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.

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.

Predictors of primary atrial fibrillation and concomitant clinical and hemodynamic changes in patients with chronic heart failure: a prospective study in 344 patients with baseline sinus rhythm.

OBJECTIVES: This study investigated the incidence, predisposing factors and significance of the onset of atrial fibrillation (AF) in patients with chronic congestive heart failure (CHF). BACKGROUND: The association between CHF and AF is well documented, but the factors that predispose to the onset of the arrhythmia and its impact remain controversial. Methods. We prospectively followed up 344 patients with CHF and sinus rhythm (SR). Over a period of 19 +/- 12 months (mean +/- SD), 28 patients developed atrial fibrillation (AF), which became chronic in 18. RESULTS: At baseline, no differences were found in any clinical and hemodynamic variables between patients who developed chronic AF and those who did not. Reversible AF occurring during follow-up and lower mitral flow velocity at atrial contraction as detected at the last evaluation in SR were independent predictors of the subsequent development of chronic AF. When AF occurred, New York Heart Association functional class worsened (from 2.4 +/- 0.5 to 2.9 +/- 0.6, p = 0.0001), peak exercise oxygen consumption declined (from 16 +/- 5 to 11 +/- 5 ml/kg per min, p = 0.002), cardiac index decreased (from 2.2 +/- 0.4 to 1.8 +/- 0.4, p = 0.0008), and mitral and tricuspid regurgitation increased (from grade 1.8 +/- 1.1 to grade 2.4 +/- 1.4, p = 0.0001 and from grade 1.0 +/- 1.2 to grade 1.8 +/- 1.2, p = 0.001, respectively). Systemic thromboembolism occurred in 3 of the 18 patients with AF. Nine of 18 patients died after AF, and the occurrence of AF was a predictor of major cardiac events. CONCLUSIONS: In patients with CHF, reversible AF and reduction of left atrial contribution to left ventricular filling predict the subsequent development of chronic AF. The onset of AF is associated with clinical and hemodynamic deterioration and may predispose to systemic thromboembolism and poorer prognosis.

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.

Assessing baroreflex sensitivity in post-myocardial infarction patients: comparison of spectral and phenylephrine techniques.

OBJECTIVES: This study sought to compare, in post-myocardial infarction patients, baroreflex sensitivity (BRS) measured by the phenylephrine method (Phe-BRS) with that estimated by the Robbe (Robbe-BRS) and Pagani (alpha-low frequency [LF] and alpha-high frequency [HF]) spectral techniques. BACKGROUND: BRS assessed by Phe-BRS has been shown to be of prognostic value in patients with a previous myocardial infarction, but the need for drug injection limits the use of this technique. Several noninvasive methods based on spectral analysis of systolic arterial pressure and heart period have been proposed, but their agreement with Phe-BRS has never been investigated in post-myocardial infarction patients. METHODS: The linear association and the agreement between each spectral measurement and Phe-BRS were assessed by correlation analysis and by computing the relative bias and the limits of agreement in 51 post-myocardial infarction patients. RESULTS: The correlation with Phe-BRS was r = 0.63 for Robbe-BRS, r = 0.62 for alpha-LF and r = 0.59 for alpha-HF. The relative bias was significant for alpha-LF (2.6 ms/mm Hg, p < 0.001) and alpha-HF (2.5 ms/mm Hg, p = 0.01) and not significant (-0.6 ms/mm Hg, p = 0.3) for Robbe-BRS. The normalized limits of agreement ranged from -98% to 95% for Robbe-BRS, from -67% to 126% for alpha-LF and from -108% to 143% for alpha-HF. When patients were classified according to left ventricular ejection fraction (LVEF, cutoff value 40%), the relative bias was higher in patients with a depressed LVEF, although statistical significance was high only for Robbe-BRS and was borderline for alpha-LF. The limits of agreement were similar in both groups of patients (p > 0.3). CONCLUSIONS: Despite a substantial linear association, the agreement between spectral measurements and Phe-BRS in post-myocardial infarction patients is weak because the difference can be as large as the BRS value being estimated. Phe-BRS is the measurement most associated with hemodynamic impairment. Because several factors within each method contribute to the overall difference, neither method can be defined as being better than the other in estimating baroreflex gain, nor can one be used as an alternative to the other. Ad hoc studies are needed to assess which method provides the most useful physiologic or pathophysiologic information or the most accurate prediction of prognosis.

Peak exercise oxygen consumption in chronic heart failure: toward efficient use in the individual patient.

OBJECTIVES: This study sought to 1) assess the short-, medium-and long-term prognostic power of peak oxygen consumption (VO2) in patients with heart failure; 2) verify the consistency of a nonmeasurable anaerobic threshold (AT) as a criterion of nonapplicability of peak VO2; 3) develop simple rules for the efficient use of peak VO2 in individualized prognostic stratification and clinical decision making. BACKGROUND: Peak VO2, when AT is identified, is among the indicators for heart transplant eligibility. However, in clinical practice the application of defined peak VO2 cutoff values to all patients could be inappropriate and misleading. METHODS: Six hundred fifty-three patients consecutively considered for eligibility for heart transplantation were followed up. Outcomes (cardiac death and urgent transplantation) were determined when all survivors had a minimum of 6 months of follow-up. RESULTS: Contraindication to the exercise test identified very high risk patients. The relatively small sample of women did not allow inferences to be drawn. In men, peak VO2 stratified into three levels (< or = 10, 10 to 18 and >18 ml/kg per min) identified groups at high, medium and low risk, respectively. The prognostic power of peak VO2 < or = 10 ml/kg per min was maintained even when the AT was not detected. In patients in New York Heart Association functional class III or IV, peak VO2 did not have prognostic power. In patients in functional class I or II, peak VO2 stratification was prognostically valuable, but less so at 6 than at 12 or 24 months. Age did not influence peak VO2 prognostic stratification. CONCLUSIONS: A contraindication to exercise testing should be considered a priority for listing patients for heart transplantation. Only in less symptomatic male patients does a peak VO2 < or = 10 ml/kg per min identify short-, medium- and long-term high risk groups. A peak VO2 >18 ml/kg per min implies good prognosis with medical therapy.

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.

Leave-one-out prediction error of systolic arterial pressure time series under paced breathing.

In this paper, we consider systolic arterial pressure time series from healthy subjects and chronic heart failure patients, undergoing paced respiration, and show that different physiological states and pathological conditions may be characterized in terms of predictability of time series signals from the underlying biological system. We model time series by the regularized least-squares approach and quantify predictability by the leave-one-out error. We find that the entrainment mechanism connected to paced breath, that renders the arterial blood pressure signal more regular and thus more predictable, is less effective in patients, and this effect correlates with the seriousness of the heart failure. Using a Gaussian kernel, so that all orders of nonlinearity are taken into account, the leave-one-out error separates controls from patients (probability less than 10(-7)), and alive patients from patients for whom cardiac death occurred (probability less than 0.01).

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.

Nutritional status and airflow obstruction: two independent contributors to CO diffusing capacity impairment in COPD.

BACKGROUND: The association between weight loss and Chronic Obstructive Pulmonary Disease (COPD) has been recognised from many years. Based on the evidence that nutritional status reflects metabolic disturbances in COPD, the relationship between body mass index (BMI), severity of airflow obstruction and CO diffusing capacity (DL(CO)), that is the functional hallmark of emphysema, is relevant to the management of COPD phenotypes. METHODS: We reviewed 104 patients with COPD (82 males), aged 66 +/- 9 years (mean +/- SD). Height averaged 165 +/- 8 cm, weight 71 +/- 16 Kg, FEV1 50 +/- 18 (% of predicted), RV 169 +/- 49%, and DL(CO) 56 +/- 26%. Multiple linear regression was performed using BMI, FEV1 and RV, as explanatory variables for DL(CO). Patients were also classified into four groups according to BMI < or = 18.5 (low), > 18.5 and < or = 25 (ideal), > 25 and < or = 30 (overweight), > 30 (obese), and post-bronchodilator FEV1 < 50%. Using this categorisation, a two-factor analysis of variance, testing for interaction and main effects (BMI and FEV1) was performed as confirmatory analysis for the association between BMI (kg/m2), FEV1% and DL(CO)%. RESULTS: FEV1 and BMI were significantly and independently associated to DL(CO) according to the equation: DL(CO) = -18.32 + 0.65 x FEV1 + 1.59 x BMI (R2 = 0.40, p < 0.0001). The contribution of RV % to DL(CO) % was largely non-significant (p = 0.16). A close relationship was found between BMI (kg/m2) and DL(CO) %, for all of the four BMI groups segregated by post-bronchodilator FEV1 %, (p < .0001). No interaction was found between these two factors (p = 0.30). CONCLUSION: Nutritional status as assessed by BMI contributes substantially to impairment of DL(CO) independently of the severity of airflow obstruction. This data confirms the association between emphysematous process and weight loss in advanced COPD, independent of the airflow obstruction severity.

Reproducibility of the six-minute walking test in patients with chronic congestive heart failure: practical implications.

This study assesses the reproducibility of the 6-minute walking test in patients with chronic heart failure using 2 different measurement protocols. Practical suggestions for the clinical setting are given.

Association between hemodynamic impairment and Cheyne-Stokes respiration and periodic breathing in chronic stable congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

Irregular breathing occurs frequently in patients with congestive heart failure (CHF) both during daytime and nighttime. Many factors are involved in the genesis of these breathing abnormalities, but the role of the hemodynamic impairment remains controversial. This study investigated the relation between worsening ventricular function and the frequency of respiratory disorders in patients with mild to severe CHF. One hundred fifty patients with CHF (mean age 53 +/- 8 years, left ventricular (LV) ejection fraction 26 +/- 7, in New York Heart Association [NYHA] classes II to IV, and who underwent stable therapy for > or =2 weeks) were studied. Analysis of instantaneous lung volume signal and arterial oxygen saturation during awake daytime revealed a normal respiratory pattern in 63 patients, whereas 87 had a persistent alteration of breathing, with a typical Cheyne-Stokes respiration (CSR) in 42 and periodic breathing (PB [oscillation of tidal volumes without apnea]) in 45 patients. Patients with PB and CSR showed a more pronounced hemodynamic impairment with a significantly reduced cardiac index, an increased pulmonary arterial wedge pressure, and a longer lung-to-ear circulation time (LECT) compared with patients with normal respiratory patterns. In a logistic regression model that included all of the variables significantly associated with breathing disorders, cardiac index and LECT emerged as the major determinants of CSR. In those patients with LECT > or =30 seconds (upper quartile) and cardiac index < or =1.9 L/min/m2 (lower quartiles), the incidence of CSR was significantly higher (69%) than in patients with lower LECT and higher cardiac index (14%, p <0.001). In conclusion, abnormalities of breathing activity during daytime are significantly associated with a prolonged circulation time and a more severe impairment of systolic and diastolic LV indexes.

The development of hyperventilation in patients with chronic heart failure and Cheyne-Strokes respiration: a possible role of chronic hypoxia.

AIM: To analyze the relationship between daytime respiratory and cardiac function in patients with compensated chronic heart failure (CHF) with and without periodic breathing (PB) or Cheyne-Stokes respiration (CSR). PATIENTS: We studied 132 patients (female, 13%; mean age, 53+/-8 years; body mass index, 25.9+/-3.5 kg/m2; left ventricular ejection fraction <40%; 23% in New York Heart Association class I, 43% in class II, and 34% in class III-IV). METHODS: Measurement of pulmonary function and blood gases, hemodynamic evaluation, analysis of breathing profile, echocardiography, recording of ECG, beat-to-beat arterial oxygen saturation, and respiration during spontaneous breathing. RESULTS: Fifty-eight percent of patients showed PB or CSR. Patients with PB or CSR have greater cardiac function impairment. Mean values of lung volumes and PaO2 were similar in the three groups of patients considered. In contrast, patients with PB or CSR had an increased minute ventilation and reduced PaCO2 values. Interestingly, patients with PB or CSR had lower values of arterial content of O2 and systemic oxygen transport (SOT) than patients with a normal breathing pattern (SOT, 394+/-9.8, 347+/-9.6, 438+/-11 mL of O2/min/m2, respectively; analysis of variance p<0.001). Weak correlations were found among lung volumes, blood gases, and cardiac function parameters: ie, vital capacity was correlated inversely with pulmonary capillary wedge pressure (PCWP) (-0.25; p<0.05); PaCO2 with PCWP (r=0.26; p<0.05), lung-to-ear circulation time (LECT) (r=-0.4; p<0.05), SOT (r=-0.33; p<0.0001), and cardiac index (CI) (r=0.27; p=0.003). Multiple regression analyses showed that arterial PCO2 was significantly correlated with SOT, LECT, and CI (r=0.51; r2=0.26; p<0.000001); the correlation became stronger considering only CSR patients (r=0.64; r2=0.4; p<0.001). CONCLUSIONS: Our study shows that patients with daytime breathing disorders have chronic hypocapnia. A reduced SOT may be one of the stimuli determining increased minute ventilation in these patients.

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.

Arterial baroreflex modulation of heart rate in patients early after heart transplantation: lack of parasympathetic reinnervation.

BACKGROUND: Orthotopic heart transplantation results in cardiac denervation. The presence of cardiac parasympathetic reinnervation in humans has been widely debated based on the application of differing indirect measures of autonomic control. However no attempt has been made to analyse the reflex heart rate response to baroreceptor stimulation whose occurrence is generally considered a reliable marker of the ability to activate cardiac vagal reflexes. This study tested the hypothesis that the presence of donor heart RR interval lengthening following phenylephrine induced blood pressure increase would be an index of parasympathetic reinnervation. METHODS: Baroreflex sensitivity (BRS) was assessed in 30 patients (mean age 51+/-12 years) 1-24 months after heart transplantation carried out by the standard Lower-Shumway technique. In 6 patients the recipient atrium rate response (P-P interval) to baroreceptor stimulation by phenylephrine was also simultaneously determined by transesophageal recording. RESULTS: None of the 30 patients showed prolongation of RR intervals in the donor heart. The average BRS value was -0.28+/-0.54 ms/mmHg (range -1.3-0.7 ms/mm Hg). In the 6 patients in whom BRS was obtained at both the recipient atrium (P-P) and donor heart (R-R) the changes were 7.6+/-5.7 ms/mm Hg and -0.38+/-0.58 ms/mm Hg respectively (p = 0.02), thus confirming that the absent RR interval lengthening in the donor heart is the consequence of efferent vagal fiber interruption. CONCLUSIONS: The absence of any RR interval prolongation following phenylephrine induced baroreceptor stimulation demonstrates that vagal efferent reinnervation of the donor heart does not occur up to 24 months in patients operated via the standard Lower-Shumway procedure. It is also suggested that analysis of baroreceptor reflexes is a more specific method in the examination of cardiac parasympathetic reinnervation.

Invasive and non-invasive determinants of pulmonary hypertension in patients with chronic heart failure.

BACKGROUND: In patients with chronic heart failure, pulmonary hypertension is an important predictive marker of adverse outcome. Its invasive and non-invasive determinants have not been evaluated. OBJECTIVE: This study was performed to evaluate hemodynamic determinants of pulmonary hypertension in chronic heart failure and to compare the predictive value of Doppler indices with that of invasively measured hemodynamic indices. METHODS: Right heart catheterization and transthoracic echo-Doppler were simultaneously performed in 259 consecutive patients with chronic heart failure (ejection fraction 24% +/- 7%) who were in sinus rhythm and receiving optimized medical therapy. Systolic pulmonary artery pressure (sPAP), cardiac index, transpulmonary gradient pressure, and pulmonary wedge pressure (PWP) were measured invasively. Left atrial and ventricular systolic and diastolic volumes, the ratio of maximal early to late diastolic filling velocities (E/A ratio), deceleration time (DT) and atrial filling fraction (AFF) of transmitral flow, systolic fraction of forward pulmonary venous flow (SFpvf), and mitral regurgitation were quantified by echo-Doppler. RESULTS: Patients with pulmonary hypertension had greater left atrial systolic and diastolic dysfunction, more left ventricular diastolic abnormalities, and greater hemodynamic impairment. The correlations between systolic left ventricular indices, mitral regurgitation, and sPAP were generally poor. Among invasive and non-invasive measurements, PWP (r = 0.89, p < 0.0001) and SFpvf (r = -0.68, p < 0.0001) showed the strongest correlation with sPAP. When we compared all patients with those without mitral regurgitation, the correlations between E/A ratio (r = 0.56 vs r = 0. 74, p < 0.002), SFpvf (r = -0.68 vs r = -0.84, p < 0.03), and systolic pulmonary artery pressure were significantly stronger. Multivariate analysis revealed that PWP was the strongest invasive independent predictor of systolic pulmonary artery pressure in patients with (R(2) = 0.87, p < 0.0001) and without (R(2) = 0.90, p < 0.0001) mitral regurgitation. A PWP > or= 18 mm Hg (odds ratio [95% CL], 142 (41-570) was strongly associated with systolic pulmonary hypertension. Among non-invasive variables DT, SFpvf, and AFF were identified as independent predictors of sPAP in patients with (R(2) = 0.56, p < 0.0001) and without (R(2) = 0.78, p < 0.0001) mitral regurgitation. A DT < 130 (odds ratio [95% CL], 3.5 (1.3-8.5), SFfvp < 40% (odds ratio [95% CL], 333 (41-1,007), and AFF < 30% (odds ratio [95% CL], 2 (1.3-7) most strongly predicted systolic pulmonary hypertension. CONCLUSIONS: The results of this study indicate that in patients with chronic heart failure, venous pulmonary congestion is an important determinant of systolic pulmonary artery hypertension. Hemodynamic and Doppler determinants showed similar predictive power in identifying systolic pulmonary artery hypertension.

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.

Effects of record length selection on the accuracy of spectral estimates of heart rate variability: a simulation study.

To evaluate the effects of record length selection on the accuracy of spectral estimates of heart rate variability (HRV), a simulation study was carried out using a set of 58 signals obtained by autoregressive (AR) fitting a representative sample of real HRV signals. Four record lengths of 180, 300, 420, and 540 s were considered. Spectral estimation was performed by both the Blackman-Tukey (B-T) and AR methods. Accuracy was assessed for: 1) point spectral estimates, by computing the normalized averaged bias (NAB) and variance (NAV); and 2) the most commonly used spectral parameters [total power (TP) and the powers in the bands: very low frequency (VLF) (0 divided by 0.04 Hz), low frequency (LF) (0.04 divided by 0.15 Hz), and high frequency (HF) (0.15 divided by 0.45 Hz)], by computing the normalized bias (NB) and variance (NV). The results are: whatever the record length considered, the 90th percentiles (90P) of the NAB were < 10%, whereas those of the NB were < 9% for TP, LF, and HF powers, and < 14% for the VLF power, in both methods. The NAV was proportional to the reciprocal of record length, showing high 90P values for the shortest record length (26.4% for B-T and 44.2% for AR). The NV showed the same trend but 90P values were much lower (< 8% for TP, LF, and HF powers and < 19% for VLF power, in both methods). In the final part of the paper a procedure for the computation of approximate upper bounds of the relative absolute error of spectral measures at each record length, based on the knowledge of the NB and NV, is presented.

Phase shifts of synchronized oscillators and the systolic-diastolic blood pressure relation.

We study the phase-synchronization properties of systolic and diastolic arterial pressure in healthy subjects. We find that delays in the oscillatory components of the time series depend on the frequency bands that are considered, in particular we find a change of sign in the phase shift going from the very low frequency band to the high frequency band. This behavior should reflect a collective behavior of a system of nonlinear interacting elementary oscillators. We prove that some models describing such systems, e.g., the Winfree and the Kuramoto models, offer a clue to this phenomenon. For these theoretical models there is a linear relationship between phase shifts and the difference of natural frequencies of oscillators and a change of sign in the phase shift naturally emerges.