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(Chest. 2004;126:838-844.)
© 2004 American College of Chest Physicians

Inspiratory Muscle Weakness in Diastolic Dysfunction*

Marc H. Lavietes, MD, FCCP; Christine M. Gerula, MD; Kristin G. Fless, MD, FCCP; Neil S. Cherniack, MD and Rohit R. Arora, MD

* From the Divisions of Cardiology (Drs. Gerula and Arora) and Pulmonary/Critical Care (Drs. Lavietes, Fless, and Cherniack), Department of Medicine, UMD–New Jersey Medical School, Newark, NJ.

Correspondence to: Marc H. Lavietes, MD, FCCP, University Hospital #I354, 100 Bergen St, Newark, NJ 07103; e-mail: lavietmh{at}umdnj.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objectives: To test the hypothesis that patients with well-documented diastolic dysfunction (DD) in the setting of normal systolic function will have inspiratory muscle weakness when compared to normal control subjects, and will experience dyspnea and tachypnea during exercise.

Background: Respiratory muscle weakness has been described in patients with (systolic) congestive heart failure; however, whether or not patients with DD may present with the findings of congestive heart failure is not known.

Methods: We selected for study 14 patients with DD previously referred for cardiopulmonary evaluation whose diagnosis had been confirmed by data obtained at cardiac catheterization. Seven control subjects matched for age, sex, and weight were recruited from the hospital community. Subjects performed both basic pulmonary function tests and tests of muscle strength: handgrip strength (Hgr), and maximal subatmospheric static inspiratory muscle pressure (PImax). Subjects then performed a graded exercise test on a bicycle ergometer. Minute ventilation, oxygen consumption, carbon dioxide production, and heart rate were monitored continuously. Echocardiography was performed three times: before exercise, at a selected submaximal exercise level (20% of a predicted maximal workload), and at maximal exercise. Subjects rated their degree of dyspnea using the Borg scale at the same three time intervals.

Results: PImax was – 102 ± 17 cm H2O in control subjects, and – 77 ± 19 cm H2O in patients with DD (p = 0.013) [mean ± SD]. Hgr was similar between the groups. At the selected submaximal exercise level, patients with DD rated dyspnea to be 2.6 ± 2.2 Borg scale units (control subjects, 0.5 ± 0.8 Borg scale units). Hey plots described a rapid, shallow breathing pattern in patients with DD during exercise. Patients with DD and control subjects achieved similar maximal work loads.

Conclusion: Patients with DD have diminished PImax, adopt a rapid, shallow breathing pattern during exercise, and experience dyspnea at low work loads when compared to matched control subjects.

Key Words: diastole • dyspnea • exercise • heart failure, congestive • muscle weakness, inspiratory


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Dyspnea is a cardinal symptom of heart failure. Both pulmonary venous distention and pulmonary congestion may cause dyspnea in patients with left ventricular systolic failure. Data suggest that muscle weakness, in particular inspiratory muscle weakness, is common in patients with heart failure and may account, in part, for this symptom.1

Patients with diastolic dysfunction (DD) in the setting of normal systolic and valvular function have been identified by means of Doppler echocardiography.23 DD is thought to be a consequence of many dissimilar pathologic conditions such as coronary artery disease, myocardial hypertrophy, and myocardial fibrosis. Clinical surveys45678 have suggested that many patients with the signs and symptoms of congestive heart failure may have DD as the only physiologic abnormality to explain their presentation. While a potential link between DD, the sensation of dyspnea on exertion, and exercise intolerance has been recognized, there have been no studies describing either lung function, muscle strength, or the ventilatory response to exercise in patients with DD.91011 This study investigates whether patients with DD will demonstrate muscle weakness, and whether they become tachypneic and dyspneic (when compared to matched control subjects) during exercise.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
We studied 14 subjects who presented for cardiac evaluation with complaints of chest pain and/or fatigue. All presented with chest pain and/or fatigue and were thought to have coronary disease. None described dyspnea as a major feature of their illness. All patients had abnormal stress ECG test results, and therefore were advised to undergo catheterization. At catheterization, all patients had elevated left ventricular end-diastolic pressures (LVEDPs) but normal left ventricular systolic pressures and normal coronary arteriograms, thus meeting criteria for the diagnosis of DD.2

The patients were then invited to participate in this study, and to read and sign an informed consent form. Both the protocol and consent form were approved by the local institutional review board. All study subjects were in normal sinus rhythm. For control subjects, we selected seven subjects matched to the patients with DD with respect to sex, age, and weight. All subjects were asymptomatic, were in normal sinus rhythm, and had no history of cardiopulmonary disease. To exclude subjects with occult coronary artery disease, control subjects were required to undergo normal 12-lead ECG during standard exercise testing. Subjects were asked to omit antihypertensive medications for 12 h prior to study. Some subjects in each group were receiving antihypertensive medications that may have affected diastolic function. This should not have interfered with the primary goal of our study, which was to investigate the relationship between myocardial relaxation and dyspnea.

Procedures
Pulmonary Function Testing: Slow and forced vital capacities were obtained by standard methods (W.E. Collins; Braintree, MA). Total lung capacity was obtained by the helium dilution method. Maximal static subatmospheric inspiratory muscle pressure (PImax) was obtained by the method of Black and Hyatt.12 Care was taken to teach subjects to perform maximal efforts and to obtain two reproducible maximal efforts from each subject. Handgrip strength (Hgr) was measured with a Jamar dynamometer (Therapeutic Equipment Corporation; Clifton, NJ).13 Hgr was taken as an average of maximal force developed by right and left hands and given as a percentage of a predicted value.

Cardiopulmonary Testing: Routine cardiac catheterization (GE Marquette; Milwaukee, WI) and two-dimensional echocardiography (Acuson; Iselin, NJ) were performed with standard equipment. Cardiopulmonary testing for this protocol was performed with equipment designed specifically for cardiopulmonary exercise testing (CPX; W.E. Collins).

Protocol
Pulmonary function, Hgr and respiratory muscle strength testing, and BP measurements were performed on or close to the day of the cardiopulmonary exercise test. For exercise testing, subjects sat on a stationary bicycle. Pulse oximetry and a one-lead ECG were monitored continuously. Subjects breathed via a mouthpiece through a pneumotachograph. Expired gas was continuously sampled for measurement of oxygen and carbon dioxide concentrations. Data were first collected for 1 min while the subject sat quietly on the bicycle. The subject then pedaled at an established speed while the work required to pedal increased in a ramp fashion, at the rate of 15 W/min. Ventilatory data were collected continuously, while echocardiography was performed at three intervals: during the resting period, at the time the subject was working at a rate of 20% of a predicted maximal workload, and finally at the maximal workload. While the probe was positioned to obtain optimal views of mitral inflow in all subjects, reliable measures of ventricular wall mass could be obtained for four of the patients with DD as well. To measure the degree of shortness of breath, each subject rated his sensation of dyspnea on the modified Borg scale each time the echocardiogram was recorded.14

Data Analysis
Minute ventilation (E), tidal volume (VT), breathing frequency, inspiratory time, and total time for one breathing cycle were recorded on a breath-by-breath basis during exercise. Borg score and an echocardiogram were obtained at the three designated time intervals. The isovolumic relaxation time (IVRT) was computed and used as the echocardiographic index of diastolic function. IVRT is affected by heart rate (HR); therefore, to normalize the data, the IVRT was corrected for HR.15 Left ventricular mass was computed with the Penn convention.16 HR response (HRR) was taken as the ratio of {Delta}HR and {Delta}oxygen consumption (O2) during progressive exercise; ventilatory reserve (VR) was calculated as described.17

To illustrate differences in the pattern of breathing between the two study groups, measures of both VT and respiratory rate during exercise were taken at three specific intervals. These intervals were taken as three levels of ventilation (10 L/min, 20 L/min, and 30 L/min). These data are presented in conventional Hey plots.18 One patient failed to pedal to a maximal work value. Otherwise, data were complete for all subjects.

Statistical analyses were performed with a standard statistical package (JMP; SAS Institute; Cary, NC). The unpaired t test was used for comparisons between study and control groups. To analyze data presented in the Hey plots, a two-way analysis of variance (ANOVA) with repeated measures was used for simultaneous comparisons between both groups and time. In addition, to determine whether group differences in PImax were greater than group differences for Hgr, PImax values were converted to percentage units (of a predicted value) and a two-way ANOVA with repeated measures with an interactive factor performed.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Baseline characteristics of subjects appear in Table 1 . There were no significant differences between groups with respect to age, weight, or BP. Twelve of the 14 patients with DD and all control subjects were women. Thirteen of 14 patients with DD and 6 control subjects were receiving treatment for hypertension at the time of study. A list of medications used appears in Table 2 . Both cigarette usage (three DD/one control) and incidence of diabetes (four DD/one control) were similar in the two groups. Pulmonary function test results appear in Table 3 . Subjects, on the average, had normal pulmonary function. There were no significant differences between the groups. At catheterization, LVEDP was 22 ± 5 SD mm Hg in the DD group; all patients with DD had normal left ventricular stroke volume and coronary arteriograms. Ejection fraction was 63 ± 5% (± SD) for the patients with DD. Taken together, these data show that, save for DD in the study group, the two groups had identical cardiopulmonary function.


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  		Table 1.. Baseline Characteristics of Study Subjects*

 

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  		Table 2.. Baseline Characteristics*

 

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  		Table 3.. Pulmonary Function Test Results*

 
Data obtained from echocardiography during the exercise testing period appear in Table 4 . The IVRT/HR ratio in patients with DD at rest (1.38 ± 0.37) was greater than that for control subjects (1.00 ± 0.14). The ANOVA showed that the IVRT/HR differed both between subject groups and time intervals (for subjects, F = 14.4, p = 0.0003; for time, F = 25.9, p < 0.0001; interactive factor = not significant). These data confirm that cardiac function in diastole differed between study groups throughout the protocol.


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  		Table 4.. Echocardiographic Data

 
Data for inspiratory muscle strength and Hgr appear in Figure 1 . PImax for control subjects (– 102 ± 17 cm H2O) was more subatmospheric than that for patients with DD (– 77 ± 19 cm H2O; t = 2.8, p = 0.013). Hgr tended to be greater in control subjects when compared to patients with DD (125 ± 16% predicted vs 114 ± 17% predicted). This difference was not statistically significant. Two-way ANOVA showed a difference between DD and control subjects in both PImax and Hgr; however, the interaction did not reach statistical significance (p = 0.11).



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  		Figure 1.. PImax and generalized Hgr for patient and control groups. Data appear as mean ± SD.

 
Differences in the breathing patterns between patients with DD and control subjects during exercise are illustrated in Hey plots (Fig 2 ). At a ventilation of 10 L/m, control subjects breathed 15 ± 0.9 breaths/min (SEM), and patients with DD breathed 19 ± 1.4 breaths/min. This difference persisted at both the 20 L/m and 30 L/m ventilation levels. Two-way ANOVA showed that the F for the comparison of DD vs control groups was 8.7 (p = 0.005). By contrast, VT at a ventilation of 10 L/m for the control group (0.79 ± 0.08 L) [± SEM] was greater than that for the DD group (0.65 ± 0.04 L). This difference persisted at the higher levels of ventilation. Two-way ANOVA for the difference between groups yielded F = 8.0 (p = 0.002).



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  		Figure 2.. Hey plots. Data appear as mean ± SE.

 
Borg scale scores obtained at rest and while subjects were cycling at a work rate of 20% of their maximal predicted work rate appear in Figure 3 . At rest, four patients with DD had Borg scores greater than zero; all control subjects quantified dyspnea at rest as zero. Borg scores at submaximal exercise were 2.6 ± 2.2 for patients with DD (0.5 ± 0.8 for control subjects). The ANOVA showed that differences were significant for both group (F = 6.06; p = 0.02) and time (F = 10.2; p = 0.003).



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  		Figure 3.. Borg scale scores for patient and control groups during resting period (time 0) and at submaximal exercise (time 20% of a predicted maximal work output). Data appear as mean ± SD.

 
Maximal Exercise
Two patients reached their maximal predicted HR for maximal exercise at an exercise level below their predicted maximum and were asked to stop. Data for maximal exercise could not be obtained for one patient with DD who quit exercising shortly after reaching the submaximal work rate but was not symptomatic. All other subjects stopped exercise because they felt "fatigue" or "dyspnea." Control subjects were able to exercise more than patients with DD (94 ± 19% of a predicted maximal work value vs 70 ± 29%), but this difference was not statistically significant (unpaired t test = 1.90; p = 0.07). There were no differences in either HRR or VR between groups. Regression analysis showed that when maximal work achieved by the 13 patients with DD was considered as the dependent variable, measures of strength, HRR, and VR did not serve as independent variables to predict maximal work. Finally, O2 at anaerobic threshold (given as a percentage of a predicted maximal O2 at maximal work) for the patients with DD (42 ± 22%) [± SD] did not differ from the control group (47 ± 21%). For all subjects, there was strong correlation between the degree of dyspnea reported at a workload of 20% of a predicted maximal value and the maximal level of exercise achieved: maximal work (%) = 92 – 7 Borg/20 (n = 20; r = 0.53; p < 0.01)


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This prospective study shows that when compared to a carefully selected matching control group, patients with DD in the setting of normal systolic function show mild inspiratory muscle weakness. Ventilatory data obtained during exercise show that patients with DD, compared to control subjects, demonstrated rapid, shallow breathing. Muscle weakness and its resultant rapid, shallow breathing pattern may explain the dyspnea described by the patients with DD during low-intensity exercise.

Cardiac Physiology
IVRT was longer in patients with DD than control subjects whether or not corrected for HR throughout the exercise protocol. Data derived from a study of normal dogs suggest that IVRT prolongation may be a reflection of either an increased afterload or an increased relative load.19 The term relative load refers to the ratio of baseline left ventricular systolic pressure to an experimentally induced maximal, or isovolumetric, left ventricular systolic pressure. In this study, DD and control groups had identical systolic pressures and, therefore, identical afterload. The possibility that the BP response to exercise differed between groups was not excluded, however. The relative load concept would suggest that for patients with DD, the left ventricular pressure generated to achieve the stroke volume at rest or during exercise approximates the maximal pressure the ventricle is able to generate. By contrast, the left ventricular pressure generated by the control subjects’ hearts may represent a small percentage of the maximum pressure that the heart can generate. Thus, increased IVRT in the DD group may be an early manifestation of a failing heart. For either mechanism, the acute induction of an increased afterload, eg, by infusion of a vasoconstricting substance, can prolong IVRT in the absence of myocardial hypertrophy. To this end, we found—in the four patients with DD for whom data were available— left ventricular mass to be within normal limits (130 ± 10 g/m2).

Neither age nor body weight per se can explain our echocardiographic findings. IVRT is a function of age.20 IVRT at rest for age-matched subjects given in the literature (76 ± 11 ms) is similar to that for our control subjects (90 ± 7 ms) but shorter than that for our DD group (109 ± 22 ms). Similarly, obesity does not explain an increased LVEDP at rest. Data published from the study of massively obese people (body mass index [BMI] > 50), for example, show normal LVEDP at rest with only a modest increase during mild exercise.21 Our control group was selected such that there would be no difference in weight between groups; for all of our subjects, there was no correlation between BMI and either maximal work output or HRR. Published data2223 also suggest that IVRT is increased in heavy people; IVRT in our control subjects—but not in our study subjects—is similar to that published for obese subjects.

Muscle Weakness
Decreased inspiratory muscle strength was observed in patients with DD when compared to control subjects. Inspiratory pressures generated by our normal subjects are similar to those found in groups of overweight but otherwise healthy adults.2425 In any given patient, PImax > – 80 cm H2O excludes clinically significant respiratory muscle weakness.26 Among our subjects, 8 of 14 patients with DD but only 1 of 7 control subjects had PImax < – 80 cm H2O.

Previous investigators2728 have observed diminished PImax out of proportion to handgrip weakness in patients with chronic heart failure. The explanation for this finding is not obvious. While Hgr in our two subject groups was similar, analysis of our data by ANOVA did not uphold the notion that inspiratory muscles were preferentially weakened in our DD group. Common causes of muscle weakness such as disuse, malnutrition, and electrolyte abnormality ought not to affect inspiratory muscles preferentially.29 This is the first study to evaluate either lung function or muscle strength in groups of DD patients and carefully matched control subjects. Residual volume was normal for both study groups. This would suggest that the diaphragms of all subjects were in a configuration of maximal curvature when the PImax maneuver was performed. Differences in the mechanical advantage of the diaphragm between DD and control subjects therefore could not have explained our findings.

Dyspnea
Inspiratory muscle weakness may explain dyspnea. Weaknesses of either respiratory or peripheral muscles are thought to contribute to the dyspnea reported by patients with cardiopulmonary disorders. In one study30 of heart failure patients during exercise, for example, a twofold increase in PImax was accompanied by a decrease of 25% in the intensity of dyspnea at any given power output. The fact that our patients with DD tended to have diminished exercise capacity, reported greater dyspnea at low levels of exercise intensity, and had lower Pimax when compared to control subjects gives some support to this explanation. The rapid, shallow breathing shown by the DD group is a known consequence of respiratory muscle weakness and may be a cause of dyspnea.31

Pulmonary venous distention may be an alternate explanation for both the dyspnea and rapid, shallow breathing of the DD group.323334 An elevated left ventricular diastolic filling pattern predicts a limitation of functional capacity in patients with chronic heart failure.35 Such subjects with overt heart failure terminate exercise because of either dyspnea or fatigue. Our patients with DD reported dyspnea at low work levels but did not immediately terminate exercise because of this sensation. The facts that our patients with DD had elevated LVEDP at rest and longer IVRT when compared to control subjects throughout the exercise period suggest that the patients with DD had higher left ventricular filling pressures throughout the protocol.

The link between tachypnea (rapid, shallow breathing) and dyspnea (the subjective sensation of shortness of breath) is, however, speculative. The observation that dyspnea and tachypnea coincide in this study does not prove causality.

Achievement of Maximal Work
Control subjects tended to exercise longer than patients with DD, although the difference in maximal exercise between the two groups was not statistically significant. Two of the patients with DD were asked to terminate exercise because they had reached a maximal predicted HR before achieving maximal exercise. For those two subjects, exercise appeared to be limited by cardiac function. All others stopped exercise because of "tiredness" or "fatigue." The high VR in each group rules against any respiratory limitation to exercise. The high HRR seen in both groups, along with the normal anaerobic threshold, suggest that our subjects were poorly conditioned. Poor conditioning has been described in a retrospective series of patients with DD at exercise.36 The use of ß-blockers may have played a role in this difference, given that four patients with DD but only one control subject were receiving this medication.

High report of dyspnea at submaximal exercise work loads was a predictor of reduced maximal work for all of our subjects. This relationship has been noted previously.37


   Acknowledgements
 
The authors thank Dr. Shikha Sharma, and Mr. Waldo Duran, Ms. Gail Smith, and Ms. Sauying Yip for technical assistance.


   Footnotes
 
Abbreviations: ANOVA = analysis of variance; BMI = body mass index; DD = diastolic dysfunction; Hgr = handgrip strength; HR = heart rate; HRR = heart rate response; IVRT = isovolumic relaxation time; LVEDP = left ventricular end-diastolic pressure; PImax = maximal subatmospheric static inspiratory muscle pressure; E = minute ventilation; O2 = oxygen consumption; VR = ventilatory reserve; VT = tidal volume

Received for publication October 21, 2003. Accepted for publication March 4, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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