INTRODUCTION
Exercise intolerance is the primary symptom of chronic diastolic heart failure (DHF). This chapter discusses the fundamental aspects of exercise physiology and the assessment, pathophysiology, and potential treatment of exercise intolerance associated with DHF.
Exercise intolerance is central to the very definition of heart failure, as well as its pathophysiology, diagnosis, prognosis, and therapy. Heart failure is defined as a syndrome in which cardiac output is insufficient to meet metabolic demands. Inherent in this definition is that consequences of insufficient cardiac output will be expressed symptomatically. Indeed, while the natural history of heart failure is punctuated by occasional episodes of acute decompensation with overt systemic volume overload and pulmonary edema, the primary chronic symptoms in patients with chronic heart failure, whether associated with reduced or normal ejection fraction, are exertional fatigue and dyspnea. In addition, these symptoms are the primary determinants of patients’ health-related quality of life. Furthermore, measures of exercise tolerance are powerful independent predictors of mortality.
The severity of exercise intolerance can be quantified by a variety of methods. These include semiquantitative assessments, such as interviews (New York Heart Association [NYHA] classification) and surveys (the Minnesota Living with Heart Failure and Kansas City Cardiomyopathy questionnaires), and quantitative methods, including timed walking tests (6-minute walk distance) and graded exercise treadmill or bicycle exercise tests.
Cardiopulmonary exercise testing on a motorized treadmill or a bicycle ergometer provides the most accurate and reliable assessment of exercise tolerance and yields multiple important outcomes, including exercise time, exercise workload, rate-pressure product, and metabolic equivalents (METs). Peak oxygen consumption (VO 2 ) and carbon dioxide generation (VCO 2 ) can be measured simultaneously by expired gas analysis using instruments that are reliable and highly automated. The quality of the exercise data, and in particular whether the patient gave a maximal or near-maximal effort, can be assessed not only by perceived exertion scales, such as the Borg scale, and percent age-predicted maximal heart rate, but also by the respiratory exchange ratio, which is unbiased by other variables. In addition to assessing peak exercise capacity with peak VO 2 , submaximal exercise capacity can be assessed by determining the ventilatory anaerobic threshold. Submaximal exercise capacity is more applicable to everyday life and is relatively effort independent. We have shown that measurements of both peak and ventilatory anaerobic threshold with automatic instruments are valid and highly reproducible in elderly patients with diastolic as well as systolic heart failure ( Fig. 17-1 ). In addition to these key variables, cardiopulmonary exercise testing with expired gas analysis can assess the slope of expired ventilation (VE)/VCO 2 , which is a powerful predictor of survival, independent of VO 2 .
PATHOPHYSIOLOGY OF EXERCISE INTOLERANCE
In a comparative study from our laboratory, maximal exercise testing with expired gas was performed in 119 older subjects divided among three groups: heart failure with severe LV systolic dysfunction (mean ejection fraction [EF], 30%); isolated DHF (EF >50%; no significant coronary, valvular, pericardial, or pulmonary disease; and no anemia); and age-matched controls. In comparison with the normal controls, peak VO 2 , an objective measure of exercise capacity, was severely reduced in the patients with DHF, and to a similar degree as in those with systolic heart failure (SHF) ( Fig. 17-2 ). In addition, submaximal exercise capacity, as measured by the ventilatory anaerobic threshold, was similarly reduced in patients with DHF versus those with SHF, and this was accompanied by reduced health-related quality of life.
Determinants of Oxygen Consumption
Assessment of peak VO 2 gives insight into the pathophysiology of exercise intolerance, since, by the Fick equation, it is the product of cardiac output and arteriovenous oxygen (A-V O 2 ) difference. Thus, exercise intolerance will be closely related to one or both of these factors and to the factors that comprise them. Measurement of peak exercise VO 2 and at least one of these other two factors (cardiac output or A-V O 2 ) allows one to calculate the remaining unknown factor and therefore to isolate specific factors that contribute to exercise intolerance within individual patients and groups ( Fig. 17-3 ).
We performed a series of cardiopulmonary exercise studies in order to examine the determinants of exercise performance in normal humans and in patients with heart failure. The methods included symptom-limited upright bicycle exercise with indwelling pulmonary artery and brachial artery catheters, and simultaneous expired gas analysis and radionuclide ventriculography. Cardiac output was determined by the Fick principle for oxygen and was indexed to body surface area. The left ventricular (LV) end diastolic volume index (EDVI) and end systolic volume index (ESVI) were calculated from the Fick stroke volume index (SVI) and the radionuclide LV ejection fraction (LVEF), according to the formulas: EDVI = SVI/LVEF, and ESVI = EDVI − SVI.
During upright bicycle exercise in healthy young and middle-aged male volunteers, VO 2 increased 7.7-fold from rest to peak exercise. This was achieved by a 3.2-fold increase in cardiac output and a 2.5-fold increase in A-V O 2 difference. The increase in cardiac output resulted from a 2.5-fold increase in heart rate and a 1.4-fold increase in stroke volume. Stroke volume increased during the initial low levels of exercise via the Frank-Starling mechanism, whereas end diastolic volume increased with small increases in pulmonary wedge pressure. During higher levels of exercise, stroke volume increased predominantly because of increased contractility with decreases in end systolic volume; end diastolic volume may even decline slightly because of tachycardia and limited filling time. A similar hemodynamic exercise response occurs in healthy women.
Aging is known to be accompanied by reduced peak exercise VO 2 . This is due to age-related declines in peak exercise cardiac output, heart rate, stroke volume, LVEF, and end diastolic volume, while pulmonary wedge pressure is relatively unaffected. Thus, stroke volume and end diastolic volume response are important contributors to the increase in VO 2 and cardiac output during upright exercise in normal subjects and are altered by normal aging but not by gender.
Exercise Intolerance in Systolic Versus Diastolic Heart Failure
In order to examine the cardiovascular response to exercise in classic SHF, 30 patients with heart failure associated with severe LV systolic dysfunction (mean LVEF = 24 ± 8%) were compared with 12 healthy volunteers of similar gender and age group. Exercise tolerance was severely reduced in the patients, whose mean peak workload was 50% of that achieved by the healthy subjects. Maximal VO 2 was reduced by 53%, and this was associated with a 53% reduction in cardiac output; maximal A-V O 2 difference was lower but not significantly different from normals. Maximal stroke volume was severely reduced in the patients. In addition, maximal heart rate was mildly reduced, a finding that has been reported by others as well. When the patients were grouped according to whether their exercise was limited by fatigue or by dyspnea, the peak pulmonary capillary wedge pressure (PCWP) was similar in both groups. Furthermore, in a significant fraction of patients, pulmonary wedge pressure was normal during rest and exercise, even though all had marked exercise intolerance and early lactate formation at submaximal workloads. These data suggest that in patients with chronic heart failure and severe systolic LV dysfunction, exercise intolerance is closely related to reduced exercise cardiac output, which is caused by severely reduced stroke volume and mildly reduced heart rate responses during exercise.
A subsequent report in 40 patients with severe LV systolic dysfunction confirmed that stroke volume was reduced during rest and exercise compared with normal subjects. However, the relative increase in stroke volume from rest to peak exercise was similar and was 48% in patients and 42% in normal subjects. While some of the increase in stroke volume during exercise was attributable to increased contractility, stroke volume increased in patients in whom there was no change in LVEF. Furthermore, there was a significantly greater increase in EDVI during exercise in the patients compared with the normal subjects, and the increase in LV end diastolic volume per increase in PCWP was nearly threefold greater in patients compared with normal subjects. Shen et al. reported similar findings, although some patients do not increase end diastolic volume during exercise, due either to diastolic LV dysfunction or to pericardial constraint. Thus, in most patients with heart failure caused by systolic LV dysfunction, the Frank-Starling mechanism not only contributes significantly to the increase in stroke volume during exercise but also partially compensates for reduced inotropic and chronotropic reserves.
With these background data in SHF, we sought to examine the cardiovascular response to exercise in patients with DHF by performing similar cardiopulmonary exercise testing in seven patients with severe but stable chronic heart failure (NYHA functional class III or IV). Six of the patients had had at least one episode of clinically and radiographically documented pulmonary edema. No patient was included who had significant coronary artery disease by coronary angiography, abnormal LVEF (<50%), wall motion abnormalities by radionuclide ventriculography, or clinical or echocardiographic evidence of valvular or pericardial disease. Most of the patients had a history of chronic systemic hypertension; there was also increased LV wall thickness and mass by echocardiography compared with normal controls (107 ± 27 vs. 79 ± 14 g/m 2 ; p < 0.01). Ten age-matched and gender-matched healthy volunteers underwent similar testing to serve as normal controls.
The patients with DHF exhibited marked exercise intolerance, indicated by a reduction in peak workload compared with the normal subjects. This corresponded to a 48% reduction in peak VO 2 (11.6 ± 4.0 vs. 22.7 ± 6.1 ml/kg/min; p < 0.001). In all patients and normal subjects, exercise was limited primarily by leg fatigue, although dyspnea was also frequently reported at peak exercise. The peak respiratory exchange ratio was similar in patients and normal subjects (1.24 ± 0.15 vs. 1.33 ± 0.16; p = 0.24), suggesting a near-maximal exercise effort in both groups. Arterial lactate concentration increased from 0.5 ± 0.3 mmol/liter at rest to 3.7 ± 2.8 mmol/liter at peak exercise in the patients and from 0.5 ± 0.4 mmol/liter to 7.2 ± 2.0 mmol/liter in the normal subjects. During submaximal exercise at 50 watts, where VO 2 was similar in patients and normals, lactate concentration tended to be higher in the patients compared with the normal subjects (2.2 ± 1.1 vs. 1.4 ± 0.7 mmol/liter; p < 0.07).
At rest, there were no differences in cardiac output, central A-V O 2 difference, SVI, or heart rate between the two groups. However, during exercise in the patients compared with normal subjects, cardiac output was significantly reduced at comparable submaximal workloads and was markedly reduced by 41% at peak exercise ( p < 0.001), in proportion to the reduction in peak VO 2 ( Fig. 17-4A ). Central A-V O 2 difference was increased by approximately 10% in the patients during the submaximal exercise workloads, partially compensating for the reduced cardiac output ( Fig. 17-4B ). However, at peak exercise, this mechanism was outstripped, and A-V O 2 difference was reduced by 13% compared with the normal subjects ( p = 0.08). In the patients, the change in cardiac output from rest to peak exercise correlated closely with the increase in VO 2 during exercise ( r = 0.81, p < 0.03), but the change in A-V O 2 difference did not ( r = 0.34, p = 0.43).
Hemodynamic Alterations During Exercise in Heart Failure Patients
Stroke Volume
The indexed stroke volume is reduced by 26% in heart failure patients compared with the normal subjects during submaximal exercise ( p < 0.01) ( Fig. 17-4C ). In contrast to the increase in SVI during low levels of exercise followed by a plateau observed in the normal subjects, a flat stroke volume response was observed in these patients. Heart rate increased slightly in patients compared with controls during submaximal exercise, but was reduced by 18% compared with controls at peak exercise ( p < 0.01) ( Fig. 17-4D ). The change in SVI from rest to peak exercise correlated closely with the increase in cardiac output during exercise ( r = 0.86, p < 0.01) in heart failure patients, but the change in heart rate did not ( r = 0.60, p = 0.14). Thus, in patients with DHF at peak exercise, reduced SVI was the primary factor responsible for reduced cardiac output, and reduced peak cardiac output was the primary factor responsible for the 48% reduction in peak VO 2 observed in our study.
Factors that could contribute to the abnormal stroke volume response in patients with DHF are displayed in Figure 17-5 . The LVEF and ESVI during rest and exercise and the change from rest to peak exercise were not different from those in the normal subjects (see Fig. 17-5A and B). In contrast, EDVI was reduced markedly during submaximal and at peak exercise in patients compared with normal subjects. This results in an abnormal, flattened curve that is similar to the abnormal stroke volume response (see Fig. 17-5C ). In patients with DHF, the change in EDVI from rest to peak exercise correlated strongly with the change in SVI ( r = 0.97, p < 0.0001) and in cardiac output ( r = 0.80, p < 0.03) during exercise.
Left Ventricular Filling Pressures
Pulmonary wedge pressure was mildly increased in patients with DHF compared with normal subjects at rest and became markedly elevated during exercise (see Fig. 17-5D ). However, the change in pulmonary wedge pressure from rest to peak exercise did not correlate significantly with the change in SVI or the increase in VO 2 during exercise.
Left Ventricular Compliance
Although the LV end diastolic pressure-volume ratio tended to be elevated in patients with DHF compared with normal subjects (0.12 ± 0.11 vs. 0.03 ± 0.03 mmHg/ml; p = 0.07) at rest, during exercise this ratio became markedly elevated in the patients compared with the normal subjects (peak, 0.28 ± 0.15 vs. 0.06 ± 0.05 mmHg/ml; p < 0.0001).
The abnormal LV end diastolic pressure-volume relationship demonstrated by patients with DHF is further illustrated in Figure 17-6 . At rest, the patients demonstrated a shift upward and to the left. In contrast to the normal subjects, who demonstrated approximately linear increases in end diastolic volume and pulmonary wedge pressure during exercise, the patients’ exaggerated and progressive increases in pulmonary wedge pressure were not accompanied by increases in end diastolic volume. Thus, these patients with normal rest and exercise LVEF demonstrated an abnormal pressure-volume relationship during exercise and an inability to augment stroke volume by means of the Frank-Starling mechanism, suggesting that their exercise intolerance was due primarily to diastolic LV dysfunction. This is in contrast to patients with heart failure and reduced systolic function, who have an operating pressure-volume relationship that is shifted upward and to the right during exercise.
Noninvasive Measures of Left Ventricular Filling Pressures
The pattern of invasively assessed LV filling pressures offers key insights into exercise intolerance; however, their invasive nature limits their overall utility. Noninvasive Doppler mitral filling indices have given substantial insight into LV diastolic function but are confounded by many variables. The more recently developed tissue Doppler indices are relatively free of confounding influence. Further, the time constant of isovolumic pressure decline (τ) can be estimated noninvasively by measuring the early diastolic velocity of the mitral annulus (E′). In addition, the ratio of early LV diastolic filling velocity (E) to E′ correlates well with invasively measured LV end diastolic pressures. Notably, an increased E/E′ ratio at rest has been correlated with maximal and submaximal exercise intolerance.
Moreover, an increase in E/E′ during exercise correlates with exercise intolerance. M-mode color Doppler has been used to noninvasively estimate the intraventricular pressure gradient (IVPG) from the left atrium to the left ventricle, a correlate of τ and an analogue of ventricular “suction.” Changes in the IVPG from rest to peak exercise are powerful independent predictors of maximal exercise tolerance in patients with heart failure and systolic dysfunction. These eloquent noninvasively obtained data confirm findings from invasive studies and show that individuals with heart failure as a group have increased LV filling pressures at rest and during exercise associated with impaired diastolic function and that impaired myocardial relaxation is associated with reduced diastolic suction during exercise.
It is instructive to compare and contrast the exercise cardiovascular responses in the two different groups of heart failure patients described: those with normal EFs and those with reduced EFs. Both heart failure patient groups have severe exertional symptoms and objective evidence of exercise intolerance, as well as markedly reduced peak cardiac output and stroke volume, mildly reduced peak heart rate, and slightly reduced peak A-V O 2 difference ( Fig. 17-7 ). In addition, both groups had mildly elevated resting and markedly elevated exercise mean PCWPs. However, the mechanisms by which LV stroke volume was reduced differed markedly between the two groups. In one group, patients had profound systolic contractile dysfunction and were able to utilize markedly increased LV filling pressure to produce greater than normal use of the Frank-Starling mechanism to partially compensate and maintain some increase in exercise stroke volume. In the other group, despite normal systolic contractile function, patients were unable to use the Frank-Starling mechanism to increase stroke volume during exercise and had markedly increased LV filling pressure. These data highlight the pivotal influence of the end diastolic pressure-volume response during exercise in healthy subjects and in patients with heart failure (see Fig. 17-7 ).
