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Am J Physiol Heart Circ Physiol 291: H2396-H2402, 2006. First published June 30, 2006; doi:10.1152/ajpheart.00437.2006
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Exercise metaboreflex activation and endothelial function impairment in atrial fibrillation

Marco Guazzi,1 Marco Berti,2 Sebastiano Belletti,1 Giuseppe Reina,3 and Maurizio D. Guazzi4

1Endothelial Function and Cardiopulmonary Unit, University of Milano, and Cardiology Division, San Paolo Hospital; 2Cardiologic Center "Monzino"; 3Institute of Statistics and Biometry; and 4Institute of Cardiology, University of Milano, Milan, Italy

Submitted 2 May 2006 ; accepted in final form 29 June 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Exercising muscle hypoperfusion stimulates afferents (metaboreceptors) involved in the regulation of ventilation. Atrial fibrillation (AF), particularly when combined with diseases causing endothelial (ED) impairment, such as hypertension (HP) and diabetes mellitus (DM), depresses the ED activity and enhances exercise hyperventilation. The relationship between these two functions and the underlying mechanisms have not been explored previously. In lone AF or AF associated with HP or DM (12 subjects in each cohort), we investigated the brachial artery flow-mediated dilatation (ED function) and ventilation during the recovery phase of handgrip (metaboreflex) exercise for subjects receiving placebo or oral vitamin C (double-blind crossover), both before and after cardioversion (CV) to sinus rhythm. Baseline ED impairment was increasingly more severe and the ergoreflex activity more pronounced in AF + HP and AF + DM compared with lone AF. Vitamin C and CV significantly improved both flow-mediated dilatation and metaboreflex activity in lone AF and AF + HP, and vitamin C did not produce any additive effect when administered after CV. In AF + DM, neither vitamin C nor CV was effective. This study provides the following information: AF generates oxidative injury, which is less when the arrhythmia is lone AF and greater when the arrhythmia is associated with HP. In DM, the oxidative injury generated by AF is refractory to a rather weak antioxidant, like vitamin C, or the baseline damage is such as to prevent any additive influence of AF. In AF, a cause-effect link exists between ED dysfunction and metaboreflex activity. Ventilatory advantages of CV seem to be inversely related with the extension of the underlying ED oxidative impairment.

arrhythmia; diabetes; endothelium; hypertension

INADEQUATE PERFUSION OF EXERCISING muscles may cause local overproduction and accumulation of muscle metabolic by-products, which trigger stimulation of group III and IV neural afferents located in the skeletal muscle. These afferents, which are conventionally called ergoreceptors, have two subtypes: metaboreceptors (sensitive to metabolic products of muscle work) and mechanoreceptors (activated by deformational changes in limbs and joints). An overstimulation of these receptors affects patient's symptoms and the ventilatory response to exercise (22, 26). Endothelium, by modulating the exercise-induced neurogenic vasoconstriction and increasing arterial conductance, contributes to the adequacy of exercising muscle perfusion (13, 17), suggesting the possibility of an interaction with ergoreceptors. Despite the physiological and clinical implications, this possibility has not been explored previously.

We reasoned that, for an endothelium-ergoreceptor link to be proven, it should be demonstrated that 1) the receptor stimulation is proportional to the degree of baseline endothelial dysfunction; 2) interventions that improve endothelium also attenuate the ergoreflex; and 3) the response is paired independently of the type of intervention set into action. We aimed at investigating these points and considered atrial fibrillation (AF) an ideal pathophysiological model, because the intrinsic endothelial dysfunction of this arrhythmia (3, 9, 10, 27) is emphasized (10, 11) when it is associated with comorbidities causing endothelial impairment, such as hypertension and diabetes mellitus (15, 20, 23), and because endothelial activity can promptly be restored with sinus rhythm cardioversion (CV) (9, 10).

We investigated the metaboreflex activity and the brachial artery flow-mediated dilatation (FMD) in patients with lone AF and in patients with Type 2 diabetes mellitus or high blood pressure, as comorbid diseases. CV was utilized as an intervention to improve endothelial responsiveness. Because increased metabolic burden developed in fibrillating myocytes suggests that augmented production of reactive oxygen species is likely in AF (21), we also used the antioxidant vitamin C as an alternative endothelium-protective method.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Study population. The study population consisted of 12 consecutive patients with lone AF (group 1) who satisfied the inclusion criteria and of an equal number of patients with AF and high blood pressure (group 2), or Type 2 non-insulin-dependent diabetes mellitus (group 3) as comorbidities, who were matched to the 12 patients with lone AF according to the matching criteria reported below. Five patients in group 1 (41%), four in group 2 (34%), and five in group 3 (41%) had hypercholesterolemia or hypertriglyceridemia as defined by values of total cholesterol >6.2 mmol/l and triglycerides >2.3 mmol/l. According to the referring physicians' reports, these patients had stable AF for 3–5 mo. Stability was confirmed by ambulatory ECG evidence of fibrillation in the last two follow-up visits, separated by an interval of 1 mo. Patients were enrolled if they had not had previous myocardial infarction; if they had no significant valvular heart disease; if they did not suffer from angina pectoris or lung disease; if their New York Heart Association functional class did not exceed class II; and if their age was 60 yr or younger, to minimize the influence of aging on endothelial function (1, 12). Type 2 diabetes mellitus was diagnosed according to the criteria elaborated by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (28). In these patients, diabetes was known for 5.2 ± 1.1 yr. They had no history of cardiovascular disease but AF, they had stable weight and fasting glucose levels over a minimum of 5 wk before enrollment; control of diabetes was achieved with diet alone (3 patients) or diet plus biguanide or sulfonylurea preparations (9 patients). They had diabetes without known coronary or vascular disease, known diabetic retinopathy, clinically evident distal neuropathy, or autonomic insufficiency measured by variations in RR interval with cycled breathing and by the presence of >20-mmHg decrease of upright blood pressure without a change in heart rate. Glycosylated hemoglobin levels were <7% with therapy. Two patients in group 3 reported taking angiotensin-converting enzyme (ACE) inhibitors for a few months until 6 mo before enrollment. They were normotensive at the time of recruitment. Hypertensive patients had a blood pressure reading (the average of 3 measurements, each performed in 3 separate days) ≥150/90 and ≤170/105 mmHg. Clinical sitting blood pressure was measured after 15 min of rest. Diastolic pressure was read as phase V of Korotkoff sounds. All of these patients had no evidence of secondary hypertension according to tests including plasma renin activity, serum potassium, plasma aldosterone and catecholamine concentrations, and ultrasonic duplex scanning of the renal arteries (14). The duration of hypertension could be determined in all cases and averaged 5.9 ± 2.6 yr. Among them, five patients were untreated and seven had received one or more antihypertensive agents for at least 2.8 yr. Current drug therapy consisted of diuretics in three cases, ACE inhibitors in three cases, and both drugs in one case. Treated patients were requested to discontinue medications 2 wk before studies, and, during that period, blood pressure was closely monitored for any evidence of accelerated hypertension (increase of diastolic pressure >10 mmHg). If temporary treatment withholding was judged risky (mostly because of the poor response to the current therapy), that case was excluded from the study.

Participants were not involved in any regular physical training program and were not receiving lipid-lowering agents, antioxidant vitamins, or aspirin. They had never smoked or were exsmokers of at least 8 mo, with a <10 pack-yr index of smoking. No participants were receiving beta-blockers; 57% were on digoxin, and 22% were taking verapamil. Cardioactive preparations were withheld for at least five half-lives before vascular studies. Anticoagulation therapy was such as to maintain in all patients prothrombin time within a target of 2.0–2.5 times control for at least 4 wk before external CV. The procedure was clinically indicated in any instance and was guided by the findings of transesophageal echocardiography, which in our hospital is a current procedure before CV in patients with AF. All subjects gave written informed consent before enrollment; the protocol was approved by the local Ethics Committee.

Matching. The group with lone AF was the reference group. Five variables were used to match 12 patients with hypertension and AF and 12 patients with Type 2 diabetes and AF to the 12 reference subjects: 1) sex (women all were postmenopausal and not taking estrogen replacement therapy); 2) age; 3) smoking habit (never smoker, former smoker); 4) total cholesterol plasma concentration; and 5) body mass index. Matching was exact for variables 1, 2, and 3 and was made to the nearest available subject with comorbidity for variables 4 and 5. The nearest available matching was performed with the use of a multivariate linear discriminating function (18). None of the patients recruited for this study had been involved in previous studies in our laboratory.

Vascular studies. We performed imaging studies of the brachial artery with a high-resolution ultrasound Philips 11 MHz linear-array transducer (Philips Medical System, Best, The Netherlands). After the clearest view of the artery was found, anatomic landmarks were noted, the skin was marked, and the transducer was held in a constant position by a stereotactic clamp. Images were obtained by the same investigator throughout the study. Vasodilation was assessed by measurement of the maximal change in diameter of the brachial artery during reactive hyperemia created by an inflated cuff (50 mmHg above systolic pressure for 5 min) on the forearm. Arterial diameter was measured in millimeters, coincident with the R waves on the ECG, for six cardiac cycles, and the six measurements were averaged. Evaluations of the vasodilator response from repeated studies were performed by an individual who was blinded to the sequence. Images were stored on a video format and then analyzed with an image analysis software. Flow velocity was assessed by pulsed Doppler with the range gate (1.5 mm) in the center of the artery. The cuff was inflated for 5 min and then rapidly deflated. A 90-s scan was taken immediately after deflation.

Blood flow was calculated by multiplying the velocity-time integral of the Doppler flow signal by the cross-sectional area of the vessel and heart rate. FMD was calculated as the absolute and percent [(reactive hyperemia – baseline)/baseline x 100] maximal increase in diameter during reactive hyperemia compared with baseline.

Antioxidant enzyme assessments. Allantoin, a marker of increased oxidative stress (19), was measured in five male subjects in each group by gas chromatography-mass spectrometry after anion exchange extraction (5). By this method, the normal value for healthy male subjects 40–70 yr old is 14.9 µmol/l (16). Glutathione peroxidase 1 activity (U/g of hemoglobin), an index of enzymatic inactivation of reactive oxygen species (2), was determined in triplicate from venous blood samples collected on three consecutive days (1) in four, three, and four male patients in groups 1, 2, and 3, respectively. Blood samples were obtained while in AF before the start of the study protocol and while in sinus rhythm after protocol completion. The value reported at either step is the mean of three samples. Glutathione peroxidase 1 was measured as previously described (2), in washed red cells obtained immediately after sampling, from whole blood hemolyzed by adding ice-cold demineralized ultrapure water to yield a 50% hemolysate. Hemolysates were frozen at –80°C for later analysis. All samples at each step from each individual were analyzed in the same analytical run.

Metaboreflex evaluation. A maximal voluntary handgrip test was measured as the greatest of the peak forces produced by three brief maximal handgrip contractions preliminarily performed before the metaboreflex test. Metaboreceptor stimulation consisted of a 3-min ventilation recording during test, followed by a handgrip session that was performed twice (4-h interval) in a random order, according to the following protocol: 1) a 5-min session of rhythmic handgrip was achieved by squeezing the balloon of a sphygmomanometer (30 squeezes/min) at 50% of the predetermined maximal capacity, followed by a 3-min control recovery; and 2) the same protocol was followed soon after interruption of exercise by 3 min of blood flow stasis on the exercise arm by inflating an upper arm biceps tourniquet to 30 mmHg above systolic blood pressure at the beginning of recovery (24). The metaboreflex contribution to ventilation was computed as the difference in ventilation between the value at the second and third minute of recovery with and without posthandgrip circulatory occlusion (22).

Echocardiography. Two-dimensional and Doppler cardiac ultrasounds were carried out by standard methods. Systolic pulmonary arterial pressure, left atrial dimension, and left ventricular end-systolic and end-diastolic chamber dimensions and volumes, by the area-length method (to evaluate ejection fraction), were measured by current methods.

CV procedures. External CV was performed under light anesthesia with thiopental sodium. Synchronized CV was carried out with a 200-J shock. A 300-J shock was administered if a 200-J shock was unsuccessful. ECG was monitored continuously, and ventilation was assisted.

Study protocol. The scheme of the study protocol is depicted in Fig. 1. Before CV, patients in each group were randomly assigned to receive placebo or extended-release vitamin C (2 g/day) (4), with crossover to the other treatment after a week. After CV, patients were maintained on the same regimen as immediately before the procedure, with crossover to the other regimen after a week. At the end of each of these periods, we determined, in all patients, plasma renin activity, serum aldosterone and catecholamine concentrations, and performed vascular and ergoreflex studies. On all occasions, studies were carried out twice, at 3 and 5 h after the last dose was administered, respectively, and averages of the results were taken as representative values.


Figure 1
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  		Fig. 1. Schematic presentation of study design. PRA, plasma renin activity.

 
The study was double-blind relative to the drug regimen, and investigators who read the results were blind to the study design and purposes.

Statistical analysis. Values are expressed as means ± SD. Patient characteristics at baseline were compared using an unpaired t-test or Fisher's exact test. Differences in FMD dilatation of the brachial artery and ergoreflex contribution to ventilation between placebo and active vitamin C and between AF and sinus rhythm states were analyzed by paired t-test. A repeated-measures ANOVA test and Newman-Keuls multiple-comparison procedure were used for testing differences among groups and between pre- and post-CV evaluations. A P value <0.05 was considered significant. Statistical analyses were performed by means of Stata 7.0 package.


   RESULTS
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 RESULTS
DISCUSSION
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Table 1 summarizes the clinical and echocardiographic characteristics of the study patients. Higher levels of systemic blood pressure in group 2 (values in Table 1 were those detected after withdrawal of the antihypertensive treatment) were the only statistically significant difference among groups. Aldosterone and norepinephrine concentrations and plasma renin activity were within normal limits in each group (Table 2). Antioxidant enzyme activity was determined in a limited number of patients in each group and showed a trend toward an increase of allantoin and a decrease of glutathione peroxidase, from group 1 to group 2 to group 3 (Table 3). A trend in the activity of both enzymes toward improvement after CV was also seen in groups 1 and 2 but not in group 3.


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  		Table 1. Clinical and echocardiographic data

 

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  		Table 2. Humoral data in the three cohorts at the various study steps

 

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  		Table 3. Antioxidant enzyme activity before and after CV

 
Vascular studies. Results of vascular studies are reported in Table 4. It did not matter if vitamin C was given before or after placebo and data were pooled together independently of the administration sequence. The baseline brachial artery lumen diameter was similar among groups and in no cases did it vary significantly with CV for subjects receiving placebo or vitamin C. Absolute and percent FMD before CV for subjects receiving placebo was significantly lower in groups 2 and 3 than in group 1. In group 1 patients and, to a lesser extent, group 2 patients receiving placebo, FMD and the ratio of changes in the artery lumen to changes in flow significantly improved with restoration of sinus rhythm. When compared with placebo, the antioxidant vitamin C produced results qualitatively similar to those when given before CV. Vitamin C did not cause any further improvement after CV in addition to that produced by restoration of sinus rhythm. In group 3, neither CV nor vitamin C affected FMD. As shown in Table 2, plasma renin activity, aldosterone, and norepinephrine remained steady at the various study steps.


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  		Table 4. Vascular assessments

 
Metaboreflex evaluation. Figure 2 illustrates the patterns of ventilation in groups 1, 2, and 3 in the presence of AF while at rest, during handgrip, and in recovery, without and with blood flow stasis by cuff inflation while on placebo and vitamin C. Figure 3 illustrates the patterns of ventilation with the same methods while on placebo, before and after restoration of sinus rhythm. A significant difference in ventilation between recovery with posthandgrip circulatory occlusion and recovery without posthandgrip circulatory occlusion reflects the metaboreflex component of the ventilatory response to exercise. In groups 2 and 3, the difference was greater than in group 1, and in groups 1 and 2 it was lost with vitamin C and with CV. Group 3 was refractory to either remedy.


Figure 2
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  		Fig. 2. Mean values of ventilation (VE) in groups 1, 2, and 3 at rest and during handgrip (5 min) and recovery (3 min) of metaboreflex test, before cardioversion (CV) to sinus rhythm, while receiving placebo and after vitamin C. *P < 0.01 vs. no occlusion; §P < 0.05 vs. corresponding value in group 1.

 

Figure 3
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  		Fig. 3. Mean values of VE for groups 1, 2, and 3 at rest and during handgrip (5 min) and recovery (3 min) of metaboreflex test, before and after cardioversion (CV) to sinus rhythm, while receiving placebo. *P < 0.05 vs. no occlusion; §P < 0.01 vs. corresponding value in group 1.

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Vascular tests performed for subjects receiving placebo before CV confirm that FMD further worsens when AF is associated with hypertension and diabetes, diseases that cause endothelial dysfunction (7, 9). This report provides the new information that the more severe the baseline endothelium impairment, the larger the exercise stimulation of the metaboreceptors. The ergoreflex, in fact, was significantly more activated in the comorbidity groups compared with the lone AF group.

FMD and CV. As already reported, CV was able to improve FMD in AF alone (8, 10, 27) or associated with high blood pressure, and not when combined with diabetes mellitus (7). This study shows, for the first time, that the ergoreflex is attenuated when FMD is augmented with CV (groups 1 and 2) and is unchanged when FMD remains unvaried (group 3). Before inferring that there is a link between the two variables, it should be critically discussed whether, in this experimental setting, FMD actually identifies with endothelial activity; the mechanisms of its improvement should also be analyzed.

In an interpretation of the factors underlying enhancement of conduit artery FMD, an important but often overlooked issue is that any process that reduces the arterial lumen could affect the measured responses to flow, without true impact on endothelial function, due to the inverse relationship between the baseline diameter and its flow-mediated increase (29). Such a mechanism can confidently be ruled out in this study, because baseline brachial artery variations at any step were insignificant in all the patient cohorts. Sinus rhythm decreases the myocardial metabolic requirement, prolongs the time for ventricular filling, and restores the booster pump properties of the atria so that cardiac performance, peripheral blood flow distribution, and endothelium-mediated vasodilation may be improved. Presumably, these changes occurred in all patient groups; group 3, however, failed to benefit from CV. Yet, similar responses to nitroglycerine (data not shown) before and after CV document that the endothelium-independent vasorelaxation is comparable. An irregular ventricular activity due to AF increases the neural adrenergic discharge and may cause a neural imbalance (30). CV would attenuate the adrenergic traffic and restore the endothelial counterregulatory function (31). This mechanism may be consonant with results with CV in groups 1 and 2 but not with those in group 3. A role for plasma renin activity, aldosterone, or norepinephrine is unlikely, because these factors did not change according to FMD with CV. On the other hand, previous studies have shown that, in AF, acetylcholine increases forearm blood flow, NO availability, plasma concentration of stable NO products like nitrite and nitrate, and endocardial nitric oxide synthase expression (27, 3). Finally, and even more significantly, results with the antioxidant vitamin C strongly support an involvement of oxidative injury in endothelial dysfunction in human AF. In this respect, it is remarkable that, at the time of the study, any drug treatment potentially interacting with the antioxidant endothelium-protective activity of vitamin C had been withheld. From all these considerations, we draw the following inferences. 1) Changes in FMD with CV actually reflect endothelial activity. 2) Variations in the flow pattern (21) and/or oxidative stress (8) (see also the antioxidant enzyme activities in Table 3) with reversion to sinus rhythm modulate the vascular endothelial function and promote its improvement. 3) Restoration of an organized atrial contraction that avoids atrial production of superoxide (7) and oxidative injury (16) could play a contributory role. 4) A link does exist between endothelial function and exercise ergoreflex activation.

CV and vitamin C in comorbidities. Vitamin C, a rather weak antioxidant, could restore FMD most in lone AF, less in AF with hypertension, and not at all in AF with diabetes. Consistently, even if reversion to sinus rhythm invariably restores conduit artery regular pulsatile blood flow, FMD after CV increased less in the hypertension group than in the lone AF group and did not improve at all in the diabetes group. These results are consonant with the pattern shown by the antioxidant enzyme activity and may suggest that the oxidative injury is lower in hypertension than in diabetes. AF exerts an additive endothelial depressive influence in the former and not in the latter comorbidity, in which the restrain of the background nitric oxide activity is probably such to impede any additive or synergistic effect.

Endothelium-ergoreflex link. In a previous study (9) that was performed in similar categories of patients, we found that the ventilatory efficiency (steep slope of the ventilation to carbon dioxide output relationship) was invariably compromised, the arterial carbon dioxide pressure was reduced, and both were brought back toward normal by CV in the lone AF and the hypertension groups. Because lung function and arterial oxygen saturation were within normal limits and were not affected by CV, we deduced that, in the presence of AF, exercise was associated with an early intervention of extrapulmonary factors increasing the ventilatory response. This mechanism was abolished in patients whose endothelial activity benefited from CV. The present study indicates metaboreceptors as the extrapulmonary factors that impair ventilatory efficiency when endothelial dysfunction causes exercising muscle underperfusion. An impaired endothelial responsiveness to vascular shear stress and lack of a physiological vasodilation, which maintains elevated the impedance to left ventricular ejection and prevents an adequate increase of stroke volume, are suggested as possible reasons of exercising muscle perfusion inadequacy in AF.

Clinical perspectives. In chronic heart failure, group IV efferents from skeletal muscles have been hypothesized to play a significant role in the generation of breathlessness and in the progress of the disease (11, 24, 25). The present study demonstrates that the metaboreceptor contribution to exercise ventilation is significantly enhanced in patients with AF (10) and provides the information that CV modulates the ergoreflex in AF alone or when it is associated with high blood pressure. This may offer an explanation for the impairment in similar patients in ventilatory efficiency and for the ability of CV to correct these inconveniencies in the former two conditions and not in patients with diabetes as a comorbid disease (7).


   GRANTS
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 ABSTRACT
 METHODS
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 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by a University of Milano FIRST Grant 2004 (to M. Guazzi), a grant from Piera Almini Radice in memory of Bruno Rinaldo Radice, and a grant from the Monzino Foundation.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. Guazzi, Endothelial Function and Cardiopulmonary Unit, Cardiology Division, Univ. of Milano, San Paolo Hospital, Via A. di Rudinì 8, 20142 Milan, Italy (e-mail: marco.guazzi{at}unimi.it)

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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