Assessing baroreflex sensitivity by the transfer function method: what are we really measuring?
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Biomedical subjects
Publications and source records attributed to Gian Domenico Pinna.
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BACKGROUND: The Home or Hospital in Heart Failure Study (HHH) is a European Community funded trial (QLGA-CT-2001-02424) which compares usual care of heart failure (HF) with three home-based interventions in a multicenter, multicountry (Italy, Poland and UK), randomized controlled clinical trial. Home telemonitoring (HT) of clinical parameters represents a potential alternative (or addition) to traditional home care models. Nocturnal respiratory disorders (periodic breathing, sleep apnea) are very common in HF, and are associated with increased morbidity and mortality. We developed an integrated HT system for monitoring of both vital signs and respiration. All measurements were patient-managed. This paper describes the architecture of this system, and assesses its feasibility. METHODS AND RESULTS: 461 clinically stable patients were randomized first to usual vs home-monitored care; the latter were further randomized to 3 strategies. Over a 12-month follow-up 2 of these 3 groups (195 patients, age: 60+/-11 years, NYHA class II-III: 97%, LVEF 28+/-7%) underwent self-administered home monitoring of vital signs (weekly--12 parameters using an interactive voice response system) and respiration (monthly--24-hour recording). Data were transmitted over conventional telephone lines; 81% of actually practicable vital signs measurements were completed by the patients (range: 75% (PL)-93% (UK)), as well as 92% of practicable respiratory recordings (range: 85% (PL)-99% (UK)). 87% of nighttime recordings were eligible for the study (good quality signals for > or = 2.5 h). CONCLUSIONS: This study, the largest so far, demonstrates that self-managed home telemonitoring of both vital signs and respiration is feasible in HF patients, with surprisingly high compliance. We found an excellent rate of acceptable nocturnal respiratory recordings, which are those with the greatest clinical relevance.
We assessed the clinical correlates of a comprehensive set of non-linear heart rate variability (HRV) indices computed from 24-h Holter recordings for 200 stable chronic heart failure (CHF) patients [median age (lower quartile, upper quartile) 54 (47, 58) years, LVEF 23% (19%, 28%)]. A total of 19 non-linear indices belonging to six major families, namely symbolic dynamics, entropy, empirical mode decomposition, fractality-multifractality, unpredictability and Poincaré plots, were considered. Most indices showed a significant association with ejection fraction and with the severity of symptoms, while only two (one each from the fractality and Poincaré plot families) showed an association with aetiology. Only one symbolic dynamics variable was associated with the presence of non-sustained ventricular tachycardia and two symbolic dynamics variables were associated with the rate of ventricular ectopic events. Our results demonstrate the existence of selective links between non-linear indexes of HRV and the clinical status and functional impairment of CHF patients. This indicates that further studies should be designed to investigate the physiopathological mechanisms involved in such links.
OBJECTIVES: We sought to assess applicability, clinical correlates, and prognostic value of the transfer function method for measuring baroreflex sensitivity (TF-BRS). BACKGROUND: Abnormalities in autonomic reflexes play an important role in the development and progression of chronic heart failure (CHF). Simple and non-invasive techniques for clinical measurement of such reflexes are desirable. METHODS: In 317 stable CHF patients in sinus rhythm (median age [interquartile range]: 54 years [48 to 59 years], New York Heart Association [NYHA] functional class II to III: 88%, left ventricular ejection fraction [LVEF]: 27% [22% to 33%]) we recorded electrocardiograms and non-invasive arterial pressure during paced breathing to measure TF-BRS. RESULTS: Owing to a high number of ectopic beats, TF-BRS could be computed in 72% of the patients; TF-BRS was lower in NYHA functional class III to IV and mitral regurgitation 2 to 3 (p < 0.0005 for both). Correlation with LVEF and standard deviation of all normal-to-normal intervals was 0.18 and 0.31 (p < 0.001 for both). During a mean follow-up of 26 months, 23% of the patients experienced a cardiac event. A depressed TF-BRS (< or =3.1 ms/mm Hg) was significantly associated with the outcome (hazard ratio 3.2, 95% confidence interval [CI] 1.7 to 6.0, p = 0.0003). Patients with a missing TF-BRS had a high event rate (36%). Combining this information with available TF-BRS measurements, a new prognostic index could be computed in 97% of the patients that significantly predicted the outcome after adjustment for clinical and functional variables (hazard ratio 2.5, 95% CI 1.3 to 4.6 p = 0.004). CONCLUSIONS: In CHF patients in sinus rhythm, TF-BRS conveys relevant clinical and prognostic information, but its measurability is markedly affected by ectopic activity. Nevertheless, a TF-BRS-based risk index carrying significant and independent prognostic information can be computed in almost all patients.
BACKGROUND: The aim of the present study was to investigate the effect of a single bout of mild exercise on autonomic nervous system activity in healthy subjects. METHODS AND RESULTS: The study group comprised 18 healthy males, aged between 20 and 24 years, who had not been training regularly for the last 3 months. A supine recording of systolic arterial pressure (SAP) and RR interval and the administration of the phenylephrine test were performed at baseline and repeated after a 60-min recovery period following treadmill exercise training for 30 min at 65% of maximal heart rate. Mean SAP and RR interval, heart rate variability (HRV) indices (the standard deviation of normal-to-normal RR intervals (SDNN), the square root of the mean of squared differences between successive intervals and the percentage of adjacent RR intervals differing more than 50 ms), noninvasive spectral baroreflex sensitivity (Spe-BRS) and phenylephrine baroreflex sensitivity (Phe-BRS) were assessed before and after training. Mean SAP measured after exercise was lower than baseline (120+/-12 mmHg vs 128+/-12 mmHg, p = 0.05). Spe-BRS and Phe-BRS increased significantly after exercise, from 11.8+/-6.1 ms/mmHg to 16.0+/-7.8 ms/mmHg (p = 0.034), and from 16.0+/-8.8 ms/mmHg to 21.9+/-9.3 ms/mmHg (p = 0.022), respectively. A parallel increase was also observed in SDNN (from 81+/-44 ms to 96+/-53 ms, p = 0.02), but the other HRV indices showed no significant differences between pre- and post-exercise. CONCLUSIONS: A single session of mild exercise performed by sedentary young men leads to significant autonomic nervous system improvement, which suggests that even mild physical activity is beneficial for neural cardiac regulation and should be recommended to sedentary healthy subjects.
UNLABELLED: Initial response of human body to exercise consists of a decrease in vagal tone, followed by an increase in sympathetic activity. After exercise cessation, the parasympathetic component quickly regains its pre-exercise level, whereas signs of sympathetic activation have been reported to persist as long as 24 hours after intense exercise. AIM: To verify in a group of young marathon runners whether extreme endurance exercise may induce an increase of sympathetic activity for up to 48 hours during recovery. MATERIAL AND METHODS: Twelve athletes aged 32+/-12 years, taking part in a marathon (42 km) were studied. We measured baroreflex sensitivity using the transfer function method (BRS-WBA), as well as standard spectral indexes of short-term heart rate variability (LF and HF power, LFnu, LF/HF). These parameters were measured before the marathon and on the second day (about 48 hours) following the event. Comparisons were made between the two measurements (after vs. before). RESULTS: We found a statistically significant decrease in BRS-WBA (15.1+/-4.5 vs. 10.5+/-3.5 ms/mmHg, p=0.013), as well as a trend towards higher values of LF/HF (1.0+/-1.0 vs. 1.4+/-1.4, p=0.09). An increase in LF (from 1048+/-874 to 1427+/-1678 ms2) was observed, but it did not reach statistical significance. CONCLUSIONS: These results suggest that increased sympathetic activity can persist for up to 24 hours after an extreme endurance exercise such as a marathon. It is thus likely that in less trained and less physically active people exposed to excessive amounts of strenuous exercise, the autonomic nervous system response can be similar. Further studies are needed, however, to verify this inference.
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AIMS: To assess whether analysis of heart rate variability (HRV) from 24 h Holter recordings provides information about the mode of death (pump failure vs. sudden death) in chronic heart failure (CHF). METHODS AND RESULTS: We analysed 24 h HRV in 330 consecutive CHF patients in sinus rhythm. Indices derived from time domain, spectral domain, and fractal analyses of 24 h automatic HRV were evaluated. Data from clinical assessment, echocardiography, right heart catheterization, exercise test, blood biochemical examination, and arrhythmia pattern were analysed. Patients were followed up for 3 years. Two simple multivariable models, both including 24 h spectral indices, were able to identify patients at higher risk of progressive pump failure and sudden death, respectively. Depressed power of night-time HRV (< or = 509 ms(2)) below 0.04 Hz [very low frequency (VLF)], high pulmonary wedge pressure (PWP > or = 18 mm Hg) and low left ventricular ejection fraction (LVEF < or = 24%) were independently related to death for progressive pump failure, while the reduction of power between 0.04 and 0.15 Hz at night (LF < or = 20 ms(2)) and increased left ventricular end-systolic diameter (LVESD > or = 61 mm) were linked to sudden mortality. CONCLUSION: Automatic spectral analysis of 24 h HRV provides independent risk indices related to mode of death in sinus rhythm CHF patients.
In cardiovascular variability analysis, the significance of the coupling between two time series is commonly assessed by setting a threshold level in the coherence function. While traditionally used statistical tests consider only the parameters of the adopted estimator, the required zero-coherence level may be affected by some features of the observed series. In this study, three procedures, based on the generation of surrogate series sharing given properties with the original but being structurally uncoupled, were considered: independent identically distributed (IID), Fourier transform (FT), and autoregressive (AR). IID surrogates maintained the distribution of the original series, while FT and AR surrogates preserved the power spectrum. The ability of the three methods to define the threshold for zero coherence was validated and compared by computer simulations reproducing typical cardiovascular interactions. While the IID threshold depended only on record length and design parameters of the coherence estimator, FT and AR thresholds were frequency-dependent with peaks corresponding to the local maxima of the estimated coherence. FT and AR surrogates were able to compensate spurious coherence peaks due to equal-frequency but independent oscillations in the two series. The benefit of frequency-dependent thresholds was evident for short series with narrow-band oscillations. Thus, surrogates preserving the power spectrum of the original series are recommended to avoid false coupling detections in the presence of oscillations occurring at nearby frequencies but produced by different mechanisms, as may frequently happen in cardiovascular and cardiorespiratory regulation.
BACKGROUND: Recent data suggest that the electrophysiological study (EPS) has limited value in the identification of high risk patients, so the aim of the present study was to evaluate if non-invasive measurement of baroreflex sensitivity (BRS), a marker of autonomic balance, provides additional prognostic information in patients surviving a sustained arrhythmic episode. METHODS AND RESULTS: The study group comprised 112 post myocardial infarction patients consecutively referred for EPS following documented ventricular fibrillation (VF) (20), sustained ventricular tachycardia (VT) (74) or a syncopal episode with subsequently documented non-sustained VT at Holter monitoring (18). BRS was assessed according to the transfer function method. A cardioverter - defibrillator (ICD) was implanted in 97 patients. During follow-up (median 315 days), appropriate ICD discharge occurred in 53 patients, and 3 more patients died suddenly. Sustained VT was induced in 84% and 77% of patients who did or did not develop arrhythmia at follow-up (p=0.34). No differences were found in age, sex, infarct site, drug therapy, resting RR interval or cycle of induced VT. Left ventricular ejection fraction (LVEF) < or =35%, New York Heart Association (NYHA) class >2 and BRS < or =3.3 ms/mmHg were found to be univariate predictors of arrhythmia recurrence. Multivariate models were obtained after grouping patients according to a moderately or severely depressed LVEF. Among the patients with LVEF < or =35%, BRS < or =3.3 ms/mmHg emerged as the only significant risk predictor of arrhythmia occurrence (sensitivity, specificity, positive and negative predictive value = 79%, 74%, 83% and 68%, respectively), whereas NYHA class >2 was a significant predictor among patients with LVEF >35%. CONCLUSIONS: Noninvasive BRS, but not EPS, is of value in predicting VT/VF episode recurrence in patients surviving a major arrhythmic event.
STUDY OBJECTIVES: To describe the results of the 6-min walking test performed on admission to an intensive rehabilitation program after cardiac surgery and to develop, through an algorithm based on a few clinical indicators, reference tables in order to apply distance walked values more efficiently in the individual patient at his/her entry into a cardiac rehabilitation program. SETTING: Intensive cardiac rehabilitation units. PATIENTS AND INTERVENTION: A total of 2,555 consecutive patients admitted between January 2001 and December 2002 to the Cardiac Rehabilitation Department of the S. Maugeri Foundation early after cardiac surgery performed a 6-min walking test within the fourth day of hospital admission. RESULTS: The mean walked distance was 296 +/- 111 m (+/- SD). At multiple regression analysis, age, sex, and comorbidity were independent predictors of walking test performance. The left ventricular ejection fraction only influenced the walked distance in men. Starting from these variables, we propose an algorithm and specific reference tables. CONCLUSIONS: Reference values for gender-, age-, comorbidity-, and systolic function-related test performance in patients after cardiac surgery at the beginning of the rehabilitative phase are provided. Once a new patient has been categorized through simple parameters, the actual distance walked could be compared with the matched reference value, thus making the interpretation of the result more efficient. The walked distance might be used to define different levels of disability and to personalize therapeutic exercise prescriptions.
UNLABELLED: Baroreflex sensitivity (BRS), as assessed using phenylephrine method, and depressed 24-hour heart rate variability (HRV) have been shown to be powerful predictors of life-threatening ventricular arrhythmias. However, before these tests are widely used, their methodology has to be simplified. The aim of this study was to assess the prognostic value of simple non-invasive BRS parameter (Robbe index, BRS-RI) and short-term HRV, together with left ventricular ejection fraction (LVEF) and late potentials (LP) assessment in patients after myocardial infarction (MI) with documented history of ventricular tachycardia (VT) and ventricular fibrillation (VF). MATERIAL AND METHODS: The observation was conducted on 53 patients after MI with documented VT or VF. They were was divided into two groups: with or without recurrence arrhythmia. During the follow-up malignant ventricular arrhythmia events occurred in 31 patients VT/VF(+), no VT or VF was recorded in the 22 subjects VT/VF(-). In all patients the following parameters were analyzed: BRS-RI (transfer function, 0.07-0.14 Hz), HRV parameters such as: SDNN, rMSSD, pNN50, LF LF (NU), LF/HF. Additionally, LVEF and LP were assessed. RESULTS: In the VT/VF(+) and VT/VF(-) groups, values of analyzed parameters were: BRS-RI: 4.4 +/- 2.5 and 8.4 +/- 6.1 ms/mm Hg (p=0.03); BRS-RI < or = 3 ms/mm Hg: 8/15 and 2/16 (p=0.02); SDNN: 23.0 +/- 18.0 and 20.0 +/- 11.6 ms (p=0.99); rMSSD: 70.9 +/- 69.8 and 34.1 +/- 30.2 ms (p=0.34); pNN50: 10.7 +/- 14.6 and 4.4 +/- 9.0% (p=0.7); LF: 204.5 +/- 509.7 and 160.7 +/- 265.8 ms2 (p=0.95); LF (NU): 0.5 +/- 0.4 and 0.5 +/- 0.3 (NU) (p=0.77); LF/HF: 1.3 +/- 1.2 and 2.1 +/- 2.2 (p=0.49); LVEF: 32.5 +/- 9.1 and 39.8 +/- 13.3% (p=0.03); LP: 19/24 and 15/19 (p=0.99). The only indices of prognostic values were Robbe-index and LVEF. Their prognostic value in prediction of arrhythmic event occurrence was independent of each other's and of age, time elapsed from MI and number of MI (p=0.007). Non-diagnostic values of BRS-RI were found in 22 patients (42%). CONCLUSIONS: Among the evaluated indices, only LVEF and Robbe-index have prognostic value in prediction of life-threatening ventricular arrhythmia recurrence after myocardial infarction. However, a high percentage of non-diagnostic values obtained in BRS-RI assessment limits the usefulness of this index.
BACKGROUND: The predictive value of heart rate variability (HRV) in chronic heart failure (CHF) has never been tested in a comprehensive multivariate model using short-term laboratory recordings designed to avoid the confounding effects of respiration and behavioral factors. METHODS AND RESULTS: A multivariate survival model for the identification of sudden (presumably arrhythmic) death was developed with data from 202 consecutive patients referred between 1991 and 1995 with moderate to severe CHF (age 52+/-9 years, left ventricular ejection fraction 24+/-7%, New York Heart Association class 2.3+/-0.7; the derivation sample). Time- and frequency-domain HRV parameters obtained from an 8' recording of ECG at baseline and during controlled breathing (12 to 15 breaths/min) were challenged against clinical and functional parameters. This model was then validated in 242 consecutive patients referred between 1996 and 2001 (validation sample). In the derivation sample, sudden death was independently predicted by a model that included low-frequency power (LFP) of HRV during controlled breathing < or =13 ms2 and left ventricular end-diastolic diameter > or =77 mm (relative risk [RR] 3.7, 95% CI 1.5 to 9.3, and RR 2.6, 95% CI 1.0 to 6.3, respectively). The derivation model was also a significant predictor in the validation sample (P=0.04). In the validation sample, LFP < or =11 ms2 during controlled breathing and > or =83 ventricular premature contractions per hour on Holter monitoring were both independent predictors of sudden death (RR 3.0, 95% CI 1.2 to 7.6, and RR 3.7, 95% CI 1.5 to 9.0, respectively). CONCLUSIONS: Reduced short-term LFP during controlled breathing is a powerful predictor of sudden death in patients with CHF that is independent of many other variables. These results refine the identification of patients who may benefit from prophylactic implantation of a cardiac defibrillator.
INTRODUCTION: This is the first study to assess T wave alternans (TWA) analyzed from routine ambulatory electrocardiograms (AECGs) to identify postmyocardial infarction (post-MI) patients at increased risk for arrhythmic events. METHODS AND RESULTS: The new method of modified moving average (MMA) analysis was used to measure TWA magnitude in 24-hour AECGs from ATRAMI, a prospective study of 1,284 post-MI patients. Using a nested case-control approach, we defined cases as patients who experienced cardiac arrest due to documented ventricular fibrillation or arrhythmic death during the follow-up period of 21 +/- 8 months. We analyzed 15 cases and 29 controls matched for sex, age, site of MI, left ventricular ejection fraction, thrombolysis, and beta-blockade therapy. TWA was reported as the maximum 15-second value at three predetermined times associated with cardiovascular stress: maximum heart rate, 8:00 A.M., and maximum ST segment deviation. TWA increased significantly from baseline in both leads at each time point (P <<0.01) in cases and controls. TWA in V5 increased more in cases than controls during peak heart rate (P = 0.005) and at 8:00 A.M. (P = 0.02). A 4- to 7-fold higher odds of life-threatening arrhythmias was predicted by TWA level above the 75th percentile during maximum heart rate in leads V1 (odds ratio [OR] 4.2, 95% confidence interval [CI]: 1.1-16.3, P = 0.04) and V5 (OR 7.9, 95% CI: 1.9-33.1, P = 0.005). TWA at 8:00 A.M. also predicted risk in leads V1 (OR = 5.0, 95% CI: 1.2-20.5, P = 0.02) and V5 (OR = 4.2, 95% CI: 1.1-16.3, P = 0.04). CONCLUSION: TWA measurement from routine 24-hour AECGs is a promising approach for risk stratification for cardiac arrest and arrhythmic death in relatively low-risk post-MI patients.
We tested an innovative approach for estimating baroreflex sensitivity (BRS) from the gain function between spontaneous oscillations of systolic arterial pressure (SAP) and heart period (HP). The major goal was to assess the practical implications of abandoning the classical coherence criterion (> or =0.5) as regards measurability of BRS, and agreement with values of BRS obtained using the phenylephrine test (Phe-BRS). We studied 19 normal subjects, 44 patients with a history of previous myocardial infarction (MI) and 45 patients with chronic heart failure (CHF). The experimental protocol included recording of SAP and HP for 10 min of supine rest, and evaluation of Phe-BRS. From resting SAP and HP, the gain and coherence functions were computed. The new BRS index was obtained in all subjects by averaging the gain function over the whole low-frequency band (0.04-0.15 Hz) (whole-band average BRS, WBA-BRS). WBA-BRS was 7.4 (5.8-10.8) ms/mmHg [median (25th-75th percentile)] in normal controls, 3.1 (1.4-5.4) ms/mmHg in MI patients (P<0.001 compared with normals) and 5.0 (3.2-6.9) ms/mmHg in CHF patients (P<0.01 compared with normals). Using the coherence criterion, BRS could be measured in only 43% and 49% of MI and CHF patients respectively, and the proportion of the low-frequency band contributing to the measurement was 21% (14-47%) and 29% (16-35%) respectively. The correlation between WBA-BRS and Phe-BRS was 0.47, 0.63 and 0.36 in the normal, MI and CHF groups respectively (all P<0.001). The relative bias of WBA-BRS was -5.2 ms/mmHg (P<0.001) in normals, -1.4 ms/mmHg (P=0.004) in MI patients and -1.0 ms/mmHg (P=0.11) in CHF patients. The limits of agreement were -13 to 2.6, -7.4 to 4.6 and -9.3 to 7.3 ms/mmHg in the normal, MI and CHF groups respectively. Thus the WBA-BRS method standardizes the computation of BRS among subjects, and dramatically increases its measurability in subjects with pathology compared with the classical spectral technique based on the coherence criterion. Compared with Phe-BRS, WBA-BRS tends to give negatively biased results. The correlation and the magnitude of the limits of agreement between the two methods are similar to those observed previously using coherence-based spectral methods.