Echocardiographic Predictors of Chronotropic Incompetence to Exercise in Patients with Heart Failure with Preserved Ejection Fraction

Exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF) is most often attributed to diastolic dysfunction (DD); however, chronotropic incompetence (CI) could also play an important role. We intended to examine whether there are predictive echocardiographic parameters of DD for impaired chronotropic response to exercise.  Patients (n = 143) with unexplained dyspnea and/or exercise intolerance who fulfilled clinical and echocardiographic criteria of HFpEF presence underwent a symptom-limited exercise test using a treadmill (ETT) according to the Bruce protocol. CI was defined as an achieved heart rate reserve (HRR) of ≤ 80%. Comparison of the groups with (n = 98) and without CI (n = 45) did not show any statistically significant difference regarding demographic and clinical character-ristics except for use of beta blockers (BB) that were more frequently present (p = 0.012) in patients with CI in comparison with those without. Patients with CI had a higher mean E-wave velocity, E/A ratio, increased E/E‵ septal, lateral as well as average ratio and abnormal IVRT/TE-e‵ index all consistent with elevated LV filling pressures. E/E‵ average ratio > 15 was statistically insignificantly more frequently present in patients with CI. In addition, by multivariate stepwise regression analysis value of E‵ septal (β = 3.697, 95%CI 0.921–6.473, p = 0.009) along with use of BB, current smoking and basal heart rate appeared as statistically significant independent predictors of lower HRR %.  Patients with HFpEF frequently have chronotropic incompetence to graded exercise which may partly be predicted with echocardiographic parameters that are consistent with elevated LV filling pressures.

Related papers:

title: Chronotropic Incompetence: Causes, Consequences, and Management
abstract: Chronotropic incompetence (CI), broadly defined as the inability of the heart to increase its rate commensurate with increased activity or demand, is common in patients with cardiovascular disease, produces exercise intolerance that impairs quality of life, and is an independent predictor of major adverse cardiovascular events and overall mortality. However, the importance of CI is underappreciated, and CI is often overlooked in clinical practice. This may be due in part to multiple definitions, the confounding effects of aging and medications, and the need for formal exercise testing for definitive diagnosis. This review discusses the definition, mechanisms, diagnosis, and treatment of CI, with particular emphasis on its prominent role in heart failure (HF). CI is common and can be diagnosed by objective, widely available, inexpensive methods; it is potentially treatable, and its management can lead to significant improvements in exercise tolerance and quality of life.

The ability to perform physical work is an important determinant of quality of life,1 and is enabled by an increase in oxygen uptake (Vo2).2 During maximal aerobic exercise in healthy humans, Vo2 increases approximately 4-fold.2 This is achieved by a 2.2-fold increase in heart rate (HR), a 0.3-fold increase in stroke volume, and a 1.5-fold increase in arteriovenous oxygen difference.2 Thus, the increase in HR is the strongest contributor to the ability to perform sustained aerobic exercise.3 It is therefore not surprising that CI can be the primary cause of or a significant contributor to severe, symptomatic exercise intolerance.

HR at any moment in time reflects the dynamic balance between the sympathetic and parasympathetic divisions of the autonomic nervous system. Although the intrinsic rate of the sinoatrial node is approximately 100 beats per minute (bpm), resting HR in humans is generally much lower (60 to 80 …

title: Comparison of heart rate reserve versus 85% of age-predicted maximum heart rate as a measure of chronotropic response in patients undergoing dobutamine stress echocardiography.
abstract: The role of heart rate (HR) reserve (HRR) in the risk stratification of patients who undergo dobutamine stress echocardiography is not well defined. This study evaluated 1,323 patients (mean age 63 +/- 13 years, 47% men) who underwent dobutamine stress echocardiography. Abnormal stress echocardiographic results were defined as those with stress-induced ischemia. HRR was defined as [(peak HR - HR at rest)/(220 - age - HR at rest)] x 100, with HRR <70% defined as low. Follow-up data (2.7 +/- 1.1 years) for confirmed myocardial infarction (n = 16) and cardiac death (n = 58) were obtained. HRR risk stratified patients into normal and abnormal subgroups (event rate 1.1%/year vs 4.2%/year, p <0.0001) and further risk stratified patients into normal (adjusted HR 1 [reference] vs 2.88, p = 0.04) and abnormal (adjusted HR 4.17 vs 10.09, p <0.0001) stress echocardiography groups. Low HRR (relative risk [RR] 2.15, 95% confidence interval [CI] 1.23 to 4.01, p = 0.013) was an independent predictor of cardiac event even after controlling for standard cardiovascular risk factors, other stress electrocardiographic variables, and stress echocardiographic variables. Low HRR (chi-square 32) was superior to 85% maximum predicted HR (MPHR; chi-square 18) and provided incremental value over stress echocardiography and 85% MPHR (global chi-square increased from 48.3 to 54 to 61.3, p <0.0001) in a model consisting of stress echocardiography, MPHR, and HRR. In conclusion, HRR can further risk stratify patients who undergo dobutamine stress echocardiography and provides independent and incremental prognostic value over standard cardiovascular risk factors and also independent of echocardiographic myocardial ischemia and left ventricular dysfunction and is superior to 85% MPHR. In the setting of low HRR, normal stress echocardiographic results are prognostically less benign, whereas abnormal stress echocardiographic results are prognostically more malignant.

title: Impaired chronotropic response to exercise stress testing as a predictor of mortality.
abstract: Chronotropic incompetence, an attenuated heart rate response to exercise, is a predictor of all-cause mortality in healthy populations. This association may be independent of exercise-induced myocardial perfusion defects.



To examine the prognostic significance of chronotropic incompetence in a low-risk cohort of patients referred for treadmill stress testing with thallium imaging.



Prospective cohort study conducted between September 1990 and December 1993.



Tertiary care academic medical center.



Consecutive patients (1877 men and 1076 women; mean age, 58 years) who were not taking beta-blockers and who were referred for symptom-limited treadmill thallium testing.



Association of chronotropic incompetence, defined as either failure to achieve 85% of the age-predicted maximum heart rate or a low chronotropic index, a heart rate response measure that accounts for effects of age, resting heart rate, and physical fitness, with all-cause mortality during 2 years of follow-up.



Three hundred sixteen patients (11%) failed to reach 85% of the age-adjusted maximum heart rate, 762 (26%) had a low chronotropic index, and 612 (21%) had thallium perfusion defects. Ninety-one patients died during the follow-up period. After adjustment for age, sex, thallium perfusion defects, and other confounders, failure to reach 85% of the age-predicted maximum heart rate was associated with increased risk of death (adjusted relative risk [RR], 1.84; 95% confidence interval [CI], 1.13-3.00; P=.01), as was a low chronotropic index (adjusted RR, 2.19; 95% CI, 1.43-3.44; P<.001).



Among patients with known or suspected coronary disease, chronotropic incompetence is independently predictive of all-cause mortality, even after considering thallium perfusion defects. Incorporation of chronotropic response into the routine interpretation of stress thallium studies may improve the prognostic power of this test.

title: Impaired heart rate response to graded exercise. Prognostic implications of chronotropic incompetence in the Framingham Heart Study.
abstract: Previous reports have suggested that an attenuated exercise heart rate response may be associated with coronary heart disease risk and with mortality. These observations may parallel the association between reduced heart rate variability during normal activities and adverse outcome. This investigation was designed to look at the prognostic implications of exercise heart rate response in a population-based sample.



In this prospective cohort investigation, 1575 male participants (mean age, 43 years) in the Framingham Offspring Study who were free of coronary heart disease, who were not taking beta-blockers, and who underwent submaximal treadmill exercise testing (Bruce protocol) were studied. Heart rate response was assessed in three ways: (1) failure to achieve 85% of the age-predicted maximum heart rate, which has been the traditional definition of chronotropic incompetence; (2) the actual increase in heart rate from rest to peak exercise; and (3) the ratio of heart rate to metabolic reserve used by stage 2 of exercise ("chronotropic response index"). Proportional hazards analyses were used to evaluate the associations of heart rate responses with all-cause mortality and with coronary heart disease incidence during 7.7 years of follow-up. Failure to achieve target heart rate occurred in 327 (21%) subjects. During follow-up there were 55 deaths (14 caused by coronary heart disease) and 95 cases of incident coronary heart disease. Failure to achieve target heart rate, a smaller increase in heart rate with exercise, and the chronotropic response index were predictive of total mortality and incident coronary heart disease (P <.01). Failure to achieve target heart rate remained predictive of incident coronary heart disease even after adjusting for age, ST-segment response, physical activity, and traditional coronary disease risk factors (adjusted hazard ratio, 1.75; 95% confidence interval, 1.11 to 2.74; P=.02). After adjusting for the same factors, the increase in exercise heart rate remained inversely predictive of total mortality (P=.04) and coronary heart disease incidence (P=.0003). The chronotropic response index also was predictive of total mortality (P=.05) and incident coronary heart disease (P=.001) after adjusting for age and other risk factors.



An attenuated heart rate response to exercise, a manifestation of chronotropic incompetence, is predictive of increased mortality and coronary heart disease incidence.

title: Chronotropic incompetence as a predictor of death among patients with normal electrograms taking beta blockers (metoprolol or atenolol).
abstract: Chronotropic incompetence, or an inability to increase heart rate during exercise, independently predicts death in patients not taking beta blockers. Whether it predicts death in patients taking beta blockers is not known. Consecutive patients (n = 3,736; mean age 58 +/- 11 years; 68% men), who were taking either metoprolol tartrate or atenolol and were referred for symptom-limited exercise testing from 1990 to 2002 at a major academic medical center, formed the prospective study cohort. None had heart failure, pacemakers, atrial fibrillation, or any electrocardiographic abnormalities. Patients were followed for a median of 4.5 years for all-cause mortality. Chronotropic response was defined as the percentage of heart rate reserve used. A value of < or =62%, which was noted in 813 patients (22%), was considered abnormal, meaning that chronotropic incompetence was present. There were 173 deaths. After adjusting for age, gender, heart rate at rest, standard risk factors, other medications, Duke treadmill score, and heart rate recovery, chronotropic incompetence predicted death (adjusted hazard ratio 1.94, 95% confidence interval 1.43 to 2.64, p <0.0001). The association of chronotropic incompetence with death was present, irrespective of which drug was taken or the number of half-lives that had elapsed since the last dose. In conclusion, in patients taking beta blockers, chronotropic incompetence is independently predictive of death.

title: Impaired Chronotropic and Vasodilator Reserves Limit Exercise Capacity in Patients With Heart Failure and a Preserved Ejection Fraction
abstract: Nearly half of patients with heart failure have a preserved ejection fraction (HFpEF). Symptoms of exercise intolerance and dyspnea are most often attributed to diastolic dysfunction; however, impaired systolic and/or arterial vasodilator reserve under stress could also play an important role.  Patients with HFpEF (n=17) and control subjects without heart failure (n=19) generally matched for age, gender, hypertension, diabetes mellitus, obesity, and the presence of left ventricular hypertrophy underwent maximal-effort upright cycle ergometry with radionuclide ventriculography to determine rest and exercise cardiovascular function. Resting cardiovascular function was similar between the 2 groups. Both had limited exercise capacity, but this was more profoundly reduced in HFpEF patients (exercise duration 180±71 versus 455±184 seconds; peak oxygen consumption 9.0±3.4 versus 14.4±3.4 mL · kg−1 · min−1; both P<0.001). At matched low-level workload, HFpEF subjects displayed ≈40% less of an increase in heart rate and cardiac output and less systemic vasodilation (all P<0.05) despite a similar rise in end-diastolic volume, stroke volume, and contractility. Heart rate recovery after exercise was also significantly delayed in HFpEF patients. Exercise capacity correlated with the change in cardiac output, heart rate, and vascular resistance but not end-diastolic volume or stroke volume. Lung blood volume and plasma norepinephrine levels rose similarly with exercise in both groups.  HFpEF patients have reduced chronotropic, vasodilator, and cardiac output reserve during exercise compared with matched subjects with hypertensive cardiac hypertrophy. These limitations cannot be ascribed to diastolic abnormalities per se and may provide novel therapeutic targets for interventions to improve exercise capacity in this disorder.

title: Impaired Heart Rate Recovery and Chronotropic Incompetence in Patients With Heart Failure With Preserved Ejection Fraction
abstract: This study assessed the chronotropic response to exercise and heart rate (HR) recovery after exercise in a carefully phenotyped group of patients with heart failure with preserved left ventricular ejection fraction (HfpEF) and a control group of similar age and gender distribution. We studied 41 patients with HfpEF, 41 healthy controls, and 16 hypertensive controls. None were taking HR-limiting medications. All study participants had clinical examination, 12-lead ECG, pulmonary function test, echocardiogram, and metabolic exercise test with HR monitoring throughout exercise. Chronotropic response was measured by the percentage of the HR reserve used during maximal exercise and the peak exercise HR as a percentage of predicted maximal HR. Patients with HfpEF were generally women (70%), overweight, aged 69±8 years. Controls were of similar gender (63%) and age (67±6 years). Patients with HfpEF had significantly reduced peak VO2 compared with controls (20±4 mL · kg−1 · min−1 v...

title: Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction.
abstract: The purpose of this study was to comprehensively examine cardiovascular reserve function with exercise in patients with heart failure and preserved ejection fraction (HFpEF).



Optimal exercise performance requires an integrated physiologic response, with coordinated increases in heart rate, contractility, lusitropy, arterial vasodilation, endothelial function, and venous return. Cardiac and vascular responses are coupled, and abnormalities in several components may interact to promote exertional intolerance in HFpEF.



Subjects with HFpEF (n = 21), hypertension without heart failure (n = 19), and no cardiovascular disease (control, n = 10) were studied before and during exercise with characterization of cardiovascular reserve function by Doppler echocardiography, peripheral arterial tonometry, and gas exchange.



Exercise capacity and tolerance were reduced in HFpEF compared with hypertensive subjects and controls, with lower VO(2) and cardiac index at peak, and more severe dyspnea and fatigue at matched low-level workloads. Endothelial function was impaired in HFpEF and in hypertensive subjects as compared with controls. However, blunted exercise-induced increases in chronotropy, contractility, and vasodilation were unique to HFpEF and resulted in impaired dynamic ventricular-arterial coupling responses during exercise. Exercise capacity and symptoms of exertional intolerance were correlated with abnormalities in each component of cardiovascular reserve function, and HFpEF subjects were more likely to display multiple abnormalities in reserve.



HFpEF is characterized by depressed reserve capacity involving multiple domains of cardiovascular function, which contribute in an integrated fashion to produce exercise limitation. Appreciation of the global nature of reserve dysfunction in HFpEF will better inform optimal design for future diagnostic and therapeutic strategies.

title: Heart failure with preserved ejection fraction is characterized by dynamic impairment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency.
abstract: We sought to evaluate the role of exercise-related changes in left ventricular (LV) relaxation and of LV contractile function and vasculoventricular coupling (VVC) in the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and to assess myocardial energetic status in these patients.



To date, no studies have investigated exercise-related changes in LV relaxation and VVC as well as in vivo myocardial energetic status in patients with HFpEF.



We studied 37 patients with HFpEF and 20 control subjects. The VVC and time to peak LV filling (nTTPF, a measure of LV active relaxation) were assessed while patients were at rest and during exercise by the use of radionuclide ventriculography. Cardiac energetic status (creatine phosphate/adenosine triphosphate ratio) was assessed by the use of (31)P magnetic resonance spectroscopy at 3-T.



When patients were at rest, nTTPF and VVC were similar in patients with HFpEF and control subjects. The cardiac creatine phosphate/adenosine triphosphate ratio was reduced in patients with HFpEF versus control subjects (1.57 +/- 0.52 vs. 2.14 +/- 0.63; p = 0.003), indicating reduced energy reserves. Peak maximal oxygen uptake and the increase in heart rate during maximal exercise were lower in patients with HFpEF versus control subjects (19 +/- 4 ml/kg/min vs. 36 +/- 8 ml/kg/min, p < 0.001, and 52 +/- 16 beats/min vs. 81 +/- 14 beats/min, p < 0.001). The relative changes in stroke volume and cardiac output during submaximal exercise were lower in patients with HFpEF versus control subjects (ratio exercise/rest: 0.99 +/- 0.34 vs. 1.25 +/- 0.47, p = 0.04, and 1.36 +/- 0.45 vs. 2.13 +/- 0.72, p < 0.001). The nTTPF decreased during exercise in control subjects but increased in patients with HFpEF (-0.03 +/- 12 s vs. +0.07 +/- 0.11 s; p = 0.005). The VVC decreased on exercise in control subjects but was unchanged in patients with HFpEF (-0.01 +/- 0.15 vs. -0.25 +/- 0.19; p < 0.001).



Patients with HFpEF have reduced cardiac energetic reserve that may underlie marked dynamic slowing of LV active relaxation and abnormal VVC during exercise.

title: Diastolic relaxation and compliance reserve during dynamic exercise in heart failure with preserved ejection fraction
abstract: Recent studies have examined haemodynamic changes with stressors such as isometric handgrip and rapid atrial pacing in heart failure with preserved ejection fraction (HFpEF), but little is known regarding left ventricular (LV) pressure–volume responses during dynamic exercise.  To assess LV haemodynamic responses to dynamic exercise in patients with HFpEF.  Twenty subjects with normal ejection fraction (EF) and exertional dyspnoea underwent invasive haemodynamic assessment during dynamic exercise to evaluate suspected HFpEF.  LV end-diastolic pressure was elevated at rest (>15 mm Hg, n=18) and with exercise (≥20 mm Hg, n=20) in all subjects, consistent with HFpEF. Heart rate (HR), blood pressure, arterial elastance and cardiac output increased with exercise (all p<0.001). Minimal and mean LV diastolic pressures increased by 43–56% with exercise (both p<0.0001), despite a trend towards a reduction in LV end-diastolic volume (p=0.08). Diastolic filling time was abbreviated with increases in HR and the proportion of diastole that elapsed prior to estimated complete relaxation increased (p<0.0001), suggesting inadequate relaxation reserve relative to the shortening of diastole. LV diastolic chamber elastance acutely increased 50% during exercise (p=0.0003). Exercise increases in LV filling pressures correlated with changes in diastolic relaxation rates, chamber stiffness and arterial afterload but were not related to alterations in preload volume, HR or cardiac output.  In patients with newly diagnosed HFpEF, LV filling pressures increase during dynamic exercise in association with inadequate enhancement of relaxation and acute increases in LV chamber stiffness. Therapies that enhance diastolic reserve function may improve symptoms of exertional intolerance in patients with hypertensive heart disease and early HFpEF.

title: Left ventricular function and exercise capacity.
abstract: Limited information exists regarding the role of left ventricular function in predicting exercise capacity and impact on age- and sex-related differences.



To determine the impact of measures of cardiac function assessed by echocardiography on exercise capacity and to determine if these associations are modified by sex or advancing age.



Cross-sectional study of patients undergoing exercise echocardiography with routine measurements of left ventricular systolic and diastolic function by 2-dimensional and Doppler techniques. Analyses were conducted to determine the strongest correlates of exercise capacity and the age and sex interactions of these variables with exercise capacity.



Large tertiary referral center in Rochester, Minnesota, in 2006.



Patients undergoing exercise echocardiography using the Bruce protocol (N = 2867). Patients with echocardiographic evidence of exercise-induced ischemia, ejection fractions lower than 50%, or significant valvular heart disease were excluded.



Exercise capacity in metabolic equivalents (METs).



Diastolic dysfunction was strongly and inversely associated with exercise capacity. Compared with normal function, after multivariate adjustment, those with moderate/severe resting diastolic dysfunction (-1.30 METs; 95% confidence interval [CI], -1.52 to -0.99; P < .001) and mild resting diastolic dysfunction (-0.70 METs; 95% CI, -0.88 to -0.46; P < .001) had substantially lower exercise capacity. Variation of left ventricular systolic function within the normal range was not associated with exercise capacity. Left ventricular filling pressures measured by resting E/e' of 15 or greater (-0.41 METs; 95% CI, -0.70 to -0.11; P = .007) or postexercise E/e' of 15 or greater (-0.41 METs; 95% CI, -0.71 to -0.11; P = .007) were similarly associated with a reduction in exercise capacity, each in separate multivariate analyses. Individuals with impaired relaxation (mild dysfunction) or resting E/e' of 15 or greater had a progressive increase in the magnitude of reduction in exercise capacity with advancing age (P < .001 and P = .02, respectively). Other independent correlates of exercise capacity were age (unstandardized beta coefficient, -0.85 METs; 95% CI, -0.92 to -0.77, per 10-year increment; P < .001), female sex (-1.98 METs; 95% CI, -2.15 to -1.84; P < .001), and body mass index greater than 30 (-1.24 METs; 95% CI, -1.41 to -1.10; P < .001).



In this large cross-sectional study of those referred for exercise echocardiography and not limited by ischemia, abnormalities of left ventricular diastolic function were independently associated with exercise capacity.

title: How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology.
abstract: Diastolic heart failure (DHF) currently accounts for more than 50% of all heart failure patients. DHF is also referred to as heart failure with normal left ventricular (LV) ejection fraction (HFNEF) to indicate that HFNEF could be a precursor of heart failure with reduced LVEF. Because of improved cardiac imaging and because of widespread clinical use of plasma levels of natriuretic peptides, diagnostic criteria for HFNEF needed to be updated. The diagnosis of HFNEF requires the following conditions to be satisfied: (i) signs or symptoms of heart failure; (ii) normal or mildly abnormal systolic LV function; (iii) evidence of diastolic LV dysfunction. Normal or mildly abnormal systolic LV function implies both an LVEF > 50% and an LV end-diastolic volume index (LVEDVI) <97 mL/m(2). Diagnostic evidence of diastolic LV dysfunction can be obtained invasively (LV end-diastolic pressure >16 mmHg or mean pulmonary capillary wedge pressure >12 mmHg) or non-invasively by tissue Doppler (TD) (E/E' > 15). If TD yields an E/E' ratio suggestive of diastolic LV dysfunction (15 > E/E' > 8), additional non-invasive investigations are required for diagnostic evidence of diastolic LV dysfunction. These can consist of blood flow Doppler of mitral valve or pulmonary veins, echo measures of LV mass index or left atrial volume index, electrocardiographic evidence of atrial fibrillation, or plasma levels of natriuretic peptides. If plasma levels of natriuretic peptides are elevated, diagnostic evidence of diastolic LV dysfunction also requires additional non-invasive investigations such as TD, blood flow Doppler of mitral valve or pulmonary veins, echo measures of LV mass index or left atrial volume index, or electrocardiographic evidence of atrial fibrillation. A similar strategy with focus on a high negative predictive value of successive investigations is proposed for the exclusion of HFNEF in patients with breathlessness and no signs of congestion. The updated strategies for the diagnosis and exclusion of HFNEF are useful not only for individual patient management but also for patient recruitment in future clinical trials exploring therapies for HFNEF.

title: Recommendations for chamber quantification.
abstract: Quantification of cardiac chamber size, ventricular mass and function ranks among the most clinically important and most frequently requested tasks of echocardiography. Over the last decades, echocardiographic methods and techniques have improved and expanded dramatically, due to the introduction of higher frequency transducers, harmonic imaging, fully digital machines, left-sided contrast agents, and other technological advancements. Furthermore, echocardiography due to its portability and versatility is now used in emergency rooms, operating rooms, and intensive care units. Standardization of measurements in echocardiography has been inconsistent and less successful, compared to other imaging techniques and consequently, echocardiographic measurements are sometimes perceived as less reliable. Therefore, the American Society of Echocardiography, working together with the European Association of Echocardiography, a branch of the European Society of Cardiology, has critically reviewed the literature and updated the recommendations for quantifying cardiac chambers using echocardiography. This document reviews the technical aspects on how to perform quantitative chamber measurements of morphology and function, which is a component of every complete echocardiographic examination.

title: Recommendations for the evaluation of left ventricular diastolic function by echocardiography.
abstract: The assessment of left ventricular (LV) diastolic function should be an integral part of a routine examination, particularly in patients presenting with dyspnea or heart failure. About half of patients with new diagnoses of heart failure have normal or near normal global ejection fractions (EFs). These patients are diagnosed with “diastolic heart failure” or “heart failure with preserved EF.”1 The assessment of LV diastolic function and filling pressures is of paramount clinical importance to distinguish this syndrome from other diseases such as pulmonary disease resulting in dyspnea, to assess prognosis, and to identify underlying cardiac disease and its best treatment.

LV filling pressures as measured invasively include mean pulmonary wedge pressure or mean left atrial (LA) pressure (both in the absence of mitral stenosis), LV end-diastolic pressure (LVEDP; the pressure at the onset of the QRS complex or after A-wave pressure), and pre-A LV diastolic pressure (Figure 1).Although these pressures are different in absolute terms, they are closely related, and they change in a predictable progression with myocardial disease, such that LVEDP increases prior to the rise in mean LA pressure.



Figure 1 
The 4 phases of diastole are marked in relation to high-fidelity pressure recordings from the left atrium (LA) and left ventricle (LV) in anesthetized dogs. The first pressure crossover corresponds to the end of isovolumic relaxation and mitral valve opening. In the first phase, left atrial pressure exceeds left ventricular pressure, accelerating mitral flow. Peak mitral E roughly corresponds to the second crossover. Thereafter, left ventricular pressure exceeds left atrial pressure, decelerating mitral flow. These two phases correspond to rapid filling. This is followed by slow filling, with almost no pressure differences. During atrial contraction, left atrial pressure again exceeds left ventricular pressure. The solid arrow points to left ventricular minimal pressure, the dotted arrow to left ventricular …

title: Clinical Recommendations for Cardiopulmonary Exercise Testing Data Assessment in Specific Patient Populations
abstract: From an evidence-based perspective, cardiopulmonary exercise testing (CPX) is a well-supported assessment technique in both the United States (US) and Europe. The combination of standard exercise testing (ET) (ie, progressive exercise provocation in association with serial electrocardiograms [ECG], hemodynamics, oxygen saturation, and subjective symptoms) and measurement of ventilatory gas exchange amounts to a superior method to: 1) accurately quantify cardiorespiratory fitness (CRF), 2) delineate the physiologic system(s) underlying exercise responses, which can be applied as a means to identify the exercise-limiting pathophysiologic mechanism(s) and/or performance differences, and 3) formulate function-based prognostic stratification. Cardiopulmonary ET certainly carries an additional cost as well as competency requirements and is not an essential component of evaluation in all patient populations. However, there are several conditions of confirmed, suspected, or unknown etiology where the data gained from this form of ET is highly valuable in terms of clinical decision making.1 
 
Several CPX statements have been published by well-respected organizations in both the US and Europe.1–5 Despite these prominent reports and the plethora of pertinent medical literature which they feature, underutilization of CPX persists. This discrepancy is at least partly attributable to the fact that the currently available CPX consensus statements are inherently complex and fail to convey succinct, clinically centered strategies to utilize CPX indices effectively. Likewise, current CPX software packages generate an overwhelming abundance of data, which to most clinicians are incomprehensible and abstract. 
 
Ironically, in contrast to the protracted scientific statements and dense CPX data outputs, the list of CPX variables that have proven clinical application is concise and uncomplicated. Therefore, the goal of this writing group is to present an approach of CPX in a way that assists in making meaningful decisions regarding a patient’s care. Experts from the European Association for Cardiovascular Prevention and Rehabilitation and American Heart Association have joined in this effort to distill easy-to-follow guidance on CPX interpretation based upon current scientific evidence. This document also provides a series of forms that are designed to highlight the utility of CPX in clinical decision-making. Not only will this improve patient management, it will also catalyze uniform and unambiguous data interpretation across laboratories on an international level. 
 
The primary target audience of this position paper is clinicians who have limited orientation with CPX but whose caregiving would be enhanced by familiarity and application of this assessment. The ultimate goal is to increase awareness of the value of CPX and to increase the number of healthcare professionals who are able to perform clinically meaningful CPX interpretation. Moreover, this document will hopefully lead to an increase in appropriate patient referrals to CPX with enhanced efficiencies in patient management. For more detailed information on CPX, including procedures for patient preparation, equipment calibration, and conducting the test, readers are encouraged to review other publications that address these and other topics in great detail.1–5

title: Exercise Electrocardiogram Testing: Beyond the ST Segment
abstract: Exercise testing remains the most widely accessible and relatively inexpensive method for initial evaluation of suspected coronary disease and for evaluation of its severity.1–3 Clinical usefulness has been limited, however, by poor sensitivity of standard ST-segment depression criteria for assessment of anatomic and functional coronary disease severity and for prediction of risk.1,2,4–6 Recent data make it clear that symptomatic obstructive plaques that typically result in exercise-mediated ischemia may be less relevant to infarction and sudden death than less obstructive unstable plaques.7 These limitations mandate a rethinking of the exercise ECG along 2 distinct lines: First, is it possible to improve the diagnostic value of the exercise ECG? Second, separate from its ability to diagnose obstructive coronary artery lesions, can the exercise test be used as a prognostic tool that can encourage effective prevention of premature deaths or coronary events? Both goals take us beyond the ST segment.

Reversible ST-segment depression is the characteristic finding associated with exercise-induced, demand-driven ischemia in patients with significant coronary obstruction but no flow limitation at rest. This process differs from the flow-limited acute coronary syndromes because exercise-related ischemia is generally limited to the subendocardium and is proportional to increases in myocardial oxygen demand. Ventricular waveforms of the ECG can be related to the net uncanceled transmural gradients between endocardial and epicardial myocardium, as extrapolated from the work of Holland and Brooks, among others.8–10 Accordingly, isoelectric TQ and ST segments in normal and in nonischemic patients can be related to comparable resting membrane and action potential plateau voltages in endocardial and epicardial action potentials. During exercise, progressive ischemia results in changing endocardial action potentials during both diastole and systole. Less negative endocardial cell resting membrane potential leads to current flow across the ischemic boundary during diastole, leading to elevation of the TQ …

title: Chronotropic incompetence and autonomic dysfunction in patients without structural heart disease.
abstract: An attenuated heart rate response to exercise, termed chronotropic incompetence (CI), has been reported to be an independent predictor of cardiovascular mortality. We examined the change in autonomic function during exercise testing and correlated the results with CI.



Exercise testing using a bicycle ergometer was performed in 172 patients who had no evidence of cardiac disease. Chronotropic incompetence was defined as the failure to achieve 85% of the age-predicted maximum heart rate, heart rate reserve <80%, or chronotropic response index <0.80. We analysed the relationship between CI and the change in two components of heart rate variability during exercise testing: high-frequency (HF) component (0.15-0.40 Hz) as an index of vagal modulation and the ratio of low-frequency (LF) component (0.04-0.15 Hz) to HF component as an index of sympathovagal balance. Heart rate variability indexes before exercise were similar in patients with and without CI. Percentage changes after exercise in the ratio of LF to HF component were higher in patients with CI than in those without CI (84 +/- 15 vs. 41 +/- 16%, P < 0.05), whereas percentage changes in an HF component were similar in the two groups.



Our data suggested that CI in patients without structural heart disease was mainly caused by a pathophysiological condition in which sympathetic activation was not well translated into heart rate increase. Further study is needed to determine the post-synaptic sensitivity of the beta-adrenergic receptor pathway in relation to CI.

title: Exercise testing for chronotropic assessment.
abstract: Cardiac chronotropic analysis has only begun to develop into a clinically relevant science. In the past, formal exercise testing was usually relegated to the assessment of ischemia or cardiac rehabilitation. The establishment of rate-responsive pacemakers as a potentially effective treatment for chronotropic incompetence forced the definition of cardiac chronotropism and assessment of the pacemaker response. Little is known about the normal chronotropic response and less has been established about patients with ventricular dysfunction or ischemia, but standards are being set and modern pacemakers have produced the ideal clinical laboratory for investigation. Advanced telemetry, including sensor and actual rate trends, histography and sensorgraphy produce previously unobtainable clinical data. Now scientific inquiry demands that chronotropic evaluations seek to match the pacemaker-augmented response of the chronotropically incompetent patient to the metabolic requirements of the body. Only with formal exercise testing will this goal be achieved.

title: Association of chronotropic incompetence with echocardiographic ischemia and prognosis.
abstract: This study sought to examine the prognostic importance of chronotropic incompetence among patients referred for stress echocardiography.



Although chronotropic incompetence has been shown to be predictive of an adverse prognosis, it is not clear if this association is independent of exercise-induced myocardial ischemia.



Consecutive patients (146 men and 85 women; mean age 57 years) who were not taking beta-adrenergic blocking agents and were referred for symptom-limited exercise echocardiography were followed for a mean of 41 months. Chronotropic incompetence was assessed in two ways: (1) failure to achieve 85% of the age-predicted maximum heart rate and (2) a low chronotropic index, a heart rate response measure that accounts for effects of age, resting heart rate and physical fitness.



The primary end point, a composite of death, nonfatal myocardial infarction, unstable angina and late (>3 months after the exercise test) myocardial revascularization, occurred in 41 patients. Failure to achieve 85% of the age-predicted maximum heart rate was predictive of events (relative risk [RR] 2.47, 95% confidence interval [CI] 1.28 to 4.79, p=0.007); similarly, a low chronotropic index was predictive (RR 2.44, 95% CI 1.31 to 4.55, p=0.005). Even after adjusting for myocardial ischemia and other possible confounders, failure to achieve 85% of age-predicted maximum heart rate was predictive (adjusted RR 2.20, 95% CI 1.11 to 4.37, p=0.02). A low chronotropic index also remained predictive (adjusted RR 1.85, 95% CI 0.98 to 3.47, p=0.06).



Chronotropic incompetence is predictive of an adverse cardiovascular prognosis even after adjusting for echocardiographic myocardial ischemia.

title: Chronotropic incompentence and functional capacity in chronic heart failure: no role of β-blockers and β-blocker dose.
abstract: To assess the effect of chronotropic incompetence on functional capacity in chronic heart failure (CHF) patients, as evaluated as NYHA and peak oxygen consumption (pVO(2) ), focusing on the presence and dose of β-blocker treatment.



Nine hundred and sixty-seven consecutive CHF patients were evaluated, 328 of whom were discarded because they failed to meet the study criteria. Of the 639 analyzed, 90 were not treated with β-blockers whereas the other 549 were. The latter were further subdivided in high (n = 184) and low (n = 365) β-blockers daily dose group in accordance with an arbitrary cut-off of 25 mg for carvedilol and of 5 mg for bisoprolol. Failure to achieve 80% of the percentage of maximum age predicted peak heart rate (%Max PHR) or of HR reserve (%HRR) constituted chronotropic incompetence.



No differences were found in NYHA or pVO2 between patients with and without β-blockers and, similarly, between high and low β-blocker dose groups. Twenty and sixty-nine percent of not β-blocked patients showed chronotropic incompetence according to %Max PHR and %HRR, respectively, whereas this prevalence rose to 61% and 84% in those on β-blocker therapy. Patients taking β-blockers without chronotropic incompetence, as inferable from both %Max PHR and %HRR, showed higher NYHA and pVO2 regardless of drug dose, whereas, in not β-blocked patients, only %HRR revealed a difference in functional capacity. At multivariable analysis, HR increase during exercise (ΔHR) was the variable most strongly associated to pVO2 (β: 0.572; SE: 0.008; P < 0.0001) and NYHA class (β: -0.499; SE: 0.001; P < 0.0001).



ΔHR is a powerful predictor of CHF severity regardless of the presence of β-blocker therapy and of β-blocker daily dose.

title: Chronic heart failure, chronotropic incompetence, and the effects of β blockade
abstract: To establish the prevalence of chronotropic incompetence in a cohort of patients with chronic heart failure (CHF) taking modern medications for heart failure, and whether this affected exercise capacity and predicted prognosis.  Heart rate response to exercise was examined in 237 patients with CHF in sinus rhythm, who were compared with 118 control volunteers. The percentage of maximum age predicted peak heart rate (%Max-PPHR) and percentage heart rate reserve (%HRR) were calculated, with a cut off of < 80% as the definition of chronotropic incompetence for both. Patients were followed up for an average (SD) of 2.8 (9) years. Mortality was related to peak oxygen consumption (pVo2), and the presence or absence of chronotropic incompetence.  %Max-PPHR < 80% identified 103 (43%) and %HRR < 80% identified 170 patients (72%) as having chronotropic incompetence. Chronotropic incompetence was more common in patients taking β blockers than in those not taking β blockers as assessed by both methods (80 (49%) v 23 (32%) by %Max-PPHR and 123 (75%) v 47 (64%) by %HRR, respectively). Patients with chronotropic incompetence by either method had a lower pVo2 than those without. These differences remained significant for both patients taking and not taking a β blocker. %HRR, Max-PPHR%, and HRR were related to New York Heart Association class and correlated with pVo2. There was no difference in the slopes relating heart rate to pVo2 between patients with and those without chronotropic incompetence (6.1 (1.7) v 5.1 (1.8), p  =  0.34). During an average 2.8 year follow up 40 patients (17%) died. In Cox proportional hazard models, pVo2 was the most powerful predictor of survival and neither measure of chronotropic incompetence independently predicted outcome.  pVo2 is a powerful marker of prognosis for patients with CHF whether they are taking β blockers or not. A low heart rate response to exercise in patients with CHF correlates with worse exercise tolerance but is unlikely to contribute to exercise impairment.

title: Chronotropic incompetence, beta‐blockers, and functional capacity in advanced congestive heart failure: Time to pace?
abstract: Chronotropic incompetence (CI) is often seen in subjects with chronic congestive heart failure (CHF). The prevalence of CI, its mechanisms and association with beta‐blocker use as well as exercise capacity have not been clearly defined.

title: Association of cigarette smoking with chronotropic incompetence and prognosis in the Framingham Heart Study.
abstract: In this study, we sought to determine whether cigarette smoking is associated with chronotropic incompetence and to explore prognostic implications of this association.



Members of the Framingham Offspring Study (1468 men and 1642 women) underwent graded exercise. Chronotropic incompetence was assessed in two ways: (1) failure to achieve an age-predicted target heart rate and (2) a low chronotropic index, a heart rate response measure that accounts for effects of age, resting heart rate, and physical fitness. Smokers were more likely to fail to reach target heart rate than were nonsmokers (men, 25% versus 15%, odds ratio [OR], 1.97; 95% confidence interval [CI], 1.51 to 2.56; women, 32% versus 18%; OR, 2.10; 95% CI, 1.63 to 2.61) and were more likely to have a low chronotropic index (men, 17% versus 12%; OR, 1.50; 95% CI, 1.12 to 2.03; women, 17% versus 8%; OR, 2.28; 95% CI, 1.68 to 3.09). These associations persisted after adjustment for age, cardiovascular risk factors, pulmonary function, and ST-segment response to graded exercise. During 8 years of follow-up, there were 48 deaths and 90 incident coronary heart disease events among the men. After adjustment for the same confounders, men who were smokers and failed to achieve target heart rate were at particularly high risk for death (adjusted relative risk [RR], 2.45; 95% CI, 1.14 to 5.24) and for coronary heart disease (adjusted RR, 4.92; 95% CI, 2.84 to 8.53). There were too few end points in women for analysis.



In this population-based cohort, cigarette smoking was predictive of chronotropic incompetence. Male smokers who manifested chronotropic incompetence were at particularly high risk for death and coronary heart disease events.

title: Association of smoking with abnormal exercise heart rate responses and long-term prognosis in a healthy, population-based cohort.
abstract: Cigarette smoking is associated with chronotropic incompetence, defined as an attenuated heart rate response to exercise. The long-term prognostic implications of this association have not been well explored.



Adults enrolled in the Lipid Research Clinics' Prevalence Study who had no history of cardiovascular disease and who were not taking beta-blockers were observed for 12 years. Chronotropic incompetence was assessed as the failure to achieve 90% of an age-predicted target heart rate during an exercise test or as a low chronotropic index, a measure of exercise heart rate response adjusted for age, resting heart rate, and physical fitness.



Of the 5,354 eligible participants (mean [+/- SD] age of 44 +/- 10 years; 61% male), 1,931 (36%) smoked cigarettes. Smokers were more likely to have a low chronotropic index (26% versus 16%, odds ratio = 1.8, 95% confidence interval [CI] 1.6 to 2.1) and fail to achieve an age-predicted target heart rate (32% versus 22%, odds ratio = 1.7, 95% CI 1.5 to 2.0). Adjustment for standard cardiac risk factors and physical fitness did not affect these associations. During follow-up, there were 327 deaths. Among subjects without chronotropic incompetence, the relative risk of mortality associated with smoking was moderately increased (hazard ratio = 1.8, 95% CI 1.3 to 2.3); among smokers with chronotropic incompetence, the relative risk of mortality was markedly increased (hazard ratio = 2.7, 95% CI 2.0 to 3.7, P for interaction = 0.02).



In this large, middle-aged population-based cohort, smoking was associated with chronotropic incompetence, which in turn identified smokers with a particularly high mortality rate.

title: Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: failure of the Frank-Starling mechanism.
abstract: Invasive cardiopulmonary exercise testing was performed in 7 patients who presented with congestive heart failure, normal left ventricular ejection fraction and no significant coronary or valvular heart disease and in 10 age-matched normal subjects. Compared with the normal subjects, patients demonstrates severe exercise intolerance with a 48% reduction in peak oxygen consumption (11.6 +/- 4.0 versus 22.7 +/- 6.1 ml/kg per min; p less than 0.001), primarily due to a 41% reduction in peak cardiac index (4.2 +/- 1.4 versus 7.1 +/- 1.1 liters/min per m2; p less than 0.001). In patients compared with normal subjects, peak left ventricular stroke volume index (34 +/- 9 versus 46 +/- 7 ml/min per m2; p less than 0.01) and end-diastolic volume index (56 +/- 14 versus 68 +/- 12 ml/min per m2; p less than 0.08) were reduced, whereas peak ejection fraction and end-systolic volume index were not different. In patients, the change in end-diastolic volume index during exercise correlated strongly with the change in stroke volume index (r = 0.97; p less than 0.0001) and cardiac index (r = 0.80; p less than 0.03). Pulmonary wedge pressure was markedly increased at peak exercise in patients compared with normal subjects (25.7 +/- 9.1 versus 7.1 +/- 4.4 mm Hg; p less than 0.0001). Patients demonstrated a shift of the left ventricular end-diastolic pressure-volume relation upward and to the left at rest. Increases in left ventricular filling pressure during exercise were not accompanied by increases in end-diastolic volume, indicating a limitation to left ventricular filling.(ABSTRACT TRUNCATED AT 250 WORDS)