Andrew L. Clark

Clinical Correlates and Prognostic Significance of the Ventilatory Response to Exercise in Chronic Heart Failure

OBJECTIVES This study sought to investigate the clinical characteristics of patients with chronic heart failure and an increased ventilatory response to exercise and to examine the prognostic usefulness of this response. BACKGROUND The ventilatory response to exercise is increased in many patients with chronic heart failure and may be characterized by the regression slope relating minute ventilation to carbon dioxide output (VE-VCO2 slope) during exercise. METHODS One hundred seventy-three consecutive patients (155 men; mean [+/-SD] age 59.8 +/- 11.5 years; radionuclide left ventricular ejection fraction [LVEF] 28.4 +/- 14.6%) underwent cardiopulmonary exercise testing (peak oxygen consumption 18.5 +/- 7.3 ml/kg per min; VE-CO2 slope 34.8 +/- 10.6) over a 2-year period. Using 1.96 standard deviations above the mean VE-VCO2 slope of 68 healthy age-matched subjects (mean slope 26.3 +/- 4.1), we defined a high ventilatory response to exercise as a slope >34. RESULTS Eighty-three patients (48%) had an increased VE-VCO2 slope (mean 43.1 +/- 8.9). There was a difference in age (62.2 vs. 57.3 years, p = 0.005), New York Heart Association functional class (2.9 vs. 2.1, p < 0.001), LVEF (24.7 vs. 31.9%, p = 0.0016), peak oxygen consumption (14.9 vs. 21.7 ml/kg per min, p < 0.0001) and radiographic cardiothoracic ratio (0.58 vs. 0.55, p = 0.002) between these patients and those with a normal slope. In the univariate Cox proportional hazards model, the E-VCO2 slope was an important prognostic factor (p < 0.0001). In the multivariate Cox analyses using several variables (age, peak oxygen consumption, VE-VCO2 slope and LVEF), the VE-VCO2 slope gave additional prognostic information (p = 0.018) beyond peak oxygen consumption (p = 0.022). Kaplan-Meier survival curves at 18 months demonstrated a survival rate of 95% in patients with a normal VE-VCO2 slope compared with 69% in those with a high slope (p < 0.0001). CONCLUSIONS A high VE-VCO2 slope selects patients with more severe heart failure and is an independent prognostic marker. The VE-VCO2 slope may be used as a supplementary index in the assessment of patients with chronic heart failure.

Clinical trials update from the American Heart Association: REPAIR‐AMI, ASTAMI, JELIS, MEGA, REVIVE‐II, SURVIVE, and PROACTIVE

This article provides information and a commentary on trials presented at the American Heart Association meeting held in November 2005, relevant to the pathophysiology, prevention and treatment of heart failure. All reports should be considered as preliminary data, as analyses may change in the final publication. In REPAIR‐AMI an improvement in ejection fraction was observed in post‐MI patients following infusion of bone marrow stem cells. However, the ASTAMI study showed no benefit of stem cell implantation in a similar patient cohort. The JELIS study reported a reduction in major coronary events in patients receiving statins plus fish oil compared to statins alone. MEGA showed that low dose statins in a low risk population reduce the incidence of major cardiovascular events. Two studies of levosimendan in acute heart failure gave conflicting results, in the REVIVE‐II study levosimendan was reported to have a superior effect on the composite primary outcome compared to placebo, however, in SURVIVE despite a trend to early benefit with levosimendan, there was no difference in effect on long‐term outcome versus dobutamine. The PROACTIVE study showed encouraging results for the use of pioglitazone in post‐myocardial infarction patients with concomitant type 2 diabetes.

Longitudinal ventricular function: normal values of atrioventricular annular and myocardial velocities measured with quantitative two-dimensional color Doppler tissue imaging.

OBJECTIVE Quantitative 2-dimensional color Doppler tissue imaging is a new method to reveal impairment of left ventricular (LV) and right ventricular (RV) longitudinal function, which is a potential marker of early myocardial disease. The aim of this study was to obtain normal values for atrioventricular annular and regional myocardial velocities using this method. METHODS A total of 123 healthy patients (age range: 22 to 89 years) underwent echocardiography including color Doppler tissue imaging using a scanner (Vivid 5, GE Vingmed, Horten, Norway) with postprocessing analysis (Echopac 6.3, GE Vingmed). Regional myocardial velocities were measured at 12 LV segments in 3 apical views and 2 segments of the free RV wall. Mitral annular velocities from 6 sites, and tricuspid annular velocities at its lateral site, were also assessed. At each site, systolic (S(m)), early diastolic (E(m)), and late diastolic (A(m)) velocities were measured, and the E(m)/A(m) ratio was calculated. RESULTS Patients were classified into 4 groups aged 20 to 39, 40 to 59, 60 to 79, and >/=80 years. Mitral annular velocity and regional LV myocardial S(m) and E(m) progressively decreased with age. A(m), whereas low in the youngest age group, increased significantly in patients more than 40 years of age. The E(m)/A(m) ratio gradually declined with aging. There were no differences between age groups in S(m) measured at the tricuspid annulus and free RV wall, but the pattern of age-related changes of diastolic velocities and E(m)/A(m) ratio was the same as in the LV. Slight but significant sex-related differences were observed in middle-aged groups. The intraobserver and interobserver reproducibility was highest for atrioventricular annular velocities. CONCLUSIONS A progressive decrease in S(m) reveals a decline in longitudinal systolic LV function with age, whereas systolic RV function remains unaffected. Atrioventricular annular velocity and regional E(m) decrease with aging in both ventricles, suggesting a deterioration in the diastolic properties of the myocardium, whereas A(m) increases from middle age implying a compensatory augmentation of atrial function. The study results can be used as reference data for the quantitative assessment of longitudinal LV and RV function in patients with cardiac disease.

Clinical trials update and cumulative meta‐analyses from the American College of Cardiology: WATCH, SCD‐HeFT, DINAMIT, CASINO, INSPIRE, STRATUS‐US, RIO‐Lipids and cardiac resynchronisation therapy in heart failure

This article continues a series of reports on recent research developments in the field of heart failure. Key presentations made at the American College of Cardiology meeting, held in New Orleans, Louisiana, USA in March 2004 are reported. These new data have been added to existing data in cumulative meta‐analyses. The WATCH study randomised 1587 patients with heart failure and left ventricular systolic dysfunction to warfarin, aspirin or clopidogrel. The study showed no difference between the effects of these agents on mortality or myocardial infarction, but hospitalisations for heart failure were higher on aspirin (22.2%) compared to warfarin (16.1%). The SCD‐HeFT study showed that ICD therapy reduced all‐cause mortality at 5 years by 23% in patients with predominantly NYHA class II heart failure and left ventricular systolic dysfunction, but amiodarone was ineffective. The DINAMIT study showed that ICD therapy was not beneficial in patients with left ventricular dysfunction after a recent MI, even in those with risk factors for arrhythmic death. In CASINO, levosimendan improved survival compared with dobutamine or placebo in patients with decompensated heart failure. INSPIRE showed that SPECT imaging can be used to assess risk early after acute MI safely and accurately. Rimonabant was shown to be safe and effective in treating the combined cardiovascular risk factors of smoking and obesity. An overview of new developments in cardiac resynchronisation therapy (CRT) in heart failure is also reported.

Chronic heart failure and micronutrients

Heart failure (HF) is associated with weight loss, and cachexia is a well-recognized complication. Patients have an increased risk of osteoporosis and lose muscle bulk early in the course of the disease. Basal metabolic rate is increased in HF, but general malnutrition may play a part in the development of cachexia, particularly in an elderly population. There is evidence for a possible role for micronutrient deficiency in HF. Selective deficiency of selenium, calcium and thiamine can directly lead to the HF syndrome. Other nutrients, particularly vitamins C and E and beta-carotene, are antioxidants and may have a protective effect on the vasculature. Vitamins B6, B12 and folate all tend to reduce levels of homocysteine, which is associated with increased oxidative stress. Carnitine, co-enzyme Q10 and creatine supplementation have resulted in improved exercise capacity in patients with HF in some studies. In this article, we review the relation between micronutrients and HF. Chronic HF is characterized by high mortality and morbidity, and research effort has centered on pharmacological management, with the successful introduction of angiotensin-converting enzyme inhibitors and beta-adrenergic antagonists into routine practice. There is sufficient evidence to support a large-scale trial of dietary micronutrient supplementation in HF.

Self-care management of heart failure: practical recommendations from the Patient Care Committee of the Heart Failure Association of the European Society of Cardiology.

Guidelines on heart failure (HF) stress the importance of lifestyle advice, although there is little evidence that such recommendations improve symptoms or prognosis. Patients experience symptoms of different intensities which impair their daily activities and reduce the quality‐of‐life. To cope with their clinical condition, many patients seek advice about lifestyle and self‐management strategies when in contact with medical care providers, particularly specialized HF services. Self‐care management is an important part of HF treatment, thus health professionals working with patients with HF have recognized the need for more specific recommendations on lifestyle advice. The present paper summarizes the available evidence, promotes self‐care management, and aims to provide practical advice for health professionals delivering care to HF patients. It also defines avenues of research to optimize self‐care strategies in a number of key areas to derive further benefits.

Diastolic heart failure: neglected or misdiagnosed?

Recent epidemiological studies suggest that 30% to 50% of patients with heart failure (HF) have preserved left ventricular (LV) systolic function. These patients, often presumed to have diastolic heart failure (DHF), appear to have lower short-term but similar long-term mortality when compared to patients with HF and LV systolic dysfunction. Rates of recurrent hospitalization and costs of care appear similar in the two groups of patients. Therefore, DHF may contribute significantly to the burden of disease caused by HF. Exertional breathlessness, the principal symptom of HF, has many causes, including obesity, pulmonary disease and myocardial ischemia. A diagnosis of DHF by exclusion, based on symptoms in the absence of important LV systolic dysfunction or major valve disease, is unsatisfactory. Unfortunately, as yet, no reliable definition with which to make a positive diagnosis of DHF has been agreed on, frequently rendering this diagnosis uncertain. Echocardiography has several limitations, whereas hemodynamic confirmation of DHF by cardiac catheterization is potentially complex and not practically feasible for many patients. Treatment of DHF remains empirical and unsatisfactory because of the lack of large-scale randomized controlled trials in this area. Currently, three large outcome studies on DHF are in progress along with other smaller trials. These should start to provide some of the answers we need to diagnose and effectively treat DHF.

Clinical Trials Update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ-2, RECOVER and RENAISSANCE and cachexia and cholesterol in heart failure. Highlights of the Scientific Sessions of the American College of Cardiology, 2001

This is a synopsis of presentations made at the American College of Cardiology (ACC) in 2001 summarising recent research developments relating to heart failure. Clinical studies of particular interest to physicians with an interest in heart failure and its prevention are reviewed. The COPERNICUS trial lends further support to the use of the beta‐blocker, carvedilol, in severe heart failure and the CAPRICORN trial to its use in patients with post‐infarction left ventricular systolic dysfunction. The MIRACLE study reinforces the evidence from three smaller trials that cardiac resynchronisation therapy is an effective treatment for the relief of symptoms in patients with severe heart failure and cardiac dyssynchrony. The STAF trial casts further doubt on the wisdom of cardioversion as a routine strategy for the management of chronic atrial fibrillation. The RITZ‐2 trial suggests that an intravenous, non‐selective endothelin antagonist is effective in improving haemodynamics and symptoms and possibly in reducing morbidity in severe heart failure. Observational studies in heart failure suggest that a moderate excess of body fat and elevated blood cholesterol may be desirable in patients with heart failure, challenging the current non‐evidenced‐based vogue for cholesterol lowering therapy in heart failure. The RENAISSANCE and RECOVER outcome studies of etanercept, a tumour necrosis factor (TNF) receptor analogue that blocks the effect of TNF, were stopped because of lack of evidence of benefit shortly after the ACC.

Origin of symptoms in chronic heart failure

Skeletal muscle abnormalities are highly prevalent in chronic heart failure and are associated with an increase in the ergoreflex, a muscle reflex stimulated by work done. Stimulation of the ergoreflex results in increased ventilation and contributes to the increased sympathetic activation of the heart failure syndrome. The origin of the skeletal myopathy is related to a chronic imbalance between catabolic and anabolic processes, presumably as a consequence of chronic haemodynamic stress. Symptoms arise from the skeletal myopathy, causing the sensation of fatigue and contributing to the sensation of breathlessness as the myopathy affects respiratory muscle. Ergoreflex activation causes a greater ventilatory response to exercise than normal, contributing to the sensation of breathlessness.

Prevalence and predictors of anxiety and depression in a sample of chronic heart failure patients with left ventricular systolic dysfunction

To determine the prevalence and predictors of anxiety and depression in patients with heart failure due to Left Ventricular Systolic Dysfunction (LVSD).