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Increased production of Heat Shock Proteins (HSP) is observed in the cells, including cardiomyocytes, to protect themselves against stress stimuli. These proteins, that appear to be involved in repair processes and have a number of cellular functions such as protein assembly and folding and transport crossing intracellular membranes, are also involved in cardiovascular diseases. Increased circulating levels of Hsp 60 as well as increased titers of antibodies against mycobacterial Hsp 65 have been found to be associated with different cardiovascular diseases. Chronic heart failure (CHF) is a situation of chronic stress, characterized by the presence of factors, such as cytokines, able to increase the HSP. The concentrations of HSP in the failing hearts are increased with respect to nonfailing hearts, both in humans and in animal models. However data about the presence of HSP or their antibodies in peripheral circulation in this situation are so far lacking. For this, circulating anti-mycobacterial 65kDa protein antibodies were evaluated in 78 patients with CHF (ejection fraction, LVEF, 33.6 ± 0.87, 54 in I-II NYHA class and 24 in III-IV class) and in 27 healthy subjects as control, by using an ELISA method. Scalar dilutions (from 1:100 to 1:1600) of each serum sample were assayed. Scalar dilution of a negative sample and of 2 different positive samples were also evaluated in each run for quality control purpose. Antibodies to Hsp 65 were found in the 70% of the patients with CHF (titres ranged from 1:100 to 1:1600) and in the 68% of controls (titres ranged from 1:100 to 1:400). Mean (±SEM) antibody titres resulted: 222 ± 32 in controls, 304 ± 43 and 408 ± 55 in CHF patients in I-II and III-IV NYHA class, respectively (p=0.035 III-IV class vs. controls by Fisher test after ANOVA). No significant association between antibody titre and degree of myocardial dysfunction, as assessed by LVEF, was found. The positive correlation of the anti-Hsp 65 titres with clinical severity (NYHA class) suggests a role for HSP in this disease, however the clinical relevance of this determination has to be assessed by the comparison with the distribution of anti-Hsp 65 antibodies in larger age- and sex-matched healthy population (whose recruitment is now in progress), as well as by the comparison with hemodynamic and biohumoral markers of CHF. 314 Heat shock protein 72 in heart failure

The question of whether respiratory sinus arrhythmia (RSA) originates mainly from a central coupling between respiration and heart rate, or from baroreflex mechanisms, is a subject of controversy. If there is a major contribution of baroreflexes to RSA, cardiocirculatory coupling during breathing and during cyclic baroreflex stimulation should show similarities. We applied a sinusoidal stimulus to the carotid baroreceptors and generated heart rate fluctuations of the same magnitude as RSA with a frequency similar to, but different from, the breathing frequency (0.2 Hz, compared with 0.25 Hz), and at 0.1 Hz, in 17 supine healthy subjects (age 28–39 years). The data were analysed using discrete Fourier-transform and transfer function analysis. Respiratory fluctuations in systolic blood pressure preceded RSA with a time lag equal to that between baroreceptor stimulation and oscillations in RR interval (0.62±0.18 s compared with 0.57±0.28 s at 0.2 Hz neck suction). The response of systolic blood pressure to neck suction at 0.2 Hz was 5 times less than the respiratory blood pressure fluctuations. Neck suction at 0.1 Hz largely increased fluctuations in blood pressure and RR interval, whereas the spontaneous phase relationship between blood pressure and RR interval remained unchanged. Our results are not consistent with the hypothesis that the origin of RSA is predominantly a central phenomenon which secondarily generates fluctuations in blood pressure, but suggest that, under the condition of fixed-frequency breathing at 0.25 Hz, baroreflex mechanisms contribute to respiratory fluctuations in RR interval.

ObjectivesThe aim of the present study was to investigate the prognostic significance of chemosensitivity to hypercapnia in chronic heart failure (HF).BackgroundIncreased chemosensitivity to hypoxia and hypercapnia has been observed in HF. The potential value of enhanced chemosensitivity to hypercapnia to risk prediction in systolic HF has not been specifically evaluated.MethodsOne hundred ten consecutive systolic HF patients (age 62 ± 15 years, left ventricular ejection fraction [LVEF] 31 ± 7%) underwent assessment of chemosensitivity to hypoxia and hypercapnia (rebreathing technique) and were followed up for a median period of 29 months (range 1 to 54 months). The end point was a composite of cardiac death and aborted cardiac death (ventricular tachyarrhythmia treated by cardioverter-defibrillator).ResultsAt baseline, 31 patients (28%) had enhanced chemosensitivity to both hypoxia and hypercapnia. Although they had the same LVEF as the 43 patients (39%) with normal chemosensitivity, they were more symptomatic (New York Heart Association functional class), had higher plasma brain natriuretic peptide and norepinephrine, steeper regression slope relating minute ventilation to carbon dioxide output (Ve/Vco2slope), more Cheyne-Stokes respiration, and more ventricular arrhythmias (all p < 0.05). Four-year survival was only 49%, in marked contrast to 100% for patients with normal chemosensitivity (p < 0.001). On multivariate analysis, combined elevation in chemosensitivity was the strongest independent prognostic marker, even when adjusted for univariate predictors (Ve/Vco2slope, Cheyne-Stokes respiration, LVEF, and brain natriuretic peptide, p < 0.05).ConclusionsIncreased chemosensitivity to both hypoxia and hypercapnia, eliciting neurohormonal derangement, ventilation instability, and ventricular arrhythmias, is a very serious adverse prognostic marker in HF.

To face the challenge of chronic heart failure diagnostic work-up, an information system (CHeF) has been developed, which allows data collection from ambulatory and/or inpatients in order to improve individual care and to establish a database for prospective/retrospective analyses. A scalable structure has been adopted to let the system run in different environments (from stand-alone systems to those strictly integrated with external systems). The CHeF core system was designed as a meta-definition database, in order to follow frequently updated parameter tracking and to fit physicians' research results. This structure, characterized by a dynamic interface developed in Java, permits rapid changes to structure and functionality.

Background The contribution of the lung or the plant gain ( PG ; ie, change in blood gases per unit change in ventilation) to Cheyne‐Stokes respiration ( CSR ) in heart failure has only been hypothesized by mathematical models, but never been directly evaluated. Methods and Results Twenty patients with systolic heart failure (age, 72.4±6.4 years; left ventricular ejection fraction, 31.5±5.8%), 10 with relevant CSR (24‐hour apnea‐hypopnea index [ AHI ] ≥10 events/h) and 10 without ( AHI ) and hypercapnia ( ) by rebreathing technique, lung‐to‐finger circulation time, and PG assessment through a visual system. PG test was feasible and reproducible (intraclass correlation coefficient, 0.98; 95% CI , 0.91–0.99); the best‐fitting curve to express the PG was a hyperbola ( R 2 ≥0.98). Patients with CSR showed increased PG , (but not ), and lung‐to‐finger circulation time, compared with patients without CSR (all P PG was the only predictor of the daytime AHI ( R =0.56, P =0.01) and together with the also predicted the nighttime AHI ( R =0.81, P =0.0003) and the 24‐hour AHI ( R =0.71, P =0.001). Lung‐to‐finger circulation time was the only predictor of CSR cycle length ( R =0.82, P =0.00006). Conclusions PG is a powerful contributor of CSR and should be evaluated together with the CG and circulation time to individualize treatments aimed at stabilizing breathing in heart failure.

Although periodic breathing (PB: hyperventilation/hypopneas) and Cheyne-Stokes respiration (CSR: hyperventilation/apneas) are usually considered to occur in lying and sleeping conditions in patients with heart failure (HF), there are recent evidences that both phenomena may spread throughout the 24

1. To evaluate the activity of the autonomic nervous system on the heart and peripheral circulation in native high-altitude residents, during a Himalayan expedition we studied 12 men (age: 48 +/- 4, mean +/- SEM), life-long resident in a village at 4800 m (Sumdo village, Zanskar, India) and 7 healthy sea-level residents (age: 37 +/- 4) after 7 days of acclimatization (acclimatized lowlanders) at the same altitude. Furthermore 25 sea level residents (age: 46 +/- 2) underwent the same protocol at sea level. 2. R-R interval (RR), respiratory signal, non-invasive blood pressure, and skin arteriolar blood flow were evaluated in three different conditions: during free breathing in supine position and during controlled breathing (at 0.15 Hz), in supine and upright position, and analysed by autoregressive spectral analysis [low- (around 0.1 Hz) and high-frequency (respiratory) fluctuations, LF and HF, markers of sympathetic and vagal activity, respectively]. 3. High-altitude residents showed in supine position a higher RR than acclimatized lowlanders, similar to sea-level residents. RR variability was reduced in acclimatized lowlanders compared to both high-altitude residents and sea level residents. Systolic blood pressure (SBP) did not show significant differences between the three groups. High altitude residents showed in supine lower LF in RR signal compared to sea-level residents, and, compared to acclimatized lowlanders, higher HF and lower LF/HF ratio; high-altitude residents showed a reduction in skin microcirculation variability compared to sea-level residents, but this was eight fold greater than in acclimatized lowlander, thus indicating a much greater vasoconstriction in acclimatized lowlanders than in high-altitude residents. 4. In upright position, high-altitude residents showed the same behaviour as sea-level residents, with increase in LF-RR, and decrease in HF and LF-SBP. Acclimatized lowlanders showed similar directional trends though not significant changes for RR-LF. 5. After one week of acclimatization, lowlanders still manifested sympathetic activation and skin vasoconstriction; high-altitude residents did not show reduced vagal tone compared to sea-level residents, but a mild vasoconstriction appeared to be present. In conclusion, normal or enhanced vagal tone and preserved vasomotion are probably evidence of adaptation at high altitude hypoxia.

Ventricular repolarization analysis allows extraction from the ECG signal of quantitative indexes (namely the QT interval), of prognostic value in unselected populations and cardiac patients, being related with arrhythmic risk. Several attempts to improve automatic ECG waveform detection have been accomplished, using signal derivatives, digital filtering, wavelet analysis, neural network techniques, nonlinear approaches. In the present study, a single-lead low-pass differentiation detector of ECG significant points (PulseMeter) has been evaluated. The algorithm performance has been validated against the manual annotation of the "QT database" (http://www.physionet.org/), developed for validation purposes. QRS complex and other ECG waveform boundaries were independently evaluated in the present study. The mean values and standard deviations computed improve the result of automatic annotation in QT database, especially in T wave detection. The QRS detector has a sensitivity of 99.96% and a positive predictivity of 99.96% on the first lead and a sensitivity of 99.90% and a positive predictivity of 99.94% on the second lead, showing a better performance than the automatic annotation in the QT database.

Background After heart transplantation, respiration-synchronous fluctuations (0.18 to 0.35 Hz, high frequency [HF]) in RR interval may result from atrial stretch caused by changes in venous return, but slower fluctuations (0.03 to 0.15 Hz, low frequency [LF]) not due to respiration suggest reinnervation. In normal subjects, sinusoidal neck suction selectively stimulates carotid baroreceptors and causes reflex oscillations of RR interval. Methods and Results To evaluate the presence of reinnervation, we measured the power of RR-LF and RR-HF in 26 heart transplant recipients and 16 control subjects before and during sinusoidal neck suction at 0.1 Hz and 0.20 Hz (similar to but distinct from that of controlled respiration, 0.25 Hz) and before and during administration of atropine or β-blocker (esmolol hydrochloride) by spectral analysis. All transplant recipients showed small respiratory HF fluctuations. Nonrespiratory LF fluctuations were present in 13 of 26 transplant recipients and increased with months since transplantation ( r =.53, P 2 , P 2 , P Conclusions The presence of baroreceptor-induced RR oscillations is evidence of functional, although incomplete, autonomic reinnervation.

Respiratory sinus arrhythmia (RSA) high-frequency oscillations (HF) and slow fluctuations in heart rate (LF) are thought to result from entrainment of a medullary oscillator, from the baroreflex, or from a combination of both central and baroreflex mechanisms. We sought to distinguish between the alternatives by examining with spectral analysis the behavior of heart rate (R-R interval) and blood pressure in 10 healthy subjects (mean age 27 +/- 1 yr) during apnea, altering the rate of preapnea entrainment stimuli by changing the frequency either of respiration (controlled at 0.1 or 0.25 Hz) or of baroreceptor stimulation by sinusoidal neck suction (0 to -30 mmHg, 0.1 or 0.2 Hz). During apnea the RSA-EF power decreased (from 6.73 +/- 0.15 to 3.67 +/- 0.10 In ms2: P < 0.0001), regardless of preapnea conditions, whereas LF power was reduced only if preceded by 0.1-Hz respiration or neck suction [from 8.71 +/- 0.18 to 6.52 +/- 0.11 In ms2 (P < 0.001) and from 8.31 +/- 0.23 to 6.90 +/- 0.38 In ms2 (P < 0.01), respectively]. The LF frequency seen in the R-R interval during apnea was slower than the spontaneous LF during 0.25-Hz breathing (0.082 +/- 0.01 vs. 0.112 +/- 0.001 Hz, P < 0.001), but the maneuvers during preapnea had no influence on the observed frequency or other characteristics of the slow oscillations during apnea. Moreover, we found no evidence of a progressive decrease in the power of the oscillation during apnea. The same behavior was observed on the mean blood pressure signal. In conclusion, a slow rhythm is present during apnea. In healthy subjects at rest the characteristics of this oscillation indicate that it could be generated by a central oscillator this may thus contribute to the origin of LF present during normal respiration, in addition to the baroreflex.

Heart rate variability (HRV) investigated by spectral analysis is widely accepted as a tool for the investigation of the autonomic influence on heart activity. The possibility that HRV indexes should be corrected per the heart rate, before using them is currently overlooked. RR interval derived from EKG recording in 15 healthy subjects, during quiet supine mute resting has been analysed over consecutive 256 beat long windows by autoregressive spectral analysis. The formula ln(power spectral density)/ln(RR interval) was then applied when a dependence of power values from RR interval was found. Spectral total power, VLF, LF, and HF power were significantly related to RR interval. After the application of the correction formula no significant correlation was found. In conclusion, some spectral indexes (associated with parasympathetic drive to the sinus node and with sympatho/vagal balance) are dependent of heart rate and need a correction before analysis and interpretation. A simple effective formula. to make spectral indexes independent by heart rate is proposed which is effective.

A model for distributed signal acquisition and processing has been designed and implemented. The model is based on a LAN client-server structure: it allows signal acquisition on a dedicated server and acquired samples distribution to different client workstations for signal representation and/or processing. The communication between server and clients is based on TCP/IP protocol. A set of specific commands allows the client to get the server acquisition configuration and to request/receive signal samples. In order to facilitate the development of client own system for signal analysis a library of Java functions (or classes) was created including the basis of biosignal processing and display; these classes have to be included by the developer into the user specific program for signal acquisition and elaboration. The system is under test in the research LAN of our Institute. It consists of one PC-server with an AID converter board and one client workstation for displaying and processing cardiovascular and respiratory signals obtained from patients studied with autonomic testing.