Current Vascular Pharmacology, 2009, 7, 557-569
557
The Impact of Pharmacotherapy on the Cardiopulmonary Exercise Test Response in Patients with Heart Failure: A Mini Review Marco Guazzi1 and Ross Arena2,* 1
Cardiopulmonary Laboratory, Cardiology Division, University of Milano, San Paolo Hospital, Milano, Italy; Departments of Internal Medicine, Physiology and Physical Therapy, Virginia Commonwealth University, Richmond, VA, USA 2
Abstract: Cardiopulmonary exercise testing (CPX) is a well-recognized assessment technique in patients with HF. Ventilatory efficiency, aerobic capacity and heart rate recovery are several parameters obtained from CPX that accurately reflect physiologic function and provide robust prognostic information. Pharmacotherapy is a vital component to the management of patients with HF. Numerous pharmacologic interventions, such as ACE inhibition and beta-blockade have demonstrated significant physiologic and prognostic improvement in this population. Furthermore, a number of investigations demonstrating a positive change in the CPX response resulting from a pharmacologic intervention now exist. Because CPX variables reflect pathophysiologic processes differently, their response to a given pharmacologic is unique. For example, beta-blockade has been shown to significantly improve ventilatory efficiency, one of the most powerful prognostic markers obtained from CPX, while not altering aerobic capacity or heart rate recovery. Conversely, ACE and phosphodiesterase-5 inhibition appears to improve ventilatory efficiency and aerobic capacity. Given the prognostic value of CPX, gauging its improvement from pharmacotherapy may be advantageous in facilitating optimal titration of medications. A comprehensive review describing the physiologic and prognostic importance of CPX in the context of pharmacotherapy does not exist. This mini review will: 1. Identify key CPX variables obtained from CPX including aerobic capacity, ventilatory efficiency and heart rate recovery, 2. Describe the physiologic and prognostic significance of CPX in the heart failure population, and, 3. Summarize the present body of evidence addressing the change in CPX in response to different pharmacologic interventions including beta-blockade, renin-angiotensin-aldosterone axis inhibition and sildenafil.
Keywords: Ventilatory expired gas, ventilatory efficiency, aerobic capacity, pharmacologic. INTRODUCTION The management of patients with systolic heart failure (HF) continues to evolve in hopes of further improving quality of life and functional capacity while reducing morbidity and mortality. Pharmacotherapy continues to play a central role in the treatment of this patient population, a trend that will certainly continue for the foreseeable future. Based upon a large body of scientific evidence, current HF practice guidelines recommend the use of beta-blockers and inhibitors of the renin-angiotensin-aldosternone axis in these patients [1, 2]. Other pharmacologic agents, such as phosphodiesterase-5 inhibitors [3], may also emerge as standards of care as this area continues to move forward. There are several clinically acceptable agents within each drug class used to treat the patient with HF, all with a varying range in acceptable dosages. The physiologic mechanism(s) of action of these pharmacologic agents on the cellular/single system level (i.e. vascular, central cardiac function, pulmonary function) has been extensively investigated. Given the numerous pharmacologic options in combination with a heterogeneous physiologic response from 1 patient to the next, gauging the *Address correspondence to this author at the Departments of Internal Medicine, Physiology and Physical Therapy, Box 980224, Virginia Commonwealth University, Health Sciences Campus, Richmond, VA 232980224, USA; Tel: 804-828-0234; Fax: 804-828-8111; E-mail:
[email protected] 1570-1611/09 $55.00+.00
physiologic response to therapy from clinical perspective likewise becomes an important issue. From this clinical perspective, assessing the impact of a given intervention on the aerobic exercise performance of a patient with HF is afforded a high level of importance [1]. Cardiopulmonary exercise testing (CPX) is a highly reliable [4] and well accepted assessment technique for this purpose in the HF population. The American College of Cardiology/American Heart Association guidelines for exercise testing afford CPX a Class I rating (Conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective) for the “evaluation of exercise capacity and response to therapy in patients with heart failure who are being considered for heart transplantation” [5]. This excerpt implies the use of CPX to assess the response to pharmacotherapy is warranted in patients with HF. While supported by a well-accepted clinical guideline, the use of serial CPX to assess the effectiveness of titration in pharmacotherapy is infrequent in practice. In present-day clinical practice, CPX is primarily used as a one-time evaluation for prognostic purposes, which is also well supported by the body of scientific evidence examining this topic [6]. From a research perspective, a number of investigations examining the affect of various pharmacologic agents in HF have included CPX as either a primary or secondary endpoint. Several pharmacologic agents, presently considered a
© 2009 Bentham Science Publishers Ltd.
558 Current Vascular Pharmacology, 2009, Vol. 7, No. 4
standard of care, have been shown to favorably impact the CPX response in patients with HF. The use of CPX to identify optimal response to pharmacotherapy may therefore prove to be advantageous, particularly given the fact that it allows for a physiologic assessment during physical exertion. A comprehensive review describing the physiologic and prognostic importance of CPX in the context of pharmacotherapy does not exist. The proposed mini-review will: 1. Identify key variables obtained from CPX including but not exclusive to aerobic capacity, ventilatory efficiency and heart rate recovery; 2. Describe the physiologic and prognostic significance of CPX variables in the heart failure population, and, 3. Summarize the present body of evidence addressing the change in the CPX response with different pharmacologic interventions including beta-blockers and inhibitors of the renin-angiotensin-aldosternone system as well as more novel approaches.
Guazzi and Arena
strated a significant correlation between cardiac output and peak VO2 in patients with HF [20-23]. On average, peak VO2 is approximately 50% lower in patients with HF compared to values observed in apparently healthy individuals matched for age and sex. Furthermore, peak VO2 is approximately 25% lower in the HF population compared to those diagnosed with coronary artery disease and have preserved left ventricular function [24]. The Weber classification system grades the patient with HF according to peak VO2 and is commonly used in clinical practice when a CPX is performed [25]. The peak VO2 response for an apparently healthy subject and four patients with HF, each falling into a different Weber class is illustrated in Fig. (1).
OVERVIEW OF CARDIOPULMONARY EXERCISE TESTING IN HEART FAILURE Cardiopulmonary exercise testing consists of standard exercise testing procedures in conjunction with ventilatory expired gas analysis. The treadmill and lower extremity ergometer are accepted modes of exercise for such testing. Irrespective of the exercise mode employed, a conservative exercise protocol, with a gradual progression in workload, is most appropriate for this patient population [7]. A recent publication [8] reported a significantly higher oxygen consumption (VO2) achieved at peak exercise when patients with HF underwent an exercise test employing a conservative adjustment in work rate per stage compared to more aggressive protocols. When CPX is performed serially to assess the response to an intervention, the same exercise mode and protocol should be used for all tests. Standard exercise testing procedures include ECG and hemodynamic monitoring as well as rating the patient’s perceived exertion, dyspnea and angina. Ventilatory expired gas allows for the measurement of oxygen VO2, carbon dioxide production (VCO2) and minute ventilation (VE) across time. The reader is referred to other established guidelines and scientific statements for detailed information regarding exercise testing procedures [5, 9-12]. The following sections will address key variables obtained from CPX in patients with HF. KEY VARIABLES OBTAINED FROM CARDIOPULMONARY EXERCISE TESTING Peak Oxygen Consumption Peak VO2 is the most frequently analyzed CPX variable in clinical practice. Peak VO2 is the product of maximal cardiac output and arterial-venous oxygen difference during exercise. Of the central and peripheral component, it is the former (cardiac output) that is the primary determinant of the peak VO2 response. Decreased alveolar-capillary membrane conductance [13], decreased heart rate variability [14], increased pulmonary vascular pressures [15, 16] and increased brain natriuretic peptide [17-19] have also been significantly correlated with a lower peak VO2 in patients with HF. Given the detrimental impact HF has on cardiac function, it should be of no surprise that peak VO2 is often dramatically reduced in this population. Previous investigations have demon-
Fig. (1). Illustration of peak VO2 in an apparently healthy individual* and 4 subjects with heart failure at different Weber Class levels.
There is a robust body of literature demonstrating the prognostic value of peak VO2 in the HF population [26-28]. As a testament to its strong prognostic history, clinical practice guidelines advocate the use of CPX for heart transplant evaluations with a peak VO2
