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Background and aims: Chronic coffee consuption has been reported to be associated with a modest but significant increase in blood pressure (BP), although some recent studies have shown the opposite. These data, however, largely refer to clinic BP and virtually no study evaluated cross-sectionally the association between chronic coffee consuption, out-of-office BP and BP variability. Methods and results: In 2045 subjects belonging to the population of the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study, we analyzed cross-sectionally the association between clinic, 24-hour, home BP and BP variability and level of chronic coffee consumption. Results show that when adjusted for confounders (age, gender, body mass index, cigarette smoking, physical activity and alcohol drinking) chronic coffee consumption does not appear to have any major lowering effect on BP values, particulary when they are assessed via 24-hour ambulatory (0 Cup/day: 118.5±0.7/72.8±0.4mmHg vs 3 cups/day: 120.2±0.4/74.8±0.3mmHg, PNS) or home BP monitoring (0 cup/day: 124.1±1.2/75.4±0.7mmHg vs 3 cups/day: 123.3±0.6/76.4±0.36mmHg, PNS). However, daytime BP was significantly higher in coffee consumers (about 2mmHg), suggesting some pressor effects of coffee which vanish during nighttime. Both BP and HR 24-hour HR variability were unaffected. Conclusion: Thus chronic coffee consumption does not appear to have any major lowering effect either on absolute BP values, particulary when they are assessed via 24-hour ambulatory or home BP monitoring, or on 24-hour BP variability.

Background Results of recent clinical trials have shown that in heart failure (HF) heart rate (HR) values > 70 beats/minute are associated with an increased cardiovascular risk. No information is available on whether the sympathetic nervous system is differently activated in HF patients displaying resting HR values above or below this cutoff. Methods In 103 HF patients aged 62.7 ± 0.9 (mean ± SEM) years and in 62 heathy controls of similar age we evaluated muscle sympathetic nerve traffic (MSNA, microneurography) and venous plasma norepinephrine (NE, HPLC assay), subdividing the subjects in different groups according to their resting clinic and 24-h HR values. Results In HF progressively greater values of clinic or 24-h HR were associated with a progressive increase in both MSNA and NE. HR cutoff values adopted in large scale clinical trials for determining cardiovascular risk, i.e., 70 beats/minute, were associated with MSNA values significantly greater than the ones detected in patients with lower HR, this being the case also for NE. In HF both MSNA and NE were significantly related to clinic (r = 0.92, P r = 0.81, P r = 0.91, P r = 0.79, P Conclusions Both clinic and 24-h HR values greater than 70 beats/minute are associated with an increased sympathetic activation, which parallels for magnitude the HR elevations. These findings support the relevance of using in the therapeutic approach to HF drugs exerting sympathomoderating properties. Graphical abstract

Purpose of Review To examine published and unpublished data collected in the context of the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study on the relationships between serum uric acid (SUA), office and out-of-office blood pressure (BP), and organ damage. Recent Findings SUA values were directly and significantly related to a large number of covariates that participate at cardiovascular risk determination, such as blood glucose, total serum cholesterol, serum triglycerides, body mass index, and serum creatinine. Additional variables included echocardiographically-determined left ventricular mass index and BP values, the latter not just when measured in the office but also when evaluated at home or over the 24-h period. White-coat hypertension and masked hypertension were characterized, as sustained hypertension, by a significant increase in SUA levels, which were also directly related to different indices of 24-h BP variability. No substantial difference in SUA levels was found when data were analyzed according to the dipping or non-dipping nocturnal BP profile. Summary Data collected in the frame of the PAMELA study document the presence of a close relationship between SUA levels and BP values independently on the hypertensive phenotype patterns of BP increase (office, 24 h, or both) and nighttime BP profile. They also document the increase in SUA as a potential factor favoring the occurrence of new hypertension and new left ventricular hypertrophy.

Background: Left ventricular hypertrophy (LVH) is an independent predictor of cardiovascular events, and evidence has been obtained that an increase of a normal left ventricular mass (LVM) or new-onset LVH over time augments cardiovascular outcomes. Methods: We addressed this issue in a sample of a general population at relatively low cardiovascular risk. We analyzed subjects with normal echocardiographic LVM enrolled in the PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni) study to follow the increase of LVM over time and assess the prognostic impact of this change on the incidence of cardiovascular events (mean follow-up 18.5 years). Results: In 990 subjects with no LVH at baseline, there was a significant average increase of LVM (21.2%), LVMI BSA (18.9%), and LVMI HT (22.3%) more than 10 years later. About a quarter developed LVH. The LVMI BSA change exhibited an association with the cardiovascular risk mortality during the following 18.5 years, and the association remained significant after adjustment for confounders (hazard ratio, 1.2 [1.0–1.5]). Similar findings were obtained for LVM in absolute values or indexed for height. The association was seen in both genders, but the link with the cardiovascular risk was statistically significant in males only. Conclusions: Thus, although over 10 years, the LVM increase does not reach a LVH status, it is associated with an augmented cardiovascular mortality risk. This suggests that it might be important to consider periodical LVM assessment, even when LVM is within the normal range, to timely detect its increase and cope with the need of cardiovascular risk restratification.

Aims We examined whether to what extent resting heart rate (HR) values are capable to reflect in the metabolic syndrome (MS) a different degree of sympathetic activation. We also thought to determine at which HR cutoff values the sympathetic nervous system becomes more activated in the MS. Methods In 70 MS patients aged 55.5 ± 1.8 (mean ± SEM) years we evaluated muscle sympathetic nerve traffic (MSNA, microneurography) and venous plasma norepinephrine (NE, HPLC assay), subdividing the study population in three different subgroups according to resting clinic and 24-h HR values ( Results MS patients with clinic HR values ≥ 80 beats/min displayed MSNA and NE values significantly increased when compared to those found in MS with HR between 70 and 79 beats/min or below 70 beats/min (MSNA: 55.2 ± 0.9 vs 44.6 ± 0.6 and 39.2 ± 0.6 bursts/min, P P r = 0.89 and r = 0.91, P Conclusions In the MS HR values ≥ 80 beats/min are associated with an increased sympathetic activation, both when assessed by direct recording of MSNA and when evaluated as plasma NE. The sympathetic overdrive parallels for magnitude the HR elevations, this being the case for both clinic and 24-h HR.

Objective: Whether and to what extent the reported BP lowering effects of renal denervation (RD) are mediated by a sympathetic deactivation induced by the procedure is still largely undefined. We examined this issue by performing a meta-analysis of the microneurographic studies published so far based on the evaluation of the blood pressure (BP) and muscle sympathetic nerve traffic (MSNA) responses to RD. Design and method: The meta-analysis was based on 12 studies including a total of 394 patients with resistant hypertension underwent RD and followed up to 12 months. Evaluation was extended to the relationships of MSNA with heart rate (HR) and clinic or ambulatory blood pressure (BP) values (expressed such as mean and 95% confidence interval). Results: Baseline MSNA values amounted to 48.25 (43.86-52.64) bursts/minute, clinic HR to 66.35 (65.02-67.67) beats/minute and systo/diastolic clinic BP to 167.3 (157.6-177.01) and 90.54 (84.81-96.27) mmHg. RD caused a significant BP reduction at 3/6/12 months following the procedure amounting to 12.6 mmHg for systolic (range 20.9 to 4.39 mmhg, p = 0.003) and to 6.4 mmHg for diastolic BP (range -11.9 t0 0.9 mmHg, p = 0.02) respectively. No significant change in MSNA (-2.65, range -6.7 to 1.4 bursts/minute, P = NS) and HR (-0.58, range -3.98 to 2.81 b/min, P = NS) were concomitantly observed. No relationship was found between the number of renal ablations and the magnitude of the blood pressure or MSNA changes, this being the case also for HR. Conclusions: This meta-analysis, the first ever done on the MSNA responses to RD, shows that in a consistent number of patients underwent RD, the BP lowering effects of the procedure are not accompanied by any significant change in 2 adrenergic markers, i.e. MSNA and HR, and thus appear not to be mediated by any sympathetic deactivation.

Previous studies have shown that white-coat and masked uncontrolled hypertension (WUCH and MUCH, respectively) are clinical conditions with very poor reproducibility over time. This is also the case for the different nighttime blood pressure (BP) patterns (dipping, nondipping, reverse dipping or extreme dipping). Whether and to what extent the phenomenon might depend on the type of antihypertensive treatment is unknown. In the present study, we addressed this issue by analyzing the data collected in the Plaque Hypertension Lipid-Lowering Italian Study (PHYLLIS), in which office and ambulatory BP were measured three times during an almost 3-year treatment period. The results showed that a limited number of WUCH or MUCH patients at an initial office measurement and 24-h systolic (S) BP measurement maintained the same status at a second set of measurements one or more years later. This was also the case for all dipping patterns, and only a minimal number of patients exhibited the same phenotype throughout all on-treatment SBP measurements. The results were similar for treatment with a thiazide diuretic or an ACE inhibitor and are in line with those of the European Lacidipine Study on Atherosclerosis (ELSA) trial, i.e., the only other available trial with multiple on-treatment office and ambulatory BP measurements, in which patients were treated with a calcium channel blocker or a beta-blocker. All the BP patterns identified in hypertensive patients treated by joint office and ambulatory BP measurements display poor reproducibility, and this is unrelated to the type of antihypertensive treatment used.

Background: Scarce and non-homogeneous data are available on the prognostic value of clinic heart rate (HR) in coronavirus disease 2019 (COVID-19). Methods: The present study evaluated in 389 patients hospitalized for COVID-19 the in-hospital prognostic value of resting HR, assessed over different time periods, i.e., at hospital admission, during initial 3 days and 7 days of hospitalization. Results: Results show that assessment of this hemodynamic variable during hospitalization provides information on the clinical outcome of the patients, greater HR values being associated with a worse in-hospital prognosis. The prognostic value of elevated HR during COVID-19: 1) was independent on other confounders such as age, gender, comorbidities and fever, 2) appeared to be strengthened by repeated measurements of HR during the initial 3/7 days of hospitalization, and 3) was detectable in patients in which the therapeutic intervention did not include drugs, such as beta-blockers, calcium antagonists, digoxin, ivabradine and antiarrhythmic compounds known to interfere with HR. Conclusions: Heart rate may represent an important marker of a patient’s outcome in COVID-19.

Background: According to some guidelines, white-coat hypertension (WCH) carries little or no increase of cardiovascular risk in the absence of organ damage (OD), but no data are available on this issue. Methods: Using the population data from PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni), we evaluated cardiovascular and total mortality over a median follow-up of 29 years in WCH (elevated office and normal 24-hour or home blood pressure [BP]) and normotensive controls (normal in- and out-of-office blood pressure) with no echocardiographic left ventricular hypertrophy and no reduction of estimated glomerular filtration rate. Patients with sustained hypertension (SH, in- and out-of-office blood pressure elevation) and normotensive, WCH, and SH with cardiac and renal OD served as controls. Results: In the 1423 subjects analyzed, there were 165 cardiovascular and 526 all-cause deaths. After adjustment for confounders, no-OD WCH exhibited a risk of fatal cardiovascular events lower than that of no-OD SH but greater than that of no-ODN (hazard ratio, 2.0 [95% CI, 1.1–3.6], P =0.02), this being the case also for all-cause mortality. Compared with no-OD normotensive, no-OD WCH also exhibited a greater 10-year adjusted risk to develop new SH or OD. Similar findings were obtained in normotensive, WCH, and SH with OD. Conclusions: The present study provides the first evidence that WCH with no OD is accompanied by a noticeable increase in long-term risk of mortality, new hypertension, and new OD, thereby differing from normotension.

Objective: SARS-CoV-2 infection could be complicated by serious autonomic imbalance caused directly by the virus or through secondary release of inflammatory cytokines. Some studies suggested that elevated resting heart rate (HR) and resting tachycardia, being markers of an increased adrenergic cardiac drive, are associated with poor prognosis in COVID-19 syndrome. Design and method: We performed a retrospective analysis in an inpatient cohort of 389 subjects diagnosed with SARS-CoV-2 infection to investigate the prognostic relevance of HR in predicting the maximum care intensity needed during hospitalization according to the following four severity outcome classes: I) no need for oxygen support/need for low flow oxygen therapy; II) need for high flow oxygen therapy/continuous positive airway pressure; III) transfer to the Intensive Care Unit; IV) death. HR assessments were recorded on admission and during the first 3 and 7 days of hospitalization. Results: For each class increase in maximum care intensity we observed a corresponding significant increase in HR, considering both data collected on admission (average HR value: 90.1 ± 17 beats/minute, p-value trend = 0.0397), and during the first 3 days (p-value trend < 0.0006) or 7 days (p-value trend < 0.0001) of hospitalization. The significant trend was maintained after adjustment for age, sex, comorbidities and fever and in the subpopulation of patients (n = 118) not receiving drugs potentially active on HR both before and during hospitalization. Kaplan-Meier curves for survival based on HR displayed a significant decreased survival in patients with higher HR. Conclusions: The assessment of HR during hospitalization provides information on the clinical outcome of patients affected by SARS-CoV-2 infection independently of other confounders. HR as an in-hospital prognostic marker can be obtained both through a first assessment at the admission or mean values over the course of hospitalization with an increase of its accuracy by a 7-days longitudinal evaluation. Further studies might elucidate the association between SARS-CoV-2 infection with multiple autonomic abnormalities.

Purpose The present paper will review the impact of different therapeutic interventions on the autonomic dysfunction characterizing chronic renal failure. Methods We reviewed the results of the studies carried out in the last few years examining the effects of standard pharmacologic treatment, hemodialysis, kidney transplantation, renal nerve ablation and carotid baroreceptor stimulation on parasympathetic and sympathetic control of the cardiovascular system in patients with renal failure. Results Drugs acting on the renin–angiotensin system as well as central sympatholytic agents have been documented to improve autonomic cardiovascular control. This has also been shown for hemodialysis, although with more heterogeneous results related to the type of dialytic procedure adopted. Kidney transplantation, in contrast, particularly when performed together with the surgical removal of the native diseased kidneys, has been shown to cause profound sympathoinhibitory effects. Finally, a small amount of promising data are available on the potential favorable autonomic effects (particularly the sympathetic ones) of renal nerve ablation and carotid baroreceptor stimulation in chronic kidney disease. Conclusions Further studies are needed to clarify several aspects of the autonomic responses to therapeutic interventions in chronic renal disease. These include (1) the potential to normalize sympathetic activity in uremic patients by the various therapeutic approaches and (2) the definition of the degree of sympathetic deactivation to be achieved during treatment.

We examined in 11 young subjects (age 29.7±3.6 years, mean±SEM) whether carotid baroreceptor stimulation via the neck chamber device may affect central venous pressure (CVP), thus potentially involving other reflexogenic areas in the examined responses. Application of progressively greater neck chamber subatmospheric pressures caused a progressive lengthening in RR interval, which reached a peak at the maximal value of negative neck chamber pressure applied. This was accompanied by significant and progressively greater reduction in CVP values when the data were calculated considering the early changes occurring within the first 2 seconds of the stimulus. There was a weak correlation between the early changes in CVP and the RR interval responses when all stimuli were pooled together (r=0.32, P&nbsp

Whether blood pressure (BP) values differ when BP is measured with or without the presence of a doctor (attended and unattended BP measurements) is controversial, and no information exists on whether and to what extent neurogenic mechanisms participate at the possible BP differences between these measurements. In this study, we assessed continuous beat-to-beat finger systolic BP and diastolic BP, heart rate, muscle, and skin sympathetic nerve traffic (microneurography) before and during BP measurement by an automatic device in the presence or absence of a doctor. This was done in 18 untreated mild-to-moderate essential hypertensive patients (age, 40.2±2.8 years, mean±SEM). During attended BP measurement, there was an increase in systolic BP, diastolic BP, heart rate, and skin sympathetic nerve traffic and a muscle sympathetic nerve traffic decrease, the peak changes being +5.3%,+8.4%,+9.4%,+30.9%, and −15.2%, respectively ( P

Background Vitamin B12 deficiency-induced thrombotic microangiopathy, known as pseudothrombotic microangiopathy, is a rare condition which resembles the clinical features of thrombotic thrombocytopenic purpura but requires a markedly different treatment. Most cases of vitamin B12 deficiency have only mild hematological findings, but in approximately 10% of patients life-threatening conditions have been reported. Case presentation We report a case of a 46-year-old Moroccan man presenting with severe hemolytic anemia, thrombocytopenia, and renal failure in absence of macrocytosis, thus mimicking a genuine thrombotic thrombocytopenic purpura. Rapid improvement of renal function observed with only hydration and transfusions of packed red blood cells and the presence of pancytopenia suggested a bone marrow deficiency associated to a hemolytic component of unclear origin. Detection of low levels of vitamin B12 and rapid restitutio ad integrum with its replacement supported the diagnosis of pseudothrombotic thrombocytopenic purpura caused by vitamin B12 deficiency. Conclusions Diagnosis of pseudothrombotic thrombocytopenic purpura caused by vitamin B12 deficiency might be difficult. Awareness of clinicians toward this differential diagnosis might spare patients from unnecessary therapeutic plasma exchange that is burdened by morbidity and mortality.

Background Vitamin B12 deficiency-induced thrombotic microangiopathy, known as pseudothrombotic microangiopathy, is a rare condition which resembles the clinical features of thrombotic thrombocytopenic purpura but requires a markedly different treatment. Most cases of vitamin B12 deficiency have only mild hematological findings, but in approximately 10% of patients life-threatening conditions have been reported. Case presentation We report a case of a 46-year-old Moroccan man presenting with severe hemolytic anemia, thrombocytopenia, and renal failure in absence of macrocytosis, thus mimicking a genuine thrombotic thrombocytopenic purpura. Rapid improvement of renal function observed with only hydration and transfusions of packed red blood cells and the presence of pancytopenia suggested a bone marrow deficiency associated to a hemolytic component of unclear origin. Detection of low levels of vitamin B12 and rapid restitutio ad integrum with its replacement supported the diagnosis of pseudothrombotic thrombocytopenic purpura caused by vitamin B12 deficiency. Conclusions Diagnosis of pseudothrombotic thrombocytopenic purpura caused by vitamin B12 deficiency might be difficult. Awareness of clinicians toward this differential diagnosis might spare patients from unnecessary therapeutic plasma exchange that is burdened by morbidity and mortality. Electronic supplementary material The online version of this article (10.1186/s13256-018-1815-8) contains supplementary material, which is available to authorized users.

Rationale: Granulomatosis with polyangiitis (GPA) is an antineutrophil cytoplasmatic antibodies (ANCA)-associated vasculitis affecting small- and medium-sized blood vessels, mostly involving lung and kidney. Patient concerns: We report the case of a 33-year-old man that presented with acute respiratory distress syndrome caused by alveolar hemorrhage. Diagnoses: Aggressive GPA presenting with diffuse alveolar hemorrhage and multiorgan involvement. Inteventions: Immunosuppressive therapy, plasma exchange, extracorporeal membrane oxygenation (ECMO). Outcomes: Relapse occurred very early, despite immunosuppressive treatment, with a rare involvement of genital system (epididymitis) and rapidly progressive glomerulonephritis difficult to treat. Lessons: GPA is a challenging, multifaceted disease that can require aggressive supportive therapy and is associated with a high rate of relapse that may present with uncommon site of involvement.

A clinical pharmacogenetic characterization of DPD polymorphisms for pre-treatment screening of patients candidates to fluoropyrimidine therapy Marzia Del Re, Fotios Loupakis, Cecilia Barbara, Laura Lombardo, Tiziana Latiano, Elena Zafarana, Stefano Cordio, Luisa Toffolatti, Miriam Ricasoli, Dario Giuffrida, Jennifer Vanoli, Samantha Di Donato, Federico Grifalchi, Antonio Rinaldi, Alfredo Butera, Evaristo Maiello, Salvatore Siena, Alba Brandes, Alfredo Falcone, Federico Cappuzzo, Romano Danesi