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Background. Adjuvant trastuzumab therapy improves the outcome of patients with early breast cancer (EBC) and overexpression of human epidermal growth factor receptor 2 (HER2). However, it is potentially cardiotoxic. This study aims to evaluate the relationship between the use of angiotensin-converting enzyme inhibitors/receptor blockers (ACEi/ARBs) and/or ␤-blockers and development of heart failure (HF) and/or left ventricular dysfunction during 1 year of adjuvant trastuzumab therapy.Methods. A total of 499 women receiving adjuvant trastuzumab therapy for EBC entered in a multicenter registry and were divided into four subgroups according to treatment with ACEi/ARBs and/or ␤-blockers. Occurrence of HF and decrease of left ventricular ejection fraction (LVEF; minimum 10 percentage points) were recorded.Results. HF occurred in 2% of patients who did not take either ACEi/ARBs or ␤-blockers, 8% of patients receiving

Abstract-Previous studies have found that respiratory variations of ventricular response in atrial fibrillation are infrequent and inconsistent. This asynchrony between heart rate and respiration may characterize the physiological mechanisms coupling heart rate and systolic blood pressure oscillations in the respiratory band. The aim of this study was to evaluate whether synchronous variations in systolic blood pressure and respiration depend on a simultaneous change in heart rate. Univariate and bivariate spectral analyses were made of the R-R interval, systolic blood pressure, and respiratory signals during controlled respiration (16 breaths/min) in 24 patients with atrial fibrillation before and after efficacious electrical cardioversion and in 24 age-and sex-matched control subjects. During atrial fibrillation, the spectral coherence between respiration and heart rate was low (0.18Ϯ0.03), but there was a high level of coherence between respiration and systolic blood pressure (0.67Ϯ0.05). After cardioversion, the coherence between respiration and heart rate increased to 0.86Ϯ0.04, whereas the geometric mean values of the concomitant respiratory systolic blood pressure oscillations decreased by 72% (from 21.1 to 5.9 mm Hg 2 , PϽ0.001), which was similar to that observed in the control group (5.7 mm Hg 2 ). These results confirm the inconsistent effect of respiration on heart rate response during atrial fibrillation and demonstrate that respiratory sinus arrhythmia is not a prerequisite for systolic blood pressure oscillations but may play an antioscillatory role in respiratory systolic blood pressure variability, which is probably mediated by arterial baroreflex mechanisms. (Hypertension. 1999;34:1060-1065.) Key Words: arrhythmia Ⅲ blood pressure Ⅲ heart rate T he clinical hallmark of atrial fibrillation (AF) is an irregular ventricular rhythm. Few studies have investigated the respiratory oscillations of ventricular rhythm during AF, 1-3 and only 2 4,5 have made use of spectral analysis. These last 2 studies reported the presence of respiratory arrhythmia during AF in a small percentage of patients, but none measured respiration as a factor of analysis.The mechanisms underlying the origin of respiratory sinus arrhythmia (RSA) are still debated, but 2 main and not mutually exclusive theories have been put forward: One considers it to be the effect of cycling respiratory stimulation on arterial baroreceptors (the "peripheral" theory), and the other emphasizes the direct role of central respiratory drive (the "central" theory). Bivariate spectral analyses may quantify the relations between the heart period (R-R interval) and systolic blood pressure (SBP) but do not build causality between 2 signals: The spontaneous relation between the R-R interval and SBP fluctuations is a closed loop, and crossspectral analysis is unable to separate the mechanical R-R-SBP feedforward by baroreflex feedback from SBP to R-R. 6 A number of methods 7-11 and models 12-15 for exploring the fundamental relations between R-R and SBP o...

Spectral analysis may allow the evaluation of (baroreflex) gain and phase between the RR interval and systolic pressure oscillations synchronous with respiration but, unlike baroreflex gain, the determinants of phase are not completely understood. We evaluated the correlates of spectral phase in 92 healthy subjects (44 men) aged 10-80 years. To do so, the cardiorespiratory signals during paced breathing at 16 breaths/min were continuously recorded and analyzed. In addition, respiratory sinus arrhythmia and baroreflex gain (two indices of cardiac vagal activity) and phase were calculated by using an autoregressive spectral technique. At univariate analysis, the phase correlated with age (r = 0.48, P < 0.001), the RR interval (r = 0.32, P < 0.01), respiratory sinus arrhythmia (r = -0.3, P < 0.01), baroreflex gain (r = -0.29, P < 0.01), and body mass index (r = 0.25, P < 0.05). At multivariate analysis, age was the most important physiological correlate of phase, accounting for 23% of interindividual phase variation. Cardiac vagal activity measures (which were higher in women than men) and the RR interval were also significant independent correlates of phase. We conclude that in addition to the RR interval and cardiac vagal activity, age has a significant impact on the phase relationship between respiratory related oscillations of the RR interval and systolic blood pressure. This spectral measure may contain additional information concerning the mechanisms that influence cardiovascular rhythms.

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