Role of exercise and metabolism in heart failure with normal ejection fraction

Left ventricular dysfunction associated with metabolic disorders has a number of features that might shed light on the integrity of heart failure with normal ejection fraction. First, although these patients may be dyspneic and have a normal ejection fraction, their diastolic dysfunction is not isolated. Both experimental models and sensitive new parameters in humans have shown abnormal systolic function, even though the less sensitive parameters (such as ejection fraction) become abnormal only with stress. Moreover, the mechanistic contributors to myocardial dysfunction, including structural changes and metabolic influences on the cardiac myocyte, interstitial fibrosis, vascular disease, and altered loading, are likely to influence systolic as much as diastolic function. The responses of systolic and diastolic heart failure to exercise training show analogies, particularly with respect to the importance of peripheral adaptation, as well as a similar training response. Together, these features are more supportive of a continuum of pathophysiology between systolic and diastolic heart failure, rather than the 2 representing discreet phenomena.     

Diastolic heart failure or heart failure with a normal ejection fraction

Nearly half of patients with symptoms of heart failure are found to have an left ventricular (LV) ejection fraction which is within normal limits. These patients have variously been labeled as having diastolic heart failure, heart failure with preserved LV function or heart failure with normal ejection fraction (HFNEF). Since recent studies have shown that systolic function is not entirely normal in these patients, HFNEF is the better term. More common in elderly females it has a mortality similar to heart failure with a reduced ejection fraction (HFREF). The exact pathophysiology of the symtpoms is still not clear and, therefore, debated. As heart failure is often episodic, the underlying abnormal mechanisms may not be completely apparent at rest. It is likely there is a mixture of systolic and diastolic dysfunction which will be different to some degree in individual patients and isolated diastolic dysfunction or primary abnormalities of relaxation are probably extremely rare. The main difference between HFNEF and HFREF is the degree of ventricular remodeling with increased ventricular volumes in HFREF. The time course of remodeling depends to some extent on the aetiology being quicker post myocardial infarction--the commonest cause of HFREF, and slower with hypertension which is the most frequent aetiological factor in HFNEF. Ventricular volumes rather than ejection fraction or the concept of a pure diastolic abnormality can be used to classify patients in a more rational manner.     

Treatment of heart failure with a normal ejection fraction

Opinion statement Treatment of diastolic heart failure is divided into acute and chronic management. During acute management, the focus should be treatment of the presenting syndrome, including correction of volume overload, treating hypertension, alleviating ischemia, and controlling tachyarrhythmias. Therefore, acute treatment should include several components: treating volume overload with sodium restriction and diuretics; treating ischemie heart disease with antiplatelet therapy, anticoagulants, and β blockers; treating hypertension aggressively, using multiple agents if necessary; and treating atrial tachyarrhythmias such as atrial fibrillation with rate-controlling agents, such as β blockers and possibly nondihydropyridine calcium channel blockers such as diltiazem and verapamil. Antiarrhythmic agents with or without electrical cardioversion may be necessary. Thoroughly evaluate and manage extracardiac precipitants such as anemia and renal failure. Chronic management should also focus on precipitating factors, for which adequate control of hypertension is paramount. Patient education regarding dietary and medication compliance and lifestyle changes is also important. If ischemic heart disease is present, aggressive anti-ischemic therapy is necessary, including revascularization when indicated.     

Relation of right ventricular ejection fraction to exercise capacity in chronic left ventricular failure

Although the left ventricle is traditionally viewed as the heart's main pumping chamber, no correlation has been shown between left ventricular (LV) ejection fraction (EF) at rest and exercise capacity in patients with chronic LV failure. Because vasodilators with venodilating activity increase exercise capacity more than predominant arterial dilators in patients with LV failure, right ventricular (RV) function may relate to exercise capacity in these patients. In 25 patients with chronic LV failure, caused by coronary artery disease in 12 patients and idiopathic dilated cardiomyopathy in 13 patients, RVEF and LVEF at rest were measured by radionuclide angiography. Maximal upright bicycle exercise testing was also performed to determine maximal oxygen consumption, which averaged only 13 ± 4 ml/min/kg. The LVEF at rest was 26 ± 10% and did not correlate with maximal oxygen consumption (r = 0.08). However, the RVEF was 41 ± 12% and correlated with maximal oxygen consumption (r = 0.70, p < 0.001) in the same patients. The correlation was stronger (r = 0.88) in patients with coronary artery disease than in those with idiopathic dilated cardiomyopathy (r = 0.60). Thus, RVEF at rest is more predictive of exercise capacity than LVEF in the same patients with chronic LV failure. These results are consistent with the clinical observation that only venodilating agents increase exercise capacity of patients with chronic LV failure.     

Costs for heart failure with normal vs reduced ejection fraction

BACKGROUND: Among the elderly population, heart failure (HF) with normal ejection fraction (EF) is more common than classic HF with low EF. However, there are few data regarding the costs of HF with normal EF. In a prospective, population-based cohort of elderly participants, we compared the costs and resource use of patients with HF and normal and reduced EF. METHODS: A total of 4549 participants (84.5% white; 40.6% male) in the National Heart, Lung, and Blood Institute Cardiovascular Health Study were linked to Medicare claims from 1992 through 1998. By protocol echo examinations or clinical EF assessments, 881 participants with HF were characterized as having abnormal or normal EF. We applied semiparametric estimators to calculate mean costs per subject for a 5-year period. RESULTS: There were 495 HF participants with normal EF (186 prevalent at study entry and 309 incident during the study period) and 386 participants with abnormal EF (166 prevalent and 220 incident). Participants with abnormal EF had more cardiology encounters and cardiac procedures. However, compared with abnormal EF participants, the 5-year costs for normal EF participants were similar in both the prevalent ($33,023 with abnormal EF and $32,580 with normal EF; P=.93) and incident ($49,128 with abnormal EF and $45,604 with normal EF; P=.55) groups. In models accounting for comorbid conditions, the costs with normal and abnormal EF remained similar. CONCLUSIONS: Over a 5-year period, patients with HF and normal EF consume as many health care resources as those with reduced EF. These data highlight the substantial financial burden of HF with normal EF among the elderly population.     

Mineralocorticoid signaling in transition to heart failure with normal ejection fraction

Heart failure with normal ejection fraction occurs in elderly patients with hypertensive heart disease. We hypothesized that, in such patients, mineralocorticoid receptor activation accelerates the types of ventricular and vascular remodeling and dysfunction believed important in the transition to heart failure. We tested this hypothesis by administering deoxycorticosterone acetate (DOCA) without salt loading or nephrectomy to elderly dogs with experimental hypertension. Elderly dogs were made hypertensive by renal wrapping. After 5 weeks, dogs were randomly assigned to DOCA (1 mg/kg per day IM; old hypertensive [OH]+DOCA; n=11) or not (OH; n=11) for 3 weeks. At week 8, conscious echocardiography and hemodynamic assessment under anesthesia were performed. DOCA resulted in further increases in conscious blood pressure (P<0.05) without increases in cardiac output or diastolic volume. In the conscious state, effective arterial elastance (P<0.05) and systemic vascular resistance (P=0.06) were increased, and systemic arterial compliance (P<0.05) was decreased in OH+DOCA animals. After anesthesia, instrumentation, and autonomic blockade, blood pressure was lower, whereas left ventricular (LV) systolic elastance, LV diastolic stiffness, and ex vivo myofiber diastolic stiffness were increased in OH+DOCA animals. LV collagen was increased in OH+DOCA animals (P<0.05 for all), but LV mass, LV brain natriuretic peptide, and titin isoform profiles were not. Neither aortic stiffness nor aortic structure was altered in OH+DOCA animals. These findings suggest that age and hypertensive heart disease enhance sensitivity to exogenous mineralocorticoid administration and that mineralocorticoid receptor activation could contribute to the transition to heart failure in elderly persons by promoting increases in LV diastolic and systolic stiffness.     

射血分数正常的心力衰竭的研究进展

射血分数正常的心力衰竭(heart failure with a normal ejection fraction,HFNEF),通常也称为舒张性心力衰竭,ESC2008年的心力衰竭指南中建议称其为左室射血分数保留的心力衰竭(heart failure with preserved ejection fraction,HF-PEF),目前尚缺乏针对射血分数正常的心力衰竭的公认诊断标准及最适治疗方案.在HFNEF的发病机制乃至诊疗过程中仍存在许多问题,有待我们进一步探索.     

Heart failure with normal ejection fraction

Opinion statement Heart failure with normal ejection fraction, also known as diastolic heart failure, is a major problem for patients and health-care providers and is a substantial expense to society. The main pathophysiologic processes involved are increased left ventricular stiffness and abnormal relaxation, with resulting impaired left ventricular filling. These processes typically displace the pressure-volume relationship in an upward direction, resulting in increased left ventricular end-diastolic, left atrial, and pulmonary capillary wedge pressures, leading to symptoms of pulmonary congestion. The most common clinical disorders leading to diastolic heart failure are 1) hypertension with concentric left ventricular hypertrophy, 2) coronary artery disease with decreased left ventricular compliance, 3) hypertrophic cardiomyopathy, and 4) aortic stenosis with concentric left ventricular hypertrophy. Echocardiography and cardiac catheterization with magnetic resonance imaging hold promise as future diagnostic tools. The approach to the treatment of diastolic heart failure is focused on four treatment goals: 1) persistent control of elevated blood pressure, with regression of left ventricular hypertrophy, 2) careful reduction of central blood volume (diuretics), 3) maintenance of atrial contraction and control of heart rate (beta-blockers, digoxin, atrioventricular pacing); and 4) improvement of left ventricular relaxation. There is currently no drug treatment specific for abnormal relaxation, although efforts are being made to develop such compounds. A promising future therapy includes agents that lyse advanced glycation end-products as an approach to relieving increased ventricular stiffness. In addition to pharmacotherapy, maintaining ideal body weight and a regular exercise program are also helpful in the treatment of diastolic heart failure. Although the overall prognosis of patients with diastolic dysfunction is more favorable than that of patients with systolic dysfunction, the frequency of treatment failure and recurrent symptoms underscores the need for further improvement in treatment of this condition.     

参芪益心汤治疗射血分数正常慢性充血性心力衰竭的效果观察

目的探讨参芪益心汤治疗射血分数正常慢性充血性心力衰竭的作用。方法选择确诊的射血分数正常慢性充血性心力衰竭患者94例,将患者随机分为中医组和西医组,各47例。中医组给予中药参芪益心汤治疗,西医组给予硝酸甘油、利尿剂、血管紧张素转化酶抑制剂(ACEI)等治疗,治疗4周为1个疗程,治疗3个疗程。比较两组治疗期间以及治疗后的左室功能指标、N末端B型利钠肽原(NT-proBNP)血浆水平变化以及临床疗效。结果两组治疗后左室射血分数(LVEF)、高峰射血率(PER)明显高于治疗前,高峰射血时间(TPER)明显低于治疗前(P0.05),中医组LVEF、PER明显高于西医组,TPER比西医组明显缩短(P0.05)。两组治疗前血浆NT-proBNP水平无明显差异,治疗后均明显降低(P0.05),但中医组明显低于西医组(P0.05)。中医组显效26例,有效18例,无效3例。西医组显效17例,有效21例,无效9例,中医组疗效优于西医组(P0.05)。结论参芪益心汤加减治疗射血分数正常慢性充血性心力衰竭能有效改善患者心功能,增加其活动耐受力,疗效优于西药治疗。     

Role of gender in heart failure with normal left ventricular ejection fraction

Heart failure with normal ejection fraction (HF-NEF) is frequently believed to be more common in women than in men. However, the interaction of gender and age has rarely been analyzed in detail, and knowledge of the distinction between pre- and postmenopausal women is lacking. Some of the studies that have described a higher prevalence of HF-NEF in women relied on clinical diagnoses of HF together with normal systolic function and did not measure diastolic function. This applies to the analysis of patients hospitalized for HF and some epidemiological investigations that agree on the greater prevalence of HF-NEF in women. Population-based studies with echocardiographic determination of diastolic function have suggested equal or greater prevalence of diastolic dysfunction in men. Major risk factors for HF-NEF include hypertension, aging, obesity, diabetes, and ischemia. Hypertension is more frequent in women and can contribute to left ventricular and arterial stiffening in a gender-specific way. Aging, obesity, and diabetes affect myocardial and vascular stiffness differently and lead to different forms of myocardial hypertrophy in women and men. In contrast, ischemia may play a greater role in men. Gender differences in ventricular diastolic distensibility, in vascular stiffness and ventricular/vascular coupling, in skeletal muscle adaptation to HF, and in the perception of symptoms may contribute to a greater rate of HF-NEF in women. The underlying molecular mechanisms include gender differences in calcium handling, in the NO system, and in natriuretic peptides. Estrogen affects collagen synthesis and degradation and inhibits the renin-angiotensin system. Effects of estrogen may provide benefit to premenopausal women, and the loss of its protective mechanisms may render the heart of postmenopausal women more vulnerable. Thus, a number of molecular mechanisms can contribute to the gender differences in HF-NEF.     

Improved exercise ejection fraction with long-term prazosin therapy in patients with heart failure

To study the effect of prazosin therapy on left ventricular function in patients with chronic stable heart failure, first pass radionuclide angiography at rest and during exercise was performed in 15 patients before the administration of prazosin and after seven to 12 weeks of prazosin therapy. There was no significant change in resting ejection fraction before and during prazosin therapy (36 ± 14 per cent versus 37 ± 14 per cent) (mean ± standard deviation). However, exercise ejection fraction increased from 34 ± 14 per cent to 42 ± 17 per cent (p < 0.01). The difference in ejection fraction from rest to exercise (ejection fraction response) changed significantly from ?2 ± 6 per cent before prazosin therapy to +5 ± 7 per cent during prazosin therapy (p < 0.01). Exercise duration increased from 368 ± 82 seconds to 476 ± 82 seconds (p < 0.01). Total work capacity measured in kilojoules increased from 12.6 ± 8.3 to 18.6 ± 10.4 (p < 0.01). The improved ejection fraction response during prazosin therapy correlated with the improved work capacity (r = 0.69, p < 0.01) and exercise duration (p = 0.59, p < 0.05). This improvement occurred despite a significant weight gain with prazosin from 72.2 ± 20.8 kg to 73.5 ± 20.8 kg (p < 0.01).These data suggest that long-term prazosin therapy is effective in the treatment of heart failure. However, the beneficial effects of prazosin, an alpha₁ blocking agent, may be evident only during exercise.     

The cardio-renal-anemia syndrome in elderly subjects with heart failure and a normal ejection fraction: a comparison with heart failure and low ejection fraction

The prevalence and severity of anemia and renal dysfunction in heart failure patients with a normal ejection fraction (HFNEF) is uncharacterized. Two hundred eighty-five consecutive patients admitted to a community hospital with heart failure were stratified by the presence or absence of anemia and a normal or reduced ejection fraction. Comparisons of clinical variables were performed. In this sample, 62% of subjects were anemic, with no difference between those with a normal and a reduced ejection fraction (63% vs. 61%). Anemic HFNEF subjects had a lower glomerular filtration rate (37 +/- 21 mL/min vs. 52 +/- 35 mL/min; p < 0.05) and more severe self-reported symptom scores than nonanemic HFNEF subjects. Multivariate analysis confirmed the association of renal dysfunction and anemia. The authors conclude that the degree and magnitude of anemia in elderly inpatients with heart failure does not differ by ejection fraction. Worse symptoms and more severe renal dysfunction were seen in HFNEF subjects with anemia than in HFNEF subjects without anemia.     

Systolic dysfunction in heart failure with normal ejection fraction: speckle-tracking echocardiography

Left ventricular (LV) ejection fraction (EF) and LV end-systolic volumes are important measures of LV global function. However, in many patients with symptoms of heart failure, these measures are within normal limits. This condition is classified as heart failure with normal ejection fraction (HFNEF). Reduced EF and increased end-systolic volume, however, require impaired function in a number of LV segments. Therefore, apparently normal systolic function in HFNEF may reflect limited sensitivity of global EF, and assessment of regional systolic function may provide important diagnostic information. The recently introduced method, speckle-tracking echocardiography (STE), represents a simplified, objective, and angle-independent modality for quantification of regional myocardial deformation. The software uses conventional gray-scale B-mode recordings and tracks myocardial speckles, which serve as natural acoustic markers. Radial and longitudinal myocardial deformation can be measured simultaneously from long-axis recordings, radial and circumferential deformation from short-axis recordings, and LV torsion from assessment of apical and basal short-axis rotation. Experimental and clinical studies have demonstrated that the STE method can assess myocardial function accurately in healthy subjects in the settings of acute and chronic ischemia, dyssynchrony, and cardiomyopathy. So far, no STE studies have been performed regarding HFNEF. The purpose of this article is therefore to illustrate the potential of this novel method.