L Di Palma's research while affiliated with Sapienza University of Rome and other places

Blood pressure (BP) is recursively variable during the day-night cycle because of a physiological circadian rhythm. The aim of this study is, therefore, to show how to construct the population reference limits (desms) for BP in its time varying 24-h pattern, starting from a small sample, in order to facilitate their use in a local context. The sample for standardization comprised 427 clinically healthy subjects (211 males and 216 females), ranging in age from 16 to 100 years, attending their routine activities. The procedure begins with the statistical biometry related to the sample, and proceeds with the computation of the BP desms related to (1) the time-qualified discrete values; (2) the parameters of circadian rhythm; (3) the daily pressure load. The pertaining rules are explained step by stop, allowing each one to prepare the proper local desms for BP 24-h pattern. These standards may be useful for validating the individual BP monitoring according to the upper limits of the circadian physiological variability in the diagnostic procedure for identifying hypertensive subjects.

Background – This paper is a concrete example of the problems raised by the need of constructing the time-qualified reference limits (chronodesms) for blood pressure (BP), in order to clinically estimate the hemodynamic parameter in its intrinsic nychtohemeral variability. Methods – Assuming that the noninvasive ambulatory BP monitoring (ABPM) is the eligible technique for this need, it must be realized that the BP chronodems may be of two types, depending on the sample being used for their calculation. The first type may be regarded as “ a priori ” because of the fact that they are derived by a sample of normotensive subjects who are unavoidably recruited via “ causal ” sphygmomanometric measurements and reclassified as normotensive by comparing their ABPM to the fixed reference limits (monodesms) given by WHO (monodiagnosis). Therefore, the “ a priori ” BP chonodesms are by principle derived by subjects who could not be correctly classified as normotensive, their ABPM being not tested versus the time-varying physiological limits. The second type may regarded as “ a posteriori ” in virtue of the fact that they may be constructed on a sample which contemplates the previous subjects who result to be true normotensive via the reassessment of their ABPM versus the “ a priori ” BP chronodesms (chronodiagnosis). The “ a posteriori ” chronodesms may be regarded as biometrically reliable, whether the sample for their construction is additionally constituted by those subjects of the local population who have been erroneously monodiagnosed as hypertensive, while they result to be true normotensive via the chronodiagnostic comparison of their ABPM versus the “ a priori ” BP chronodesms. Results – The biometric reliability of the “ a posteriori ” BP chronodems is demonstrated by the fact that their upper limits are statistically significantly less pronounced due to the fact that they are provided by a sample which has been depured by the falsely monodiagnosed normotensives. Conclusions – The “ a posteriori ” BP upper chronodesms are the time-qualified reference limits which should be used in clinical practice for the chronodiagnosis of hypertension.

The present study is aimed to investigate the 24-hour pattern of Atrial Natriuretic Peptide (ANP) plasma concentration in normotensive (N) and hypertensive (H) heart transplanted patients (HTP) in order to detect the pathophysiological role of blood pressure regimen for ANP increase in HTP. Eight NHTP and five HHTP have been investigated, all being hemodynamically compensated, without histological evidence of rejection and treated by Cyclosporine, Azathioprine and Prednisone. The control group was constituted by 10 clinically healthy subjects (CHS). ANP was assayed six times over the 24 h span. The contrasts between groups were statistically analyzed by means of Student's t-test for the 24 h mean values. The t-test found a statistically significant difference between the ANP 24 h mean levels either of CHS and HTP or NHTP and HHTP. The ANP 24 h mean plasma levels are increased of 190.4% in HHTP and of 44.3% in NHTP in comparison with CHS. The findings suggest that the further elevation of ANP in HHTP is a compensatory mechanism to antagonize high blood pressure. Moreover, being the ANP percent increase in HHTP three times more.

The monodiagnosis of hypertension via ambulatory (A) blood pressure (BP) monitoring (M) is erroneous by definition. Its use has to be substituted by the chronodiagnosis. Because of the lack of an international standardization, the BP chronobiologic reference limits have to be computed on a small sample size. For this compilation, it is, however, unavoidable the recruitment of normotensive subjects using the WHO's fixed limits. These chronobiologic standards are by principle contaminated by false negatives and need a bayesian validation. Such a depuration has been made by reclassifying each subject using the BP time-qualified standards. A secondary sample was constituted on the true normotensive reclassified. This sample provided the a posteriori reference standards for BP. The bayesian chronobiologic reference standards seem to be the limits with which the chronodiagnosis of hypertension can be suitably done via ABPM.

We have investigated the circadian rhythm of plasma atrial natriuretic peptide in 13 stable output heart transplanted patients, all without evidence of histological rejection and cardiac impairment, following antirejection therapy with Cyclosporine, Azathioprine and Prednisone. The 24-h pattern of plasma renin activity, plasma aldosterone and plasma cortisol has been studied as well. All the investigated variables were assayed six times over the 24-h span. The circadian time-qualified data were analyzed by ANOVA and Cosinor method. The 24-h mean levels of atrial natriuretic peptide, plasma renin activity and plasma aldosterone are significantly increased, while the concentrations of plasma cortisol are reduced in the heart transplanted recipients. ANOVA detected a significant within-day variability of all these humoral variables only in healthy subjects. A statistically significant circadian rhythm was validated by Cosinor procedure for all the investigated molecules in healthy subjects but not in heart transplanted patients. In our opinion, the increase of atrial natriuretic peptide is a counterregulatory mechanism aimed to compensate the cyclosporine-mediated activation of the renin-angiotensin-aldosterone system. The disappearance of the plasma renin activity, aldosterone and atrial natriuretic peptide circadian rhythm can be ascribed to the constant activation of the renin-angiotensin-aldosterone system. The hypocortisolism is due, in our opinion, both to glucocorticoid therapy and increase of plasma ANP concentration.

To study the circadian pattern of plasma concentrations of vasoactive intestinal peptide (VIP) in patients with orthotopic heart transplants. Circulating VIP is known to have neural and immunological sources. 13 patients with orthotopic heart transplants were studied 12-53 months (mean 31.8 months) after operation. All were haemodynamically compensated and had no histological evidence of rejection. They were being treated with cyclosporin, azathioprine, and prednisone. Ten healthy individuals were studied as controls. Circulating VIP was assayed six times within a 24h period. Time qualified data were analysed by ANOVA and the cosinor method. Student's t test for unpaired data and Bingham's test for cosinor-derived parameters were used for statistical comparisons. Plasma concentrations of VIP were lower in the patients with orthotopic heart transplants than in the controls (p < 0.001). ANOVA and the cosinor method respectively showed a statistically significant within-day variability and circadian rhythm in the controls but not in the patients with heart transplants. The low plasma concentrations of VIP in the patients with heart transplants could be the result of the lack of contribution by the cardiac VIPergic fibres, a reduction of VIP release by the pharmacologically suppressed immune system, the inhibitory effects of cyclosporin on neural function and humoral secretions, and the effects of negative feedback on VIP release of high concentrations of atrial natriuretic peptide. The lack of the circadian rhythm suggests a structural disorder, which should be further investigated.

The present study is designed to investigate the circadian rhythm (CR) of heart rate (HR) in acute rejecting and nonrejecting heart-transplanted patients (HTP). The aim is to provide evidence that an impairment in the HR CR may be associated with episodes of acute rejection in HTP. The study was carried out by 24hour Holter monitoring in 13 HTP, investigated in ambulatory conditions 24-48 h before the programmed endomyocardial biopsy. Time data series were analyzed by Cosinor method in order to validate the occurrence of HR CR and to quantify the rhythmometric parameters. Cosinor procedure detected a highly statistically significant HR CR in nonrejecting HTP but not in rejecting HTP. Cosinor analysis provided identical results when applied to diurnal values of HR (from 07.00 to 23.00). The findings suggest that the disappearance of HR CR may be regarded as a potential tool for acute episodes of rejection in HTP.

The aim of this study was to investigate the natural history of the circadian rhythm (CR) of blood pressure (BP) and heart rate (HR) in heart-transplanted patients (HTP), before and after surgery. The research was performed on 10 heart failure patients (HFP), IV class of the NYHA, aged from 27 to 56 years, who underwent heart transplantation (HT) because of a primary congestive cardiomyopathy. The control group was constituted by 10 age-matched clinically healthy subjects (CHS). BP and HR monitorings were performed pre- and postoperatively. ANOVA and the Cosinor method validated the occurrence of a statistically significant CR either in HFP or CHS. The difference between the two groups in mean value of systolics and diastolic (D) BP and HR was statistically significant. Over the 4 days after HT, serial section analysis was unable to validate a 24-hour periodicity of BP and HR. Six months after HT, the BP and HR CR was not validated. A statistically significant difference between HTP and CHS was found in the mean value of SBP, DBP and HR. One year after HT, the BP and HR CR was statistically detected. A significant difference between the two groups was validated only for the mean value of HR. In our opinion, the consolidation of the BP and HR CR 1 year after HT can be seen as a clinical feature of a reacquired matching of the cardiac function with the vascular activity.

This study deals with a chronobiological approach to the circadian rhythm of the renin-angiotensin-aldosterone system (RAAS) and the ACTH-cortisol axis (ACA) in patients with Addison's disease (PAD). The aim is to explore the mechanism(s) for which the circadian rhythmicity of the RAAS and ACA takes place. The study has shown that both the RAAS and ACA are devoid of a circadian rhythm in PAD. The lack of rhythmicity for renin and ACTH provides indirect evidence that their rhythmic secretion is in some way related to the circadian oscillation of aldosterone and cortisol. This implies a new concept: a positive feedback may be included among the mechanisms which chronoregulate the RAAS and ACA.

The aim of this study was to investigate the natural history of the circadian rhythm of blood pressure (BP) and heart rate (HR) in 10 patients with heart failure (class IV of the New York Heart Association), who underwent heart transplantation because of primary congestive cardiomyopathy. The control group was 10 age-matched clinically healthy subjects. The BP and HR monitorings were performed before and after transplantation. Preoperatively, analysis of variance and cosinor methods validated the occurrence of a statistically significant BP and HR circadian rhythm in cardiopathic patients. Over the 4 days after surgery, both the cosinor method and serial section analysis were unable to validate a 24-h periodicity for BP and HR in patients with heart transplants. Six months after surgery, the BP and HR circadian rhythm was not detected as well. One year after transplantation, the BP and HR circadian rhythm was statistically validated. The recovery of the BP and HR circadian rhythm 1 year after heart transplantation can be regarded as a clinical sign of a reacquired susceptibility to neurovegetative chronoregulation.