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Departments of 1Science Applied to Biological Systems and 2Cardiovascular and Neurological Sciences, University of Cagliari, Cagliari, Italy; 3Department of Biomedical Sciences, University of Sassari, Sassari, Italy; and 4Department of Biological Science, University of Torino, Torino, Italy
Submitted 3 January 2007 ; accepted in final form 9 February 2007
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ABSTRACT |
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stroke volume; cardiac output; blood pressure; exercise; contractility
Recent studies conducted on canine models of CHF have shown that the limited capacity to enhance ventricular performance likely contributes to the inability to increase cardiac output (CO). In such a condition the impaired baroreflex buffering of the metaboreflex leads to an increase in systemic vascular resistance (SVR) (19) and, as a consequence, to metaboreflex-induced increase in blood pressure (16, 31). On the basis of the quoted canine models of CHF, we hypothesized that the metaboreflex could be characterized by an impaired central hemodynamic response and an exaggerated vasoconstriction also in heart failure patients. However, to the best of our knowledge, the effect of the metaboreflex on central hemodynamics has never been assessed in patients with CHF. Therefore, the existence of this functional shift is still unknown in humans. To address this question, we compared hemodynamic response during metaboreflex activation in CHF patients and control healthy individuals. Specifically, we tested the hypothesis that due to their inability to increase myocardial performance and stroke volume (SV), CHF patients have a limited capacity to increase CO during the metaboreflex. This inability in turn may be accompanied by an exaggerated increment in SVR.
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METHODS |
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First is the chronic heart failure group (CHF group), which consisted of nine subjects with CHF diagnosed on the basis of history, symptoms, and clinical examination. All subjects were male, seven of whom had a history of ischemic heart disease, whereas two suffered from idiopathic dilated cardiomiopathy. All were clinically stable and did not change medication in the 3 mo preceding the study. No one was involved in any exercise-training program. Patients were classified as being in New York Heart Association functional class II (6 patients) and III (3 patients). The demographic characteristics, ejection fraction (EF) measured with two-dimensional echocardiography, and medications at the time of the study are shown in Table 1. Inasmuch as the response to metaboreflex involves sympathetic activation (28, 45), all medications were continued during the course of the study, except for 
-blockers, which were discontinued 1 wk before the subjects entered the study.
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Each subject gave written informed consent to take part in the study, which was approved by the local institutional ethical committee and conforms to the principles of the declaration of Helsinki.
Experimental design.
All experiments were carried out in a temperature-controlled, air-conditioned room. To characterize subjects' physical capacity, before entering the study, a preliminary incremental exercise test on an electromagnetically braked cycle ergometer (Tunturi EL 400) was performed. This test consisted of a linear increase of workload (10 W/min for the CHF group and 30 W/min for the CTL group), starting from 10 W, at a pedaling frequency of 60 rpm, up to exhaustion, taken as the point at which the subject experienced muscle fatigue (i.e., was unable to maintain a pedaling rate of at least 50 rpm) or dyspnea. Oxygen uptake (
O2), carbon dioxide output (CO2), and pulmonary ventilation (E) were measured breath-by-breath throughout this preliminary test by means of a metabolic measurement cart (MedGraphics Breeze, St. Paul, MN) calibrated immediately before each exercise test. The mean ± SE values of maximum work rate, heart rate (HR), O2, CO2, and E reached by subjects in both groups are reported in Table 1. After this preliminary test (the interval was at least 3 days), each subject underwent the following study protocol, randomly assigned to eliminate any order effect.
The postexercise muscle ischemia (PEMI) session (session A) consisted of 3 min of resting, followed by 3 min of exercise, consisting of a rhythmic handgrip achieved by squeezing the balloon of a sphygmomanometer (30 squeezes/min) at 30% of the predetermined maximal capacity, followed by 3 min of PEMI on the exercised arm. At the end of the strain, PEMI was induced by rapidly (in <3 s) inflating an upper-arm bicep tourniquet to 50 mmHg above peak exercise systolic pressure. The cuff was kept inflated for 3 min. Three minutes of recovery were further allowed after the cuff was deflated, for a total of 6 min of recovery. This protocol has been shown to trap the muscle metabolites in the exercising limb and to maintain stimulation of the metaboreceptors (12, 28, 41).
The control exercise recovery (CER) session (session B), consisting of the same rest-exercise protocol used for PEMI, was performed followed by a CER of 6 min without tourniquet inflation.
Sessions A and B were spaced by a 30-min interval during which the study subject rested on a chair to completely recover.
In four subjects of the CHF group, an additional test consisting of regional circulatory occlusion (RCO) without previous exercise was performed. This additional test aimed at verifying whether or not this condition "per se" could affect hemodynamics in heart failure patients, even though we as well as others (5, 11, 12) have demonstrated that, in normal individuals, RCO that was not preceded by exercise was incapable of eliciting any substantial hemodynamic modifications. On a day following the PEMI and CER tests, a RCO session consisting of 12 min (i.e., the same duration as the PEMI and CER tests) was applied: after 6 min of resting, 3 min of regional circulatory occlusion of the arm was applied followed by 3 more min of rest.
Assessment of hemodynamic data. Hemodynamic parameters were measured throughout all phases of the study by means of impedance cardiography (NCCOM 3, BoMed, Irvine, CA), which allows continuous noninvasive cardiodynamic measuring during exercise and recovery in both healthy subjects and patients (3, 9, 12, 50).
The data acquisition method is described in detail in our previous works (9, 11, 12). Briefly, by using a digital chart recorder (ADInstruments, PowerLab 8sp, Castle Hill, Australia), we stored NCCOM 3-derived analog traces of electrocardiogram, thorax impedance (Z0), and Z0 first derivative. Afterward, the Sramek-Bernstein equation (4) was employed to calculate beat-to-beat SV from stored transthoracic impedance traces. The preejection period-to-left ventricular ejection time ratio (PEP/VET) was also calculated from impedance traces, as shown exhaustively in previous papers (9, 10, 12). This ratio correlates quite well with the angiographic EF and represents an inverse index of myocardial contractility (13, 21). HR was calculated as the reciprocal of the electrocardiogram R-R interval, and CO was obtained by multiplying SV·HR. Subjects were also connected to a noninvasive automated sphygmomanometer (NIBP 7000, Colin Medical Instrument, San Antonio, TX) that provided beat-to-beat values of systolic, diastolic, and mean (MBP) blood pressure by means of a tonometer placed around the wrist in the nonexercising arm at the height of the radial artery. This device has been shown to provide continuous beat-to-beat pressure monitoring with high accuracy (25). Pressure data from NIBP 7000 were recorded through the same chart recorder utilized for impedance traces and afterward were beat-to-beat analyzed. SVR was derived by multiplying the MBP-to-CO ratio by 80, where 80 is a conversion factor to change units to standard resistance units.
E, O2, and CO2 were assessed using the same metabolic measurement cart previously described for the preliminary incremental cycle-ergometer test.
Data analysis. Beat-to-beat hemodynamic and breath-by-breath ventilatory collected data were averaged for 3 min. Differences between groups in means ± SE of absolute values of variables during rest periods preceding handgrip runs were studied by means of the two-way analysis of variance (ANOVA) for repeated measures with group (CHF or CTL) and condition (rest before CER or before PEMI test) as main factors followed by Tukey's post hoc test when appropriate. Responses during exercise and recovery are reported as mean ± SE percent changes from corresponding rest values, and comparisons were performed using the three-way ANOVA for repeated measures (factors: condition, time, and group) followed by Tukey's post hoc test when appropriate. Statistics were carried out by utilizing commercially available software (Sigma Stat 2.03). Statistical significance was set at a P value of <0.05 in all cases.
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RESULTS |
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All subjects completed the exercise protocol, and none complained of unbearable pain or discomfort during the periods of arm circulatory occlusion. Figures 1–3 show cardiovascular and ventilatory time courses during each test.
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E (Fig. 3, bottom) appeared to return to rest level slowly during the metaboreflex session of the CHF group compared with patients' CER test and the PEMI test of the CTL group.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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The major new finding of the present study is that, in CHF patients, contractility does not increase during PEMI when a sympathetic overstimulation occurs and SVR greatly increases. The increase in SVR with no change in contractility results in a SV reduction. Thus it appears that, in humans, heart failure causes a shift from output increase to peripheral vasoconstriction in the mechanisms of the metaboreflex-induced blood pressure response. To the best of our knowledge, this is the first time that such a hemodynamic scenario, which closely mirrors what has previously been reported in animal models of CHF (16, 19, 31, 32), is described in humans.
Hemodynamic response to metaboreflex in normal subjects. The sympathetic activation arising from muscle receptor stimulation appears to be essential for a normal hemodynamic response to exercise (8, 38, 49), since its absence abolishes the normal increase in blood pressure commonly observed during effort (49).
The PEMI method is particularly useful in studying the metaboreflex. In fact, PEMI allows isolation of the metaboreflex from central command and mechanoreflex, since the reflex is studied during inactive recovery, when both central command and mechanoreflex no longer operate. The most evident hemodynamic consequence of metaboreflex engagement by the PEMI maneuver is that blood pressure does not return to preexercise level but remains at a level similar to that reached during the previous exercise. The primary function of this reflex-induced blood pressure response is to restore blood flow and arterial oxygen delivery to hypoperfused muscles (29). This pressure effect is thought to be mediated by several mechanisms: 1) a vasoconstriction in the nonischemic vascular beds (8, 38), 2) an enhancement in cardiac filling (14, 42), and 3) an improvement in myocardial contractility (11, 12, 30, 39). Furthermore, there is general consensus that HR does not participate in this response since the metaboreflex-induced increase in sympathetic tone occurring during PEMI is counterbalanced by the concomitant baroreflex-induced rise in parasympathetic activity along with the withdrawal of central command due to the cessation of exercise (8, 12, 16, 18, 26, 39).
Hence, it appears that the hemodynamic response to metaboreflex is an integrated and complex phenomenon that depends on an interplay between the modulation of SVR and the possibility of improving myocardial performance. It has been suggested that, at least in healthy individuals, when a contractility reserve is still present, the primary mechanisms mediating the metaboreflex-induced pressure increment is the rise in CO, which partially restores blood flow and oxygen delivery to the ischemic muscle (11, 12, 16, 29). On the other hand, when a cardiac reserve is no longer available, such as during strenuous efforts, the metaboreflex-mediated rise in CO reaches a plateau and the metaboreflex-induced blood pressure increment relies only on peripheral vasoconstriction in the nonischemic territories to redistribute blood flow toward the ischemic muscle (2).
In the present work, the hemodynamic data obtained from healthy subjects are in close agreement with the scenario described above. Since the exercise was of light intensity (i.e., handgrip at 30% of maximum capacity), it is likely that it did not completely recruit the cardiac reserve in the healthy subjects, whereas it caused metabolic end-product accumulation to stimulate the metaboreceptors. Actually, during the metaboreflex recruitment following this light exercise, a blood pressure increment was observed as the result of an increase in contractility and CO, which returned to baseline later than during the CER test, whereas there was little or no change in SVR. Moreover, HR showed no difference between the PEMI and CER tests, thus confirming that when the metaboreflex is evoked by PEMI, there is no HR response.
Effect of heart failure on hemodynamic response to metaboreflex. From the results of the present investigation, it appears that hemodynamics during the metaboreflex is completely subverted in CHF with respect to what is observed in normal subjects. The most evident alterations are the inability of CHF patients to recruit myocardial contractility and the consequent incapacity to increase SV. Since, as occurred in CTL subjects, the HR response was unaffected by the PEMI maneuver, there was no possibility of increasing CO. Hence, contrary to what was found in normal controls, blood pressure augmentation was reached through SVR increase, i.e., by means of vasoconstriction. This scenario is in perfect agreement with what has been described in dog models of heart failure (16, 31), where a functional shift from a flow-mediated to a vasoconstriction-mediated increase in blood pressure has been demonstrated in response to metaboreflex.
However, what causes such hemodynamic alterations is not yet totally understood. It is highly probable that the inability to enhance ventricular contractility plays a pivotal role in this phenomenon. It is well known that in healthy persons, SV generally increases during exercise because the normal heart can reduce end-systolic volume by recruiting the contractility reserve (17). This opportunity is limited in the failing heart, and SV tends to fall or to slightly increase, depending on the severity of the disease, in response to exertion (7), and this occurrence is also confirmed by our experiment. Actually, SV decreased during the rhythmic handgrip sessions, even though the effort was light. Another factor that may have limited the SV increase in response to exercise was that the Frank-Starling mechanism was probably exhausted in CHF (20), although the issue of whether or not the failing heart still has a preload reserve is controversial (7). Whatever the cause of this SV behavior, the new findings in the present work are that, in CHF subjects, this parameter decreased not only during exercise but even in response to metaboreflex and that this decrement was of the same extent as that found during exercise sessions. These phenomena support the concept that the ability of the metaboreflex to raise ventricular performance is impaired. Despite the inability to increase SV, in CHF patients the metaboreflex was still able to elicit a pressor response similar to or even higher than that of the CTL group by means of an accentuated vasoconstriction, as testified by the sustained SVR increment. This result is in accordance with previous findings and thus demonstrates that, in subjects with CHF, there is exaggerated vasoconstriction in response to the metaboreflex, which, contrary to metabolic vasodilatation, also vasoconstricts the ischemic muscle and does not effectively improve muscle perfusion (43, 47), thus probably contributing to early exertional fatigue. It should, however, be borne in mind that the mechanisms of fatigue are a very complex matter even for normal subjects. From our results it appears that when cardiac performance cannot be enhanced, the cardiovascular apparatus responds to exercise and metaboreflex by excessively increasing SVR in an attempt to achieve an increment in blood pressure. However, the mechanisms of this response are not well understood, even though recent investigations indicate that the impaired ability of arterial baroreflex to buffer metaboreflex is in part responsible for the phenomenon (19).
Hence, CHF may be considered a disease that disrupts the normal plasticity of circulatory response to exercise, which is an integrated response coordinated by the autonomic nervous system involving the recruitment of several hemodynamic reserves such as contractility and the Frank-Starling mechanism, which are exhausted in this disease.
The results of the present investigation would appear to argue against the concept that the metaboreflex is attenuated and that mechanoreceptor stimulation is responsible for the exaggerated blood pressure response observed in CHF subjects. This issue, i.e., the type of muscular receptor from which originates the abnormal hemodynamic response to exercise, has been recently debated by two groups without reaching conclusive agreement (23, 36, 40). One contender supported the thesis that muscle metaboreceptor contribution to exercise pressor reflex is blunted in heart failure and replaced by the mechanoreflex (23). These authors based their opinion on several facts: opposite to what was observed in dog model, in rat model of heart failure cardiovascular responses to stimulation of metabolite-sensitive receptors were blunted and response to mechanoreceptor was augmented compared with that in a control group (22); furthermore, in CHF patients it is was found that during exercise the contribution of the metaboreflex to renal vasoconstriction is reduced (24). In our experiment we were able to evoke a blood pressure increment during the PEMI maneuver, which clearly ruled out any contribution of mechanoreceptors since they were not operating in this setting. The blood pressure increase we noticed was the consequence of an exaggerated vasoconstriction, probably arising from a sympathetic overstimulation in response to metaboreflex, a phenomenon that has been already demonstrated in CHF (28, 45). Thus our results would seem to agree with the opinion that metaboreflex activity is exaggerated in heart failure.
Unfortunately, since our experiment was not designed to discover which receptor is responsible for sympathetic overactivity but, rather, to test the hypothesis that in CHF patients there was a hemodynamic disarrangement in response to metaboreflex, we cannot make any inference concerning mechanoreflex response. Thus we cannot exclude that even mechanoreflex is overactivated in this disease. Accordingly to the recent review by Sinoway and Li (46), probably the conflicting results in the scientific literature on whether the muscle metaboreflex is attenuated or accentuated may depend on the degree of the muscle abnormalities of CHF patients enrolled, the degree of metaboreceptor desensitization, and the mode of exercise being performed (i.e., static vs. dynamic).
As concerns ventilatory parameters, E was significantly affected by the PEMI maneuver in CHF patients. This finding is coherent with some recent reports showing that subjects with CHF have greater ventilatory responses than do controls (41).
Limitations of the method of hemodynamic measurement. The "gold standard" for hemodynamic assessment at rest and during exercise are the Fick and the dye-dilution methods, which, however, are invasive and potentially dangerous. For this reason their use in not advisable in investigations involving healthy controls and/or patients who do not require invasive procedures for diagnostic or therapeutic purposes, such as the present one. Among noninvasive techniques, the choice is restricted to rebreathing, Doppler echocardiography, and impedance cardiography, but none of them is unanimously considered accurate and reliable (51, 52). In the present investigation we employed the impedance cardiography, a method that has been already validated against the "gold standard" during rest and exercise (3, 27) and has been recently demonstrated to be feasible and reproducible in patients with heart failure (1, 15, 33).
One major concern with the impedance method is that respiration and muscular movements during heavy efforts may generate artifacts in the impedance traces, and this fact may potentially cause errors. However, the mild exercise protocol employed in the present investigation did not generate neither great enhancement in ventilation nor marked chest movements. Moreover, many of our data were collected during the recovery period, i.e., when the individuals were not moving. Nevertheless, to overcome the potential errors due to impedance artifacts, we used visual inspection of previously recorded signals to exclude from hemodynamic calculation traces affected by artifacts. Thus we did not trust in the automatic report provided by the device. We used this processing signal procedure in previous investigations involving healthy subjects as well as patients obtaining reliable results (8–11). Moreover, the aim of this work was not to study the absolute values of cardiodynamic variables but to evaluate relative changes. Therefore, the use of indirect measures of SV, on which our study conclusions depend, did not influence the outcome since the measurement of absolute values was not essential and the percent responses were clearly different between groups.
In conclusion, our results show that, during metaboreflex activation, CHF patients have a blood pressure response similar to that of healthy subjects. However, CHF patients have an exaggerated increase in SVR that is not accompanied by an increase in cardiac contractility and SV. Thus CHF patients are still able to increase blood pressure, but they achieve this result by shifting from an output-increase to a vasoconstriction-mediated mechanism. This shift may contribute to the early fatigue experienced by CHF patients.
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GRANTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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P < 0.05 vs. corresponding time point of control exercise recovery (CER) test; 
P < 0.05 vs. corresponding time point of same test of control (CTL) group. CHF, congestive heart failure; PEMI, postexercise muscle ischemia.
