Distinguishable DNA methylation defines a cardiac-specific epigenetic clock.

BACKGROUND: The present study investigates whether epigenetic differences emerge in the heart of patients undergoing cardiac surgery for an aortic valvular replacement (AVR) or coronary artery bypass graft (CABG). An algorithm is also established to determine how the pathophysiological condition might influence the human biological cardiac age. RESULTS: Blood samples and cardiac auricles were collected from patients who underwent cardiac procedures: 94 AVR and 289 CABG. The CpGs from three independent blood-derived biological clocks were selected to design a new blood- and the first cardiac-specific clocks. Specifically, 31 CpGs from six age-related genes, ELOVL2, EDARADD, ITGA2B, ASPA, PDE4C, and FHL2, were used to construct the tissue-tailored clocks. The best-fitting variables were combined to define new cardiac- and blood-tailored clocks validated through neural network analysis and elastic regression. In addition, telomere length (TL) was measured by qPCR. These new methods revealed a similarity between chronological and biological age in the blood and heart; the average TL was significantly higher in the heart than in the blood. In addition, the cardiac clock discriminated well between AVR and CABG and was sensitive to cardiovascular risk factors such as obesity and smoking. Moreover, the cardiac-specific clock identified an AVR patient's subgroup whose accelerated bioage correlated with the altered ventricular parameters, including left ventricular diastolic and systolic volume. CONCLUSION: This study reports on applying a method to evaluate the cardiac biological age revealing epigenetic features that separate subgroups of AVR and CABG.

Sodium nitroprusside for advanced heart failure. A metanalysis of literature data.

Advanced heart failure (HF) is associated with a very poor prognosis and places a big burden on health-care services. The gold standard treatment, i.e. long-term mechanical circulatory support or heart transplantation, is precluded in many patients but observational studies suggest that the use of SNP might be associated with favourable long-term clinical outcomes. We performed a metanalysis of published studies that compared sodium nitroprusside (SNP) with optimal medical therapy to examine the safety and efficacy of SNP as part of the treatment regimen of patients hospitalized for advanced heart failure (HF). We searched PUBMED, EMBASE and WEB OF SCIENCE for studies that compared SNP with optimal medical therapy in advanced HF on July 2022. After screening 700 full-text articles, data from two original articles were included in a combined analysis. The analysis demonstrated a 66% reduction in the odds of death in advanced HF patients treated with SNP. The results show the potential importance of the inclusion of SNP in the treatment regimen of patients hospitalized because of advanced HF and underlines that controlled, randomized studies are still required in this condition.

Additional predictive value of nutritional status in the prognostic assessment of heart failure patients.

BACKGROUND AND AIMS: Nutritional status (NS) is not routinely assessed in HF. We sought to evaluate whether NS may be additive to a comprehensive pre-discharge evaluation based on a clinical score that includes BMI (MAGGIC) and on an index of functional capacity (six minute walking test, 6mWT) in HF patients. METHODS AND RESULTS: The CONUT (Controlling Nutritional Status) score (including serum albumin level, total cholesterol and lymphocyte count) was computed in 466 consecutive patients (mean age 61 ± 11 years, NYHA class 2.6 ± 0.6, LVEF 34 ± 11%, BMI 27.2 ± 4.5) who had pre-discharge MAGGIC and 6MWT. The endpoint was all-cause mortality. Mild or moderate undernourishment was present in 54% of patients with no differences across BMI strata. The 12-month event rate was 7.7%. Deceased patients had a more compromised NS (CONUT 2.8 ± 1.5 vs 1.7 ± 1.3, p < 0.0001), and a more advanced HF (MAGGIC 28.2 ± 6.0 vs 22.0 ± 6.6, p < 0.0001; 6MWT 311.1 ± 102.2 vs. 408.9 ± 95.9 m, p < 0.0001). The 12-month mortality rate varied from 4% for well-nourished to 11% for undernourished patients (p = 0.008). At univariate analysis, the CONUT was predictive for all-cause mortality with a Hazard Ratio of 1.701 [95% CI 1.363-2.122], p < 0.0001. Multivariable analysis showed that the CONUT significantly added to the combination of MAGGIC and 6MWT and improved predictive discrimination and risk classification (c-index 0.82 [95% CI 0.75-0.88], integrated discrimination improvement 0.028 [95% CI 0.015-0.081]). CONCLUSIONS: In HF patients assessment of NS, significantly improves prediction of 12-month mortality on top of the information provided by clinical evaluation and functional capacity and should be incorporated in the overall assessment of HF patients.

Clinical value of baroreflex sensitivity.

The arterial baroreflex is an important determinant of the neural regulation of the cardiovascular system. It has been recognised that baroreflex-mediated sympathoexcitation contributes to the development and progression of many cardiovascular disorders. Accordingly, the quantitative estimation of the arterial baroreceptor-heart rate reflex (baroreflex sensitivity, BRS), has been regarded as a synthetic index of neural regulation at the sinus atrial node. The evaluation of BRS has been shown to provide clinical and prognostic information in a variety of cardiovascular diseases, including myocardial infarction and heart failure that are reviewed in the present article.

Non-invasive baroreflex sensitivity assessment using wavelet transfer function-based time-frequency analysis.

A novel approach for the estimation of baroreflex sensitivity (BRS) is introduced based on time-frequency analysis of the transfer function (TF). The TF method (TF-BRS) is a well-established non-invasive technique which assumes stationarity. This condition is difficult to meet, especially in cardiac patients. In this study, the classical TF was replaced with a wavelet transfer function (WTF) and the classical coherence was replaced with wavelet transform coherence (WTC), adding the time domain as an additional degree of freedom with dynamic error estimation. Error analysis and comparison between WTF-BRS and TF-BRS were performed using simulated signals with known transfer function and added noise. Similar comparisons were performed for ECG and blood pressure signals, in the supine position, of 19 normal subjects, 44 patients with a history of previous myocardial infarction (MI) and 45 patients with chronic heart failure. This yielded an excellent linear association (R > 0.94, p < 0.001) for time-averaged WTF-BRS, validating the new method as consistent with a known method. The additional advantage of dynamic analysis of coherence and TF estimates was illustrated in two physiological examples of supine rest and change of posture showing the evolution of BRS synchronized with its error estimations and sympathovagal balance.

Effects of marine n-3 fatty acids on circulating levels of soluble adhesion molecules in patients with chronic heart failure.

Inflammatory markers as circulating soluble cellular adhesion molecules (sCAMs) and high sensitive C-reactive protein (hsCRP) are elevated in patients with chronic heart failure (CHF), and may constitute an increased risk of adverse outcome. Marine n-3 polyunsaturated fatty acids ( n-3 PUFA) may have anti-inflammatory effect and reduce levels of sCAMs (soluble intercellular adhesion molecule-1 (sICAM-1), vascular adhesion molecule-1 (sVCAM-1), P-selectin) and hsCRP. In a randomized, controlled trial, 138 patients with NYHA class II-III CHF were allocated to receive a daily supplement of 0.9 g of n-3 PUFA or olive oil for 24 weeks. After supplementation, no significant changes occurred in sCAMs or hsCRP after adjusting for possible confounders. However, a significant reduction was observed in sP-selectin in patients receiving n-3 PUFA, but this result was only of borderline significance in a between-group analysis. In conclusion, a daily supplement with 0.9 g of n-3 PUFA does not significantly affect plasma levels of sCAMs or hs-CRP in patients with CHF. n-3 PUFA may reduce sP-selectin, indicating a possible effect on platelet (and endothelial) activation. The results also indicate that the low dose of n-3 PUFA used in many intervention trials does not have deleterious effects on sCAMs or hsCRP.

Long-term time-course of nocturnal breathing disorders in heart failure patients.

Some important aspects of clinical manifestations of nocturnal breathing disorders in heart failure (HF) patients are still unknown. We questioned whether the severity of these disorders, first, is stable over time; secondly, shows any systematic trend; and, thirdly, can be predicted over time by a single baseline measurement. We studied 79 stable, optimally treated, moderate-to-severe HF patients who performed a monthly cardiorespiratory recording during 1-yr follow-up. According to their behaviour over time, nocturnal breathing disorders were classified as persistent, absent or occasional. During follow-up, clinically relevant breathing disorders were persistent in approximately 50% of the patients, absent in <20% and occasional in approximately 30%. Increasing/decreasing trends were rarely observed. The positive and negative predictive value of baseline measurement for persistent behaviour over time ranged, respectively, from 71% to 91% and from 91% to 95%, depending on different levels of severity of breathing disorders. A large portion of HF patients experience persistent clinically significant nocturnal breathing disorders over long periods of time. Breathing disorders occur irregularly in about one-third of the patients and are negligible in a minority of them. Rarely do they show a steady increase or decrease over time. A single baseline recording predicts a persistent behaviour with moderate-to-high accuracy.

Effect of paced breathing on ventilatory and cardiovascular variability parameters during short-term investigations of autonomic function.

Paced breathing (PB) around 0.25 Hz has been advocated as a means to avoid confounding and to standardize measurements in short-term investigations of autonomic cardiovascular regulation. Controversy remains, however, as to whether it causes any alteration in autonomic control. We addressed this issue in 40 supine, middle-aged, healthy volunteers by assessing the changes induced by PB (0.25 Hz for 8 min) on 1) ventilatory parameters, 2) the indexes of autonomic control of cardiovascular function, and 3) the spectral indexes of cardiovascular variability. Subjects were grouped into group 1 (n = 31), if spontaneous breathing was regular and within the high-frequency (HF) band (0.15-0.45 Hz), or group 2 (n = 9), if it was irregular or slow (< 0.15 Hz). In both groups, PB was accompanied by an increase in minute ventilation (both groups, P < 0.01), whereas tidal volume increased only in group 1 (P = 0.0003). End-tidal CO2 decreased by [median (lower quartile, upper quartile)] -0.2 (-0.5, -0.1)% (group 1, P < 0.0001) and -0.6 (-0.8, -0.5)% (group 2, P = 0.008). Mean R-R interval and systolic and diastolic pressure remained remarkably stable (all P > or = 0.13, both groups). No significant changes were observed in spectral indexes of R-R and pressure variability (all P > or = 0.12, measured only in group 1 to avoid confounding), except in the HF power of pressure signals, which significantly increased (all P < 0.05) in association with increased tidal volume. In conclusion, PB at 0.25 Hz causes a slight hyperventilation and does not affect traditional indexes of autonomic control or, in subjects with spontaneous breathing in the HF band, most relevant spectral indexes of cardiovascular variability. These findings support the notion that PB does not alter cardiovascular autonomic regulation compared with spontaneous breathing.

Noninvasive measurement of blood pressure variability: accuracy of the Finometer monitor and comparison with the Finapres device.

To assess the accuracy of spectral indices of arterial pressure variability and baroreflex sensitivity obtained from beat-by-beat noninvasive blood pressure recordings by the Finometer device, we compared these measures with those obtained from intra-arterial recordings. The performance of the Finometer was also compared to the traditional Finapres device. In 19 cardiac disease patients, including myocardial infarction, heart failure and cardiac transplant, we estimated the power of systolic and diastolic pressures in the VLF (0.01-0.04 Hz), LF (0.04-0.15 Hz) and HF (0.15-0.45 Hz) bands and computed absolute and percentage errors relative to intra-arterial brachial pressure. We also computed the characteristic frequency of each band (i.e. the barycentric frequency of spectral components identified in the band). The variability of systolic pressure in the VLF and LF bands was markedly overestimated by both the Finometer and Finapres (p < 0.01), with percentage median errors of respectively 130% and 103% (Finometer), and 134% and 78% (Finapres). The HF power was substantially unchanged using the Finometer and reduced using the Finapres (-28%, p < 0.05). The limits of agreement between noninvasive and invasive spectral measurements were wide. Linear system analysis showed that most (>80%) of the power of noninvasive signals was linearly related to the power of the invasive signal. The characteristic frequency of each band was substantially preserved in both noninvasive signals. The results for diastolic pressure were similar, but the Finapres errors in the VLF and LF bands were lower. Baroreflex sensitivity was significantly underestimated by both devices (Finometer: -31%, Finapres: -24%). Despite previous studies having shown that brachial artery waveform reconstruction performed by the Finometer has improved the accuracy of blood pressure measurement compared to the Finapres device, measurement of blood pressure variability in cardiac disease patients provides worse results in most spectral parameters and a better accuracy only in the HF band of systolic pressure.

Long-term monitoring of sleep apnea at home in heart failure patients: preliminary results from the HHH study.

Sleep apnea is very common in patients with chronic heart failure (CHF) and has important implications in terms of morbidity, mortality and clinical management. Home respiratory telemonitoring might constitute a potential low-cost, widely-applicable alternative to traditional polysomnography in the evaluation and long-term monitoring of breathing disorders in these patients. In this paper we briefly describe the technological infrastructure and present preliminary results of the European Community multicountry trial HHH (Home or Hospital in Heart Failure), which is currently testing a novel system for home telemonitoring of cardiorespiratory signals in CHF patients. The recording and transmitting devices are suitable to be self-managed by the patient. We give a detailed report on the prevalence of nocturnal respiratory disorders at the beginning of the one-year follow-up and on their persistency over the following recordings (one per month). These preliminary findings clearly indicate that intermittent home telemonitoring of respiratory signals based on patient's self-management is feasible in CHF patients and the compliance is high. Reported statistics unambiguously confirm the high prevalence of nocturnal breathing disorders in these patients and clearly show that this phenomenon tends to persist over time.

Left atrial function: bridge to central and hormonal determinants of exercise capacity in patients with chronic heart failure.

UNLABELLED: The stroke volume response to exercise is a critical determinant in meeting peripheral metabolic demands in patients with chronic hear failure. The Left atrium, by its position, is important in coupling right and left ventricles, to left preload reserve and to modulate sympathetic activity. We performed this study to investigate the relationship between exercise capacity and diastolic and systolic left atrium function in patients with chronic heart failure. METHODS: We considered 128 consecutive patients with severe chronic heart failure (EF < 35%) due to ischemic or idiopathic dilated cardiomyopathy. Cardiac output, right atrial pressure, pulmonary artery pressures and mean pulmonary wedge pressure (A, X, V, Y wedge pressures) were determined during right cardiac catheterization. By Echocardiography evaluation, we measured atrial pressures and volume during early and late left atrial systolic filling and we calculated left atrial chamber stiffness by this equation P = A*eKV1. (P = left atrial pressure; A = elastic constant (mmHg*ml); e = the base of the natural logarithm; V1 = left atrial volume (ml); K = left atrial chamber stiffness constant (ml-1) = ln (V/X)/(maximal--minimal left atrial volumes)). All patients performed cardiopulmonary exercise test with modified Noughton protocol. Plasma norepinephrine and Atrial natriuretic factor levels were determined. RESULTS: Maximal and minimal left atrial volumes were inversely related to oxygen consumption (r = -.44, p < .001; r = -.61, p < .001). At rest, no differences were found in plasma norepinephrine concentrations (309 +/- 152 pg/ml vs 309 +/- 394 pg/ml; p = ns) and systemic vascular resistance (1706 +/- 435 vs 1771 +/- 524 dynes/cm sec-5; p = ns) in patients with large or normal left atrial volumes. During exercise the chronotropic response increased less in patients with large atrial volumes (56 +/- 13 vs 45 +/- 14; p = .001). The left atrial chamber stiffness constant was inversely related to peak oxygen consumption and exercise time. Patients with different chamber stiffness showed statistical difference in peak VO2 (16 +/- 4 vs 11 +/- 3 ml/kg/min; p = .0001). Left atrial ejection fraction was directly related to peak oxygen consumption (r = 0.55), but the most strongly correlation was with atrial filling fraction (r = .67). CONCLUSIONS: This study demonstrates a strong relationship between left atrial function and exercise capacity in patients with chronic heart failure.

RESP-24: a computer program for the investigation of 24-h breathing abnormalities in heart failure patients.

In this paper, we describe a computer program (RESP-24) specifically devised to assess the prevalence and characteristics of breathing disorders in ambulant chronic heart failure patients during the overall 24 h period. The system works on a single channel respiratory signal (RS) recorded through a Holter-like portable device. In the pre-processing stage RESP-24 removes noise, baseline drift and motion artefacts from the RS using a non-linear filter, enhances respiratory frequency components through high-pass filtering and derives an instantaneous tidal volume (ITV) signal. The core processing is devoted to the identification and classification of the breathing pattern into periodic breathing (PB), normal breathing or non-classifiable breathing using a 60 s segmentation, and to the identification and estimation of apnea and hypopnea events. Sustained episodes of PB are detected by cross analysis of both the spectral content and time behavior of the ITV signal. User-friendly interactive facilities allow all the results of the automatic analysis procedure to be edited. The final report provides a set of standard and non-standard parameters quantifying breathing abnormalities during the 24 h period, the night-time and the day-time, including the apnea/hypopnea index, the apnea index, the total time spent in apnea or in hypopnea and the prevalence of non-apneic and apneic PB. The accuracy of these measurements was appraised on a data set of 14 recordings, by comparing them with those provided by a trained analyst. The mean and standard deviation of the error of the automatic procedure were below respectively 6 and 8% of the reference value for all parameters considered and the mean total classification accuracy was 92%. In most cases, the individual error was <12%. We conclude that measurements provided automatically by the RESP-24 software are suitable for screening purposes and clinical trials, although a preventive check of signal quality should be recommended.

Echo-Doppler mitral flow monitoring: an operative tool to evaluate day-to-day tolerance to and effectiveness of beta-adrenergic blocking agent therapy in patients with chronic heart failure.

OBJECTIVES: The goals of this study were: 1) to assess the predictive value of baseline mitral flow pattern (MFP) and its changes after loading manipulations as regards tolerance to and effectiveness of beta-adrenergic blocking agent treatment in patients with chronic heart failure (CHF); and 2) to analyze the prognostic implications of chronic MFP modifications after beta-blocker treatment. BACKGROUND: In patients with CHF, carvedilol therapy induces clinical and hemodynamic improvements. Individual management, clinical effectiveness and prognostic implications, however, remain unclear. The MFP changes induced by loading manipulations provide independent prognostic information. METHODS: Echo-Doppler was performed at baseline and after loading manipulations in 116 consecutive patients with CHF (left ventricular ejection fraction: 25 +/- 7%); 54 patients with a baseline restrictive MFP were given nitroprusside infusion; 62 patients with a baseline nonrestrictive MFP performed passive leg lifting. According to changes in MFP, we identified four groups: 17 with irreversible restrictive MFP (Irr-rMFP), 37 with reversible restrictive MFP (Rev-rMFP), 12 with unstable nonrestrictive MFP (Un-nrMFP) and 50 with stable nonrestrictive MFP (Sta-nrMFP). Carvedilol therapy (44 +/- 27 mg) was administered blind to results of loading maneuvers. After six months, MFP was reassessed and patients reclassified according to chronic MFP changes. During follow-up, tolerance to and effectiveness of treatment and major cardiac events (death, readmission and urgent transplantation) were considered. RESULTS: Changes of MFP after loading manipulations were more accurate than baseline MFP in predicting both tolerance to (p < 0.01) and effectiveness of (p < 0.05) carvedilol. After 26 +/- 14 months of follow-up, cardiac events had occurred in 23/102 patients (23%). The event rate in patients with chronic Irr-rMFP or Un-nrMFP was markedly higher than it was in those with Rev-rMFP or Sta-nrMFP. CONCLUSIONS: In our patients, tolerance to and effectiveness of carvedilol was predicted better by echo-Doppler MFP changes after loading manipulations than by baseline MFP. Chronic changes of MFP after therapy are strong predictors of major cardiac events.

Chronic infusion of dobutamine and nitroprusside in patients with end-stage heart failure awaiting heart transplantation: safety and clinical outcome.

BACKGROUND: in patients with severe heart failure additional therapeutic support with intravenous inotropic or vasodilator drugs is frequently employed in an attempt to obtain hemodynamic and clinical control. No data comparing the use and efficacy of chronic intravenous inotropic and vasodilator therapy in patients with advanced heart failure are available. AIMS: we evaluated, in a group of patients with advanced heart failure undergoing chronic infusion with dobutamine or nitroprusside, in addition to optimized oral therapy, (1) the safety of chronic infusion, (2) the efficacy of both drugs in managing unloading therapy and (3) clinical outcome of the two therapeutic strategies. METHODS: one hundred and thirteen patients receiving optimized oral therapy, in functional class III/IV with symptoms and signs of refractory heart failure and requiring additional pharmacological support with either intravenous dobutamine or nitroprusside were evaluated. Clinical and therapeutic management and clinical outcome of the two groups were considered. RESULTS: dobutamine was administered for 12 h/day for 20+/-23 days at a dosage of 7+/-3 microg/kg/min to 43 patients. The mean dose of nitroprusside was 0.76+/-0.99 microg/kg/min. The mean duration of use of this drug, administered as a 12-h/day infusion was 22+/-38 days. Nitroprusside infusion allowed greater doses of short-term ACE-inhibitors to be used compared to pre-infusion (ACE-inhibitor dose: 55+/-30 mg/day vs. 127+/-30 mg/day P<0.0001) and during dobutamine infusion (ACE-inhibitor dose: 85+/-47 mg/day vs. 127+/-30 mg/day P<0.002). Nitroprusside unlike dobutamine significantly improved the NYHA functional class. Of the 113 patients, 109 (97%) had a cardiac event during a mean follow-up of 337+/-264 days. Forty-four patients required hospitalization for worsening congestive heart failure, 45/113 (39%) patients died during the follow-up and 27/113 (24%) patients had a heart transplant in status one. Hospitalization, because of worsening heart failure was less frequent in the nitroprusside than in the dobutamine subgroup [29/51 (57%) vs. 19/22 (86%) P<0.02]. The overall mortality was 28% (20/70) in the nitroprusside group and 58% (25/43) in the dobutamine group (odds ratio 0.33 CI 0.16 to 0.73 P<0.006). In the group treated with nitroprusside, heart transplantation in status one was performed in 16/33 patients (48%), while in the dobutamine group this was done in 11/14 patients (78%) (odds ratio 0.25 CI 0.06-1.02 P<0.06). There was a significant reduction in the combined end-point of mortality/heart transplantation in status one in patients treated with nitroprusside compared to those treated with dobutamine (36/70 (51%) vs. 36/43 (84%) - (odds ratio 0.34 CI 0.14-0.80 P<0.01). The incidence of adverse events in the patients treated with nitroprusside was similar to that in those treated with dobutamine (20% vs. 17% P=ns). CONCLUSIONS: for patients awaiting heart transplantation chronic intermittent nitroprusside infusions are more effective and safer than dobutamine in relieving symptoms, facilitating unloading therapy management and improving survival. Whether chronic intermittent infusion of nitroprusside could represent a feasible medical strategy in out-patients with severe heart failure remains to be investigated.

[Baroreflex sensitivity]. / Sensibilità barocettiva.

Arterial baroreceptors play an important role among the large number of physiological mechanisms governing the adjustment of cardiovascular system to several surrounding conditions. By baroreceptor stimulation, arterial pressure changes can modulate both sympathetical and vagal activity and, as a consequence, heart rate, contractility and vascular resistance. In the last years, many experimental and clinical observations have shown that ischemic heart disease and heart failure can change baroreceptor reflex sensitivity and cause excessive or inappropriate activity of the sympathetic system. Several methods have been developed to measure baroreceptor sensitivity by estimating the extent of change in heart rate following blood pressure oscillations being them spontaneous or brought about by application of pharmacological or mechanical stimuli. Under normal clinical conditions these measurements can be taken as the ability to activate a sympathetic answer (hypotension) or a parasympathetic one (hypertension), with the interplay of tonic vagal or sympathetic activity. The methodology most extensively used in the clinical setting relies on intravenous administration of phenylephrine, a pure alpha-agonist drug that activates arterial baroreceptors and leads to a reflex bradycardia, which can be measured as RR interval prolongation. Baroreflex sensitivity is quantified in ms of RR interval prolongation for each mmHg of arterial pressure increase. Compared to values obtained in normal subjects (average 15 ms/mmHg) baroreflex sensitivity is significantly depressed in post-infarction patients and in patients with heart failure. The application of a mechanical stimulus is carried out by means of a positive or negative pneumatic pressure through a collar around the neck. A decrease in neck chamber pressure, by stretching carotid receptors, is sensed as an arterial pressure increase and activates reflex bradycardia at the sinus node. Finally, the analysis of spontaneous oscillations of arterial pressure and heart rate can also provide information about baroreflex control of the cardiovascular system: indeed, even small physiological variations in arterial pressure can evoke a reflex heart rate response brought about by arterial baroreceptor. The potential clinical interest of these measurements (completely non-invasive) must be still studied in large populations to define both range of normality and prognostic significance.

Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials.

BACKGROUND: The need for accurate risk stratification is heightened by the expanding indications for the implantable cardioverter defibrillator. The Multicenter Automatic Defibrillator Implantation Trial (MADIT) focused interest on patients with both depressed left ventricular ejection fraction (LVEF) and the presence of nonsustained ventricular tachycardia (NSVT). Meanwhile, the prospective study Autonomic Tone and Reflexes After Myocardial Infarctio (ATRAMI) demonstrated that markers of reduced vagal activity, such as depressed baroreflex sensitivity (BRS) an heart rate variability (HRV), are strong predictors of cardiac mortality after myocardial infarction. METHODS AND RESULTS: We analyzed 1071 ATRAMI patients after myocardial infarction who had data on LVEF, 24-hour ECG recording, and BRS. During follow-up (21 +/- 8 months), 43 patients experienced cardiac death, 5 patients had episodes of sustained VT, and 30 patients experienced sudden death and/or sustained VT. NSVT, depressed BRS, or HRV were all significantly and independently associated with increased mortality. The combination of all 3 risk factor increased the risk of death by 22x. Among patients with LVEF<35%, despite the absence of NSVT, depressed BRS predicted higher mortality (18% versus 4.6%, P = 0.01). This is a clinically important finding because this grou constitutes 25% of all patients with depressed LVEF. For both cardiac and arrhythmic mortality, the sensitivity of lo BRS was higher than that of NSVT and HRV CONCLUSIONS: BRS and HRV contribute importantly and additionally to risk stratification. Particularly when LVEF is depressed, the analysis of BRS identifies a large number of patients at high risk for cardiac and arrhythmic mortalit who might benefit from implantable cardioverter defibrillator therapy without disproportionately increasing the number of false-positives.

Periodic breathing in heart failure patients: testing the hypothesis of instability of the chemoreflex loop.

In this study, we applied time- and frequency-domain signal processing techniques to the analysis of respiratory and arterial O(2) saturation (Sa(O(2))) oscillations during nonapneic periodic breathing (PB) in 37 supine awake chronic heart failure patients. O(2) was administered to eight of them at 3 l/min. Instantaneous tidal volume and instantaneous minute ventilation (IMV) signals were obtained from the lung volume signal. The main objectives were to verify 1) whether the timing relationship between IMV and Sa(O(2)) was consistent with modeling predictions derived from the instability hypothesis of PB and 2) whether O(2) administration, by decreasing loop gain and increasing O(2) stores, would have increased system stability reducing or abolishing the ventilatory oscillation. PB was centered around 0.021 Hz, whereas respiratory rate was centered around 0.33 Hz and was almost stable between hyperventilation and hypopnea. The average phase shift between IMV and Sa(O(2)) at the PB frequency was 205 degrees (95% confidence interval 198-212 degrees). In 12 of 37 patients in whom we measured the pure circulatory delay, the predicted lung-to-ear delay was 28.8 +/- 5.2 s and the corresponding observed delay was 30.9 +/- 8.8 s (P = 0.13). In seven of eight patients, O(2) administration abolished PB (in the eighth patient, Sa(O(2)) did not increase). These results show a remarkable consistency between theoretical expectations derived from the instability hypothesis and experimental observations and clearly indicate that a condition of loss of stability in the chemical feedback control of ventilation might play a determinant role in the genesis of PB in awake chronic heart failure patients.

Nonselective beta-adrenergic blocking agent, carvedilol, improves arterial baroflex gain and heart rate variability in patients with stable chronic heart failure.

OBJECTIVES: The purpose of this study was to investigate in a case-controlled study whether carvedilol increased baroreflex sensitivity and heart rate variability (HRV). BACKGROUND: In chronic heart failure (CHF), beta-adrenergic blockade improves symptoms and ventricular function and may favorably affect prognosis. Although beta-blockade therapy is supposed to decrease myocardial adrenergic activity, data on restoration of autonomic balance to the heart and, particularly, on vagal reflexes are limited. METHODS: Nineteen consecutive patients with moderate, stable CHF (age 54 +/- 7 years, New York Heart Association [NYHA] class II to III, left ventricular ejection fraction [LVEF] 24 +/- 6%), treated with optimized conventional medical therapy, received carvedilol treatment. Controls with CHF were selected from our database on the basis of the following matching criteria: age +/- 3 years, same NYHA class, LVEF +/- 3%, pulmonary wedge pressure +/- 3 mm Hg, peak volume of oxygen +/- 3 ml/kg/min, same therapy. All patients underwent analysis of baroreflex sensitivity (phenylephrine method) and of HRV (24-h Holter recording) at baseline and after six months. RESULTS: Beta-blockade therapy was associated with a significant improvement in symptoms (NYHA class 2.1 +/- 0.4 vs. 1.8 +/- 0.5, p < 0.01), systolic and diastolic function (LVEF 23 +/- 7 vs. 28 +/- 9%, p < 0.01; pulmonary wedge pressure 17 +/- 8 vs. 14 +/- 7 mm Hg, p < 0.05) and mitral regurgitation area (7.0 +/- 5.1 vs. 3.6 +/- 3.0 cm2, p < 0.01). No significant differences were observed in either clinical or hemodynamic indexes in control patients. Phenylephrine method increased significantly after carvedilol (from 3.7 +/- 3.4 to 7.1 +/- 4.9 ms/mm Hg, p < 0.01) as well as RR interval (from 791 +/- 113 to 894 +/- 110 ms, p < 0.001), 24-h standard deviation of normal RR interval and root mean square of successive differences (from 56 +/- 17 to 80 +/- 28 ms and from 12 +/- 7 to 18 +/- 9 ms, all p < 0.05), while all parameters remained unmodified in controls. During a mean follow-up of 19 +/- 8 months a reduced number of cardiac events (death plus heart transplantation, 58% vs. 31%) occurred in those patients receiving beta-blockade. CONCLUSIONS: Besides the well-known effects on ventricular function, treatment with carvedilol in CHF restores both autonomic balance and the ability to increase reflex vagal activity. This protective mechanism may contribute to the beneficial effect of beta-blockade treatment on prognosis in CHF.

Comparison between invasive and non-invasive measurements of baroreflex sensitivity; implications for studies on risk stratification after a myocardial infarction.

AIMS: The ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) study has proved the independent prognostic value of baroreflex sensitivity. A limitation of the traditional method of estimating baroreflex sensitivity by phenylephrine, is the need to monitor intra-arterial blood pressure. Our objective was to establish whether this invasive method of monitoring could be superseded by non-invasive methods, such as the Finapres device. METHODS AND RESULTS: Patients with three repeated invasive and non-invasive baroreflex sensitivity measurements were selected from the ATRAMI database (n = 454). The mean of these measurements was taken as the baroreflex sensitivity estimate. The repeatability of both methods (standard deviation of the three measurements) decreased with increasing baroreflex sensitivity. There was no constant bias between invasive and non-invasive measurements (0. 22+/-2.2 ms. mmHg(-1), P = 0.42). The linear correlation was very high (r = 0.91, P < 0.01). The normalized 95% limits of agreement were -0.5 and 0.52. On survival analysis, invasive and non-invasive baroreflex sensitivity gave similar prognostic information (likelihood ratio: 155.6 (P = 0.007) and 155.0 (P = 0.006); risk ratio: 0.79 and 0.81, respectively). According to the ATRAMI cut-off points, 85% of patients were classified concordantly by the two methods. None of the patients at high (low) risk with the invasive method were classified as low (high) risk class by the non-invasive method. CONCLUSION: Despite wide limits of agreement, invasive and non-invasive baroreflex sensitivity measurements are highly correlated and provide equivalent prognostic information.