeling and heart failure in elderly patients.     

Increased myocardial expression of osteopontin in patients with advanced heart failure

The expression of the adhesion protein osteopontin (OP) is associated with cardiac hypertrophy and is significantly increased after transition to heart failure in experimental animal models. We, therefore, hypothesized that OP could be upregulated in heart failure in humans. In the present study, we investigated the expression of OP in myocardial biopsies obtained from patients with heart failure due to dilated cardiomyopathy (mean LVEF=30.3+/-4.4%, mean+/-S.D., n=10, group A) compared to patients with a normal left-ventricular ejection fraction (mean LVEF=61+/-11.2%, n=9; group B). Myocardial immunoreactivity for OP was examined using two different antibodies against OP. The expression of cardiac myocyte OP was significantly upregulated in group A in comparison to group B (P<0.0001). Both groups also displayed OP immunoreactivity in non-myocytes, including vascular smooth muscle cells and cardiac fibroblasts (P=not significant). Statistical analysis revealed a significant correlation of increased OP immunoreactivity in cardiac myocytes of patients with impaired left ventricular function, assessed by hemodynamic data (LVEF, RVEF, LVESVI, LVEDVI and LVEDP, R=-0.828, -0.671, 0.751, 0.685 and 0.461, respectively; all P<0.05). Furthermore, OP expression correlated with cardiac myocyte hypertrophy (mean diameter 21.0+/-1.8 microm in group A and 16.6+/-2.1 microm in group B; P<0.0001). In conclusion, the present study indicates, that factors and/or mechanisms involved in heart failure in patients with dilated cardiomyopathy, lead to induction of OP expression in humans.     

Cardiovascular aging and heart failure

The aging process is a major factor that contributes to changes seen in the cardiovascular system in older people. Stiffening of the arterial tree alters afterload and left ventricular geometry and although resting left ventricular systolic function is maintained, left ventricular diastolic function changes substantially. Cardiovascular function in older people during exercise is also significantly altered but can be modified by exercise training in older adults or genetic modification in animals. Age-related changes in cardiovascular structure and function also lower the threshold at which cardiac diseases become apparent. This review describes the changes in cardiovascular structure and function at rest and during exercise in older people and highlights their consequences.     

Congestive heart failure associated with itraconazole

Itraconazole is a synthetic antifungal agent approved in the USA for the treatment of onychomycosis and serious systemic fungal infections. Animal and clinical pharmacology studies suggest negative inotropic effects with itraconazole. Data from the US Food and Drug Administration's Adverse Event Reporting System suggest that use of itraconazole is associated with congestive heart failure. We summarise the details of 58 cases suggestive of congestive heart failure in association with the use of itraconazole. Labelling of itraconazole has been changed to alert physicians to this new finding.     

Stem cells for heart failure in the aging heart

Despite a wide range of therapeutic interventions, the prognosis for most patients with heart failure remains poor. The identification of stem cells with the ability to generate cardiomyocytes and vascular cells and promote local repair and survival pathways has highlighted the ability of the heart to undergo regeneration and potentially provides a new therapeutic strategy for treatment of the failing heart. In recent years, however, clinical trials aimed at exploiting the beneficial effects of stem and progenitor cells to treat patients with cardiovascular disease have resulted in mild improvements at best, suggesting that these cells and/or the conditions in which they find themselves are not conducive to cardiac repair. Heart failure is most prevalent among older individuals, and a growing body of evidence suggests that with increasing age, cardiac stem and progenitor cells undergo senescent changes that impair their regenerative capacities. Moreover, environmental alterations over time appear to impact the capacity of these cells to improve cardiac function. Understanding these senescent changes may lead to the development of new and improved approaches to exploit the potential of stem cells to repair the aging heart. In this review, age-associated alterations in cardiac stem cell function are discussed, as well as strategies that are being investigated to promote cardiac regeneration in the patient with heart failure.     

增龄与心力衰竭的研究进展

心力衰竭(简称心衰)发病率及患病率随年龄增加而逐渐升高,研究显示增龄可独立于其他疾病造成心肌损伤,最终导致心衰发生.本文综述了增龄导致心脏的结构、功能及表型变化,着重叙述了增龄导致心衰的机制研究进展,包括心肌细胞衰老、血管衰老、细胞外基质重塑、神经内分泌失衡及非编码RNA改变等,并介绍了几种针对增龄性心衰的新兴治疗措施...     

Estrogen is associated with improved survival in aging women with congestive heart failure: analysis of the vesnarinone studies

OBJECTIVES: This study sought to evaluate the effects of postmenopausal estrogen use on mortality in aging women with congestive heart failure (CHF). BACKGROUND: The age-related increase in CHF mortality in women may be related to a menopause-associated increased incidence of coronary artery disease. In addition to inhibiting coronary atherosclerosis, estrogen may also have protective effects on cardiac myocytes independent of the coronary vasculature. We hypothesized that estrogen use is associated with improved survival in elderly women with CHF. METHODS: Associations between survival, estrogen use and patient characteristics were assessed in 1,134 women who were at least 50 years of age, had CHF and left ventricular ejection fraction (EF) < or =30% and were enrolled in one of three clinical trials of vesnarinone. RESULTS: All-cause 12-month mortality was 15.0% among the 237 estrogen users versus 27.1% among the 897 estrogen nonusers (p = 0.004 for unadjusted comparison of survival). Similar results were observed for cardiac mortality. Regression analysis demonstrated that estrogen use was independently associated with improved survival (relative risk of mortality = 0.68, 95% confidence interval 0.48 to 0.96, p = 0.03). Advanced age, low EF, New York Heart Association class IV CHF, Caucasian race and abnormal serum creatinine, sodium, potassium and transaminase were independently associated with increased mortality. CONCLUSIONS: Estrogen use among older women with CHF is associated with decreased overall and cardiac mortality.     

炎症在心力衰竭中的作用

慢性心力衰竭（chronic heart failure,CHF）是由不同病因引起的心脏功能异常,导致心排出量不能满足机体组织代谢的需要,或只能在心室充盈压增高的情况下满足机体需要的一种病理状态。CHF是大多数原发性心血管疾病的严重或终末阶段,现已日益成为威胁人类健康的重大公共健康问题。     

Congestive heart failure associated with diabetes mellitus

A case of typical congestive heart failure associated with diabetes mellitus is reported. The case was diagnosed on the basis of biopsy findings such as basal laminar thickness and of angiographically normal coronary arteries. The therapy, including insulin, resulted in normalization of electrocardiographic abnormalities and improvement of myocardial contractility.     

Sympathetic neuronal regulation of the heart in aging and heart failure

The documentation of preferential activation of the cardiac sympathetic outflow in patients with heart failure swept aside an entrenched notion that there was a functional sympathetic denervation of the failing heart and provided a theoretical basis for the clinical evaluation of beta-adrenergic blocker therapy in this condition. The demonstration that heightened sympathetic nervous system activity is central to the pathogenesis and progression of congestive heart failure (CHF) has now led to the rational use of beta-adrenoceptor blockade in CHF. More recently, it has also emerged that the aging heart exhibits some of the characteristic changes in autonomic control which are seen in CHF. Accordingly, alterations in cardiac sympathetic nerve function are now thought to contribute also to the pathophysiology of the aging heart. Furthermore, there is evidence that in humans, sympathoexcitatory rostral projections of brainstem noradrenergic neurons to the forebrain are important in the sympathetic nervous activation of both heart failure and aging. Given these similarities, in this review we compare and contrast the neurobiology of the sympathetic nervous system in the failing heart and the healthy, aging heart, and consider whether the sympathetic activation accompanying aging may, perhaps, underlie and contribute to the neural pathophysiology of heart failure. Our conclusion is, on balance, that this proposition is not supported by the available evidence.     

Crow-Fukase syndrome associated with high-output heart failure

A 64-year-old woman was admitted with systemic edema and exertional dyspnea. High-output heart failure was diagnosed by right heart catheterization and she was treated with diuretics. After 3 weeks, her symptoms disappeared but a high cardiac output state persisted. A diagnosis of Crow-Fukase syndrome was made based on the presence of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes. Her serum vascular endothelial growth factor (VEGF) level was markedly elevated after recovery from heart failure. We suspect that an elevated VEGF level and a high cardiac output state may play a role in the pathogenesis of heart failure in Crow-Fukase syndrome.     

心力衰竭相关认知障碍的研究进展

心力衰竭(HF)是由于任何心脏结构或功能异常导致心室充盈或射血功能受损的一组复杂的临床综合征,可通过不同机制影响到包括大脑在内的多种器官功能。近年来,在HF疾病的研究中"心-脑双向交互作用"逐渐受到重视,其中HF相关的认知障碍(CI)得到临床极大关注。尽管已有研究提示HF患者合并CI可明显增加再入院及死亡的风险,但在现有的临床实践中,并不常规对HF患者进行CI筛查,易出现漏诊,从而影响患者预后。因此,本文对近期HF相关CI病理生理机制的临床研究及筛选方法、治疗等方面的新进展进行综述,以期提高临床工作者对该问题的认识。     

Role of nitrates in congestive heart failure

The systemic vasoconstriction that is characteristic of patients with congestive heart failure involves arteriolar constriction, reduction in arterial compliance and reduction in venous capacitance, all of which contribute to the increased impedance and increased preload that aggravate the hemodynamic abnormality. Nitrates are effective in increasing arterial compliance and venous capacitance and thus have a favorable acute hemodynamic effect in heart failure. Long-term studies suggest that this favorable effect is maintained in response to high dose oral isosorbide dinitrate therapy and that it is associated with relief of symptoms and improved exercise tolerance. When combined with hydralazine, isosorbide dinitrate therapy has been shown in the Veterans Administration study to prolong survival in patients with class II and III congestive heart failure. Therefore, long-term nitrate therapy appears to have an important potential in patients with heart failure. It may now be appropriate to use nitrates not only to relieve symptoms, but also to improve long-term outlook in this syndrome.     

内皮功能障碍在心力衰竭中的作用

在心力衰竭的病理生理学中,内皮功能障碍的作用尚不完全清楚。氧化应激引起的内皮功能障碍会诱发心力衰竭。内皮功能和一氧化氮（NO）-环磷酸鸟苷(cGMP)途径参与心力衰竭的病理生理过程。内皮依赖性的血管舒张改变引起反复的缺血/再灌注,可诱发心肌的收缩与舒张功能障碍,NO-cGMP通路的改变直接影响心肌稳态。内皮功能障碍与心力衰竭更差的预后密切相关,与心血管事件更高的发生率密切相关。心力衰竭患者NO-cGMP途径提供了潜在的治疗策略基础,尽管目前相关临床数据尚无明确定论,但NO-cGMP途径是一个有希望的潜在治疗靶标。本文将对内皮功能障碍的病理生理机制、在心衰发生发展中的作用以及在心衰治疗的潜在价值进行综述。