Endothelial dysfunction and underperfusion of exercising muscle contribute to exercise intolerance, hyperventilation, and breathlessness in atrial fibrillation (AF). Cardioversion (CV) improves endothelial function and exercise performance. We examined whether CV is equally beneficial in diabetes and hypertension, diseases that cause endothelial dysfunction and are often associated with AF. Cardiopulmonary exercise and pulmonary and endothelial (brachial artery flow-mediated dilation) function were tested before and after CV in patients with AF alone (n = 18, group 1) or AF with hypertension (n = 19, group 2) or diabetes (n = 19, group 3). Compared with group 1, peak exercise workload, O2 consumption (V̇o2), O2 pulse, aerobic efficiency (ΔV̇o2/ΔWR), and ratio of brachial diameter changes to flow changes (ΔD/ΔF) were reduced in group 2 and, to a greater extent, in group 3; exercise ventilation efficiency (V̇e/V̇co2 slope) and dead space-to-tidal volume ratio (Vd/Vt) were similar among groups. CV had less effect on peak workload (+7% vs. +18%), peak V̇o2 (+12% vs. +17%), O2 pulse (+33% vs. +50%), ΔV̇o2/ΔWR (+7% vs. +12%), V̇e/V̇co2 slope (−6% vs. −12%), ΔD/ΔF (+7% vs. +10%), and breathlessness (Borg scale) in group 2 than in group 1 and was ineffective in group 3. The antioxidant vitamin C, tested in eight additional patients in each cohort, improved flow-mediated dilation in groups 1 and 2 before, but not after, CV and was ineffective in group 3, suggesting that the oxidative injury is least in lone AF, greater in hypertension with AF, and greater still in diabetes with AF. Comorbidities that impair endothelial activity worsen endothelial dysfunction and exercise intolerance in AF. The advantages of CV appear to be inversely related to the extent of the underlying oxidative injury.
atrial fibrillation (AF) impairs endothelial function and downregulates nitric oxide (NO) production (3, 10, 27). Exercise correlates of these dysfunctions are underperfusion of working muscle, hyperventilation, and breathlessness (10). These findings are consistent with the concept that, during exercise, an endothelium-mediated vasodilation modulates neurogenic vasoconstriction, increases arterial conductance, and upregulates muscle perfusion (6, 12, 16). Conversion to sinus rhythm [i.e., cardioversion (CV)] is beneficial in this respect (10). Irregular pulsatile blood flow in AF may impair the endothelial responsiveness to vascular shear stress, and loss of the cyclic stretch of atrial endocardial cells may decrease expression of NO synthase (3). Restoration of a regular flow regimen and atrial contactile activity with CV normalizes the endothelial physiology.
Hypertension and diabetes cause endothelial dysfunction (13, 20, 23, 26). Because AF is not uncommonly associated with high blood pressure and diabetes, we considered the pathophysiological and clinical significance of this association to investigate whether the improvement of endothelial function with CV, its exercise pathophysiological correlates, and the mechanisms that underlie the improvement are the same as in patients with lone AF.
To clarify these points, we examined cardiopulmonary exercise performance and brachial artery flow-mediated vasodilation (FMD) in patients with lone AF and patients with type 2 diabetes mellitus or high blood pressure as comorbid diseases. Because the increased metabolic burden that develops in the fibrillating myocyte suggests that augmented production of reactive oxygen species (ROS) is likely in AF (21), we investigated results with the antioxidant vitamin C in some patients to determine whether ROS are involved in endothelial impairment in AF and in the response to CV. Studies were performed before and after CV in all cases and after AF relapse in a few instances.
The population consisted of patients with lone AF (n = 18, group 1) and patients with AF and high blood pressure (n = 19, group 2) and with AF and diabetes mellitus (n = 19, group 3) as comorbid diseases. Eight additional patients in each group, with similar clinical characteristics, were involved in a trial with the antioxidant vitamin C. Total cholesterol was >6.2 mmol/l and triglycerides were >2.3 mmol/l in 38%, 42%, and 42% of patients in groups 1, 2, and 3, respectively. AF was defined as ambulatory ECG evidence of fibrillation in the last two consecutive follow-up visits, separated by a 1-mo interval. Patients were recruited if they had no significant valvular heart disease, previous myocardial infarction, angina pectoris, lung abnormalities, claudication, or any other factor potentially interfering with maximal exercise testing performance; if the New York Heart Association functional class did not exceed class II; if they were not >65 yr of age; if the duration of hypertension and diabetes could be determined; and if AF was known for ≤3 mo. Blood pressure (mean of 3 measurements, each performed on 3 separate days) was >140/90 and ≤160/105 mmHg in the hypertensive patients; clinical blood pressure with the patient seated was measured after 15 min of rest; diastolic blood pressure was read as phase V of Korotkoff sounds. All patients had a family history of high blood pressure and 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. The duration of hypertension averaged 5.5 ± 3.7 yr. Among the patients, 8 were untreated and 11 had received one or more antihypertensive agents for ≥2.5 yr. The treated patients were asked to discontinue medications 2 wk before the studies and were closely monitored for any evidence of accelerated hypertension (>10 mmHg increase of diastolic pressure). We excluded patients in whom it was deemed hazardous to withhold treatment (mostly because of the poor response to the current therapy). Type 2 diabetes mellitus was diagnosed according to the criteria reported by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (1). These patients were aware of their diabetic condition for 4.1 ± 1.6 yr. They had no history of cardiovascular disease but did have a history of AF; their weight and fasting glucose levels were stable over 4 wk before enrollment; diabetes control was achieved by diet alone (n = 7) or diet plus sulfonylurea or biguanide preparations (n = 12); they were not receiving lipid-lowering agents or antioxidant vitamins; they had no known coronary or peripheral vascular disease, diabetic retinopathy, clinically evident distal symmetric neuropathy, or autonomic insufficiency (8); and their glycosylated hemoglobin levels were <7% with therapy. Among the vitamin C trial patients with high blood pressure, the duration of hypertension averaged 5.2 ± 3.1 yr, and three were untreated and five had received antihypertensive treatment for ≥3 yr. Among the diabetic patients, diabetes was controlled with diet alone in two patients and oral antidiabetic preparations in six patients.
In all patients, anticoagulant therapy maintained prothrombin time within a target of 1.7–2.0 times control. No patients were receiving β-blockers; 50% were taking digoxin, and 28% were taking verapamil. All had a <10-pack-yr index of smoking and had abstained from tobacco products over the last 8 mo (17). Cardioactive agents were withheld for at least five half-lives before cardiopulmonary exercise testing and vascular studies. All subjects gave written informed consent before enrollment; the protocol was approved by the local ethics committee.
We performed imaging studies of the brachial artery with a high-resolution ultrasound 11-MHz linear-array transducer (Philips Medical System). Anatomic landmarks were noted on the clearest view of the artery, the skin was marked, and the transducer was held in position by a stereotactic clamp. Images were obtained by the same investigator throughout the study. 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 was used to assess vasodilation. Arterial diameter was measured in millimeters, coincident with the R waves on the ECG, for six cardiac cycles, and the six measurements were averaged. The vasodilator response from repeated studies was evaluated by an individual who was blinded to the sequence; images were stored in a video format and then analyzed with 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 obtained 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 × 100] maximal increase in diameter during reactive hyperemia compared with baseline.
Cardiopulmonary exercise tests.
Each patient performed a progressively increasing (personalized protocol) work rate (WR) cardiopulmonary exercise test (CPET) to maximum tolerance on an electromagnetically braked cycle ergometer. Gas exchange was analyzed (Cardiopulmonary Metabolic Cart, Sensormedics Vmax Spectra) at rest (3 min), during 2 min of unloaded cycling at 60 rpm, throughout exercise, and during 3 min of recovery. ECG (12-lead) and cuff blood pressure were recorded. Respiratory gases were sampled continuously from a mouthpiece, and minute ventilation (V̇e), CO2 output (V̇co2), O2 consumption (V̇o2), dead space-to-tidal volume ratio (Vd/Vt), respiratory exchange ratio, and other exercise variables were calculated breath-by-breath by computer, interpolated second-by-second, and averaged at 10-s intervals (31). The anaerobic threshold (AT) was derived by V̇-slope analysis. Exercise ventilatory efficiency was assessed by calculating the slope of the increase in ventilation with respect to V̇co2 (V̇e/V̇co2 slope). The rate at which V̇o2 increased per work rate (ΔV̇o2/ΔWR), as an indicator of aerobic efficiency, and the O2 pulse (as an index of changes in stroke volume) were determined as previously described (11). O2 arterial saturation was monitored by an ear oximeter (Sensormedics). Arterial Pco2 (PaCO2) was estimated from the end-tidal Pco2 (PetCO2) as gauged from the formula of Jones et al. (14). Peak V̇o2 was determined by the highest V̇o2 achieved during exercise. Exercise breathlessness (defined as an uncomfortable or unpleasant respiratory-related sensation that normally develops during exercise) was graded with the Borg scale (2); symptoms were related to V̇e by plotting the Borg score against V̇e and calculating the slope of this relation for each test (V̇e-Borg score slope).
Two-dimensional and Doppler cardiac ultrasounds were obtained 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.
External CV was performed under light anesthesia with thiopental sodium. CV was synchronized with a 200-J or, if necessary, a 300-J, shock. ECG was monitored continuously, and ventilation was assisted.
At 8–10 days before external CV, patients who were not involved in the vitamin C trial performed a maximal CPET on 1 day, and, on the following day, a vascular study was performed. These tests, which were carried out to familiarize the patients with the procedure, were repeated 5 and 4 days before CV, respectively. The latter results were taken as representative values. At 3 wk after persistent restoration of sinus rhythm, as defined by ambulatory ECG evidence of sinus rhythm at weekly follow-up visits, the above-mentioned procedures were repeated by each patient. The protocol was repeated in the patients in whom AF recurred in the next 2 wk (5 in group 1, 7 in group 2, and 6 in group 3). Patients involved in the vitamin C trial were randomized to receive extended-release vitamin C (2 g/day) (4) or placebo (capsules of identical appearance) in the 4 days preceding CV and in the last 4 days of a 3-wk follow-up after persistent restoration of sinus rhythm. In these patients, vascular assessments and exercise peak workload and peak V̇o2 were measured before administration of vitamin C or placebo and 3–4 h after the last dose was administered, before CV and at the end of follow-up. On each occasion, vasomotility and exercise performance were measured twice, with 2 h between the measurements.
Investigators who read the results were blind to study design and purposes.
Value are means ± SD. Patient characteristics at baseline were compared using an unpaired t-test or Fisher’s exact test. CPET differences between AF and sinus rhythm states, as well as changes in V̇e/V̇co2 slope, and V̇e-Borg score slope, were analyzed by paired t-test. Repeated-measures ANOVA and Newman-Keuls multiple comparison procedure were used to test differences among groups and between pre- and post-CV evaluations. P < 0.05 was considered significant. Statistical analyses were performed using Stata 7.0.
Table 1 summarizes the clinical and echocardiographic characteristics of the patients. The only statistically significant difference consisted of higher levels of systemic blood pressure in group 2 (pressure values in Table 1 were those recorded after treatment was withdrawn).
These variables are reported in Table 2. Before CV, peak workload, peak V̇o2, and O2 pulse in patients with comorbidities were reduced compared with patients with AF alone. CV in group 1 and, to a lesser extent, group 2 was associated with an increase in exercise workload, peak V̇o2, O2 pulse, aerobic (increase of ΔV̇o2/ΔWR) and ventilatory (decrease of V̇e/V̇co2 slope) efficiencies, and PetCO2. None of these parameters improved significantly with CV in group 3. No changes in arterial O2 saturation, peak V̇e, peak respiratory exchange ratio, and Vd/Vt were observed in any group. The findings that all subjects exercised above their AT and achieved a high peak respiratory exchange ratio indicate that patients in the three groups had developed a significant metabolic acidosis and had exercised at high work intensity. Figure 1 shows that the slopes of the V̇e/V̇co2 and V̇e-Borg scale relations were significantly diminished by CV in groups 1 and 2, but not in group 3. After restoration of regular cardiac rhythm, an increase was observed in PetCO2 for any matched exercise time, despite no changes in Vd/Vt, in groups 1 and 2, but not in group 3 (Fig. 2).
The heart rate response to exercise was comparable among the groups before and after CV. Systolic and diastolic blood pressures were elevated at rest in group 2 compared with group 1. All patients exhibited increased systolic blood pressure at peak exercise compared with pre-CV values.
In group 1, baseline arterial diameter was not affected by restoration of sinus rhythm, and FMD and the ratio of changes in lumen diameter to changes in flow were definitely improved (Table 3). In groups 2 and 3, there were no significant variations in the baseline brachial arterial lumen diameter after restoration of sinus rhythm; absolute and percent increases in FMD were improved in group 2 and remained similar to those on AF in group 3; the ratio of changes in lumen diameter to changes in flow did not vary significantly with CV in group 3 (Table 3).
In some patients in each group, AF relapsed after restoration of sinus rhythm. Interestingly, in these patients, CPET variables and endothelial function reverted to pre-CV levels in groups 1 and 2 after fibrillation relapse (Table 4).
Vitamin C trial.
Eight additional patients in each group were randomized to receive vitamin C or placebo and investigated in the control condition and after receiving the active or the inactive preparation, before and after reversion to sinus rhythm. Results are summarized in Table 5. In either condition, placebo did not change FMD and exercise performance. Administration of the active preparation, on the contrary, was associated with improvement of brachial artery FMD, ratio of changes in arterial lumen diameter to changes in flow, peak exercise workload, and V̇o2 in groups 1 and 2. In these patients, vitamin C did not further contribute to improvement of these variables produced by CV. Patients in group 3 were refractory to vitamin C as well as to sinus rhythm restoration.
AF interferes with endothelial function (10, 27) and exercise capacity (9, 18, 19, 24), and a pathophysiological link seems to exist between the two variables (10). Our results have provided evidence that sinus rhythm conversion restores endothelial function in patients with lone AF and is partially effective (hypertension) or ineffective (diabetes) in those with comorbidities that cause endothelial dysfunction. Another significant observation was that hypertension and diabetes interfere with baseline exercise performance (lower peak workload and V̇o2) and limit or prevent, respectively, its improvement with CV.
Mechanisms of endothelial dysfunction.
The precise mechanisms linking endothelium, AF, and CV are uncertain. In interpreting the mechanisms of an enhanced vasodilation, an important, but frequently neglected, point is that, because of the inverse relation between the flow-mediated increase in lumen and baseline arterial diameter (29), any process causing baseline constriction could affect the measured responses, without any true effect on endothelial function. Changes in baseline brachial artery lumen diameter after CV were insignificant in each patient group in our study. Irregular ventricular activity induced by AF increases the neural adrenergic traffic, which may become responsible for a neural imbalance (30). Restoration of sinus rhythm would modulate the neural discharge and return endothelial counterregulatory activity to normal (28, 32). This mechanism, however, might be consistent with findings in groups 1 and 2, but not group 3.
Hemostatic conditions associated with AF (3) and interfering with NO synthase expression might be hypothesized as a link between endothelial activity and AF. A solid experimental background indicates that variations in oxidative stress (7) or in the flow pattern (21) secondary to restoration of sinus rhythm can modulate vascular endothelial function and contribute to the improvement observed after CV. On the other hand, the left atrium is an important source of circulating forms of NO, because the atrial endocardium serves as an endocrine organ to modulate vascular function (3) and organized atrial contraction is needed to prevent atrial production of superoxide (5) and oxidative injury (15).
Despite a return to regular pulsatile blood flow with CV in all study groups, FMD improvement was less pronounced in group 2 than in group 1 and did not occur in group 3. A difference between high blood pressure and diabetes with regard to the physiology of the endothelium in the presence of AF seems plausible. Endothelial function was restored by vitamin C, a rather weak antioxidant, to the greatest extent in patients with lone AF, to a lesser extent in those with high blood pressure and AF, and not at all in those with diabetes and AF. This may suggest that oxidative injury is the least in patients with lone AF, greater in patients with hypertension, and greater still in patients with diabetes and that more potent antioxidants may be required to counteract the effects of ROS formation in disease states associated with more extensive oxidative injury.
The positive response to CV in hypertension demonstrates that AF has an additive depressive effect on endothelial activity in hypertensive patients. In diabetic patients, on the contrary, the inefficacy of CV in FMD would suggest that the background inhibition of NO activity in diabetes overcomes any synergistic or additive effect of AF.
Exercise performance and gas exchange.
CV in the patients with lone AF was associated with an increase in peak workload, V̇o2, O2 pulse, and ΔV̇o2/ΔWR. These results confirm that AF limits the physical performance (24) and suggest that restoration of sinus rhythm improves exercise stroke volume, peripheral blood flow distribution, and aerobic efficiency. The observed changes imply that the atrial contribution to ventricular filling improves cardiac performance, that extracardiac factors are involved in the overall exercise limitation, and their influence may be attenuated or abolished by CV. Peak workload, V̇o2, and O2 pulse were lower in groups 2 and 3 at baseline, and improvement of these parameters with reversion to normal rhythm was less than in group 1. ΔV̇o2/ΔWR was similar in all groups and did not change significantly with sinus rhythm. The discrepancies are not explained by group differences in sex, age, somatic characteristics, left ventricular and atrial dimensions, ejection fraction, pulmonary arterial pressure at rest, and heart rate and blood pressure responses to exercise.
Another main finding is that all groups presented with similar impairment in ventilatory efficiency and similar reduction of PetCO2 for any matched exercise time. CV, however, was beneficial only in groups 1 and 2. Several factors may underlie an augmented ventilatory response to exercise. The slope of the V̇e/V̇co2 relation, in fact, is determined by the amount of CO2 produced, PetCO2, and Vd/Vt. It follows that, for a given V̇co2, a steep V̇e/V̇co2 slope may be due to an increased Vd/Vt and/or a low PaCO2. A low PaCO2 originates from an augmented central or peripheral chemoreceptor command to ventilation, which drives PaCO2 below the physiological range, or from an early increase of metabolic by-products that demands ventilatory compensation. Considering that arterial O2 saturation and Vd/Vt were within a normal range and were not affected by CV and that PetCO2 (taken as an index of PaCO2) was reduced over the duration of exercise and increased significantly in groups 1 and 2 after restoration of sinus rhythm, we deduce that 1) exercise is associated with an early intervention of extrapulmonary factors, increasing the ventilatory response, 2) a low PaCO2 is likely influenced by an excessive exercise ventilation, and 3) CV is able to correct these complications in group 1, only in part in group 2, and not at all in group 3.
Endothelium and its pathophysiological correlates.
We suggest that a major pathophysiological correlate of impaired endothelial responsiveness to vascular shear stress in AF is underperfusion of exercising muscle, which contributes to a peripheral reflex increase in ventilation. Some considerations corroborate this view. AT occurred at V̇o2 significantly lower during AF than after CV; V̇co2 and H+ are powerful stimuli to ventilation (25) and account for hyperventilation and breathlessness for any matched workload. Exercise peak V̇o2 was increased in patients showing improvement in brachial artery FMD after treatment with the antioxidant vitamin C. Full restoration of normal vascular shear stress responsiveness and exercising muscle perfusion in group 1 and partial restoration in group 2 can well represent a background difference in the effects of CV on the peripheral contribution to hyperventilation and breathlessness among the groups.
An intuitive factor for a reduced exercise capacity in AF is the failure of cardiac performance to meet metabolic requirements. The mechanisms whereby restoration of sinus rhythm can improve cardiac performance are restitution of the booster pump properties of the atria, prolongation of the time for ventricular filling, possible decrease of the myocardial V̇o2, and atrioventricular valve regurgitation. Presumably, these changes were common to patients in all groups. Nonetheless, improvement in peak workload, V̇o2, ΔV̇o2/ΔWR, and O2 pulse after CV was less in the presence of comorbidity. It is true that these discrepancies may be related to altered myocardial contractile properties in groups 2 and 3 because of the systemic diseases (1a, 22). It is tempting, however, to consider in this context a role also for the disordered endothelium, because the lack of a physiological vasodilation on exercise could lead to an elevated impedance to left ventricular ejection, thus preventing an adequate increase in stroke volume (O2 pulse augmented by 50% in group 1, 33% in group 2, and 23% in group 3) and keeping the myocardial metabolic requirement high.
Laboratory techniques were not performed to characterize the release of relaxing paracrine agents. Invasive measurements were discouraged, and more precise evaluation of cardiac function in different circumstances was not performed. For the same reasons, changes in PaCO2 during incremental exercise and for Vd/Vt calculation were not directly measured; however, a normal lung diffusion capacity (94% of normal predicted in group 1, 92% in group 2, and 93% in group 3) with a normal alveolar-capillary membrane conductance makes the estimation of PaCO2 by PetCO2 highly reliable.
In conclusion, AF impairs endothelial activity as well as the cardiopulmonary response to exercise, and CV is beneficial. Comorbidities causing endothelial dysfunction exacerbate the effects of AF on vascular function and exercise and limit the advantages of CV. With respect to our data, the advantages of CV seem to be inversely related to the extent of the underlying oxidative injury.
This study was supported by a University of Milan FIRST Grant 2004 to M. Guazzi and by a grant from Piera Almini Radice in memory of Bruno Rinaldo Radice.
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