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In patients with end-stage renal disease (ESRD) undergoing haemodialysis, hypertension is of common detection and frequently inadequately controlled. Multiple pathophysiological mechanisms are involved in the development and progression of the ESRD-related high blood pressure state, which has been implicated in the increased cardiovascular risk reported in this hypertensive clinical phenotype. Renal sympathetic efferent and afferent nerves play a relevant role in the development and progression of elevated blood pressure values in patients with ESRD, often leading to resistant hypertension. Catheter-based bilateral renal nerves ablation has been shown to exert blood pressure lowering effects in resistant hypertensive patients with normal kidney function. Promising data on the procedure in ESRD patients with resistant hypertension have been reported in small scale pilot studies. Denervation of the native non-functioning kidney’s neural excitatory influences on central sympathetic drive could reduce the elevated cardiovascular morbidity and mortality seen in ESRD patients. The present review article will focus on the promising results obtained with renal denervation in patients with ESRD, its mechanisms of action and future perspectives in these high risk patients.

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 ± 0.4 mmHg vs 3 cups/day: 120.2 ± 0.4/74.8 ± 0.3 mmHg, PNS) or home BP monitoring (0 cup/day: 124.1 ± 1.2/75.4 ± 0.7 mmHg vs 3 cups/day: 123.3 ± 0.6/76.4 ± 0.36 mmHg, PNS). However, daytime BP was significantly higher in coffee consumers (about 2 mmHg), 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. L’ipertrofia ventricolare sinistra (LVH) costituisce un fattore predittivo indipendente di eventi e mortalità cardiovascolare (CV) e nel tempo l’aumento della massa ventricolare sinistra (LVM) o la comparsa di LVH sono state associate a un incremento di outcomes CV, in particolare nel contesto di malattie cardiovascolari conclamate o di alto rischio CV. Lo scopo del nostro studio era di valutare quest’associazione tra l’aumento della LVM nel tempo e il rischio CV in un campione rappresentativo della popolazione generale a rischio CV relativamente basso. Metodi. Sono stati analizzati soggetti con normale LVM all’ecocardiogramma arruolati nello studio PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni) per seguire la variazione della LVM in un intervallo di tempo di 10 anni e per determinare l’effetto di questa variazione sul rischio di mortalità CV e per tutte le cause a un follow-up medio successivo di 18,5 anni. Risultati. In 990 soggetti senza LVH al basale si è osservato un significativo aumento 10 anni dopo della LVM non indicizzata (21.2%), LVMIBSA (18.9%) e LVMIHT (22.3%) ovvero della LVM indicizzata rispettivamente per BSA (body surface area) e HT (altezza elevata alla 2,7). Solo circa un quarto dei soggetti ha sviluppato LVH franca e quindi la maggior parte è rimasta con valori di LVM nei range di normalità. La variazione di LVMIBSA si è associata a un aumento del rischio di mortalità CV nei successivi 18,5 anni secondo il modello di regressione di Cox (hazard ratio o HR per 1 standard deviation (SD): 1,9, intervallo di confidenza o IC del 95% o 1,6-2,3, p<0.0001) e l’associazione ha mantenuto la significatività anche dopo correzione per i fattori clinico-demografici di aggiustamento, inclusi i valori pressori clinici e delle 24h al basale e le loro variazioni nel tempo (HR 1,2, 1,0-1,5). Risultati analoghi sono stati ottenuti per la LVM non indicizzata e indicizzata per altezza2,7. Sia negli uomini che nelle donne si è osservato, Background. Left ventricular hypertrophy (LVH) is an independent predictor of cardiovascular (CV) events and death and in several high CV risk conditions or diseases evidence has been obtained that an increase of a normal LVM or new onset LVH over time increases CV outcomes. We addressed this issue in a sample of a general population at relatively low CV risk. Methods. We analysed subjects with normal echocardiographic LVM enrolled in the PAMELA study (Pressioni Arteriose Monitorate E Loro Associazioni) to follow the increase of LVM over more than 10 years and assess the prognostic impact of this change on the subsequent incidence and risk of CV and all-cause mortality (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%), LVMIBSA (18.9%) and LVMIHT (22.3%) more than 10 years later. About a quarter developed LVH and thus the large majority remained with a normal LVM. The LVMIBSA change exhibited an association with the risk of CV mortality during the following 18.5 years as assessed by the Cox model (hazard ratio or HR for 1 SD increase: 1.9 ,95% confidence intervals or CI 1.6-2.3, p<0.0001) and the association remained significant after adjustment for demographic and clinical confounders including baseline and time-related changes in office and 24h blood pressure (HR: 1.2 ,1.0-1.5). Similar findings were obtained for LVM in absolute values or indexed for height. The association between the increase in LVM exhibited an increase both in males and in females but their association with the risk of CV mortality was statistically significantly in males only. There were similar qualitative changes for the risk of all-cause mortality, which, however, did not reach statistical significance. Conclusions. Our data provide evidence on the relationship between increases in echocardiographic LVMI or LVM indices and CV mortality in people with normal baseline LVMI in a low CV risk sample of the popula

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%), LVMIBSA(18.9%), and LVMIHT(22.3%) more than 10 years later. About a quarter developed LVH. The LVMIBSAchange 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.

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 < 0.0001 and r = 0.81, P < 0.0001, respectively) and 24-h (r = 0.91, P < 0.0001 and r = 0.79, P < 0.0001, respectively) HR. The behavior of sympathetic markers described in HF was specific for this clinical condition, being not observed in healthy controls. 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.

We assessed the value of 3 electrocardiographic (EKG) voltage criteria in detecting variations of left ventricular mass (LVM) over time, taking echocardiographic (ECHO) LVM as reference, in the Pressioni Arteriose Monitorate E Loro Associazioni study. In 927 subjects (age 47 +/- 13 years on entry, 49.9% men) an ECHO evaluation of LVM and EKG suitable for measurement of EKG-LVH criteria (Sokolow-Lyon voltage, Cornell voltage and R-wave voltage in aVL) were available at baseline and at a 2(nd) evaluation performed 10 years later. Delta (delta) LVM, Delta LVMI, and Delta EKG parameters values were calculated from 2(nd) evaluation to baseline. The sensitivity of the EKG criteria in the diagnosis of LVH, poor at baseline, becomes even worse after 10 years, reaching very low values. Only the sensitivity of R-wave amplitude exhibited slight increase over time but with unsatisfactory absolute values. Despite the prevalence of ECHO-LVH at the 2(nd) evaluation was threefold increased compared to baseline (29.3% and 33.7% for LVM indexed to BSA and height(2.7), respectively), the prevalence of EKG-LVH was unchanged when evaluated by Sokolow-Lyon criteria, significantly reduced when assessed by Cornell voltage index, while significantly increased using R-wave voltage in aVL criteria. Despite an ECHO-LVM increase over the time, mean EKG changes were of opposite sign, except for R-wave amplitude in aVL. Our study highlights the discrepancy between ECHO and EKG in monitoring LVM changes over the time, especially for Sokolow-Lyon and Cornell voltage. Thus, EKG is an unsuitable method for the longitudinal evaluation of LVM variations.

Rationale:Whereas metronidazole-induced hepatotoxicity is quite rare in the general population, in individuals carrying a nucleotide excision repair disorder, namely Cockayne syndrome, there is a high risk of developing this complication.Patient concerns:We report the case of a 44-year-old man, affected by xeroderma pigmentosum, who was admitted to the hospital presenting aspiration pneumoniae caused by worsening dysphagia and with severe hepatotoxicity during the hospitalization.Diagnoses:Acute hepatitis, which was leading to acute liver failure, occurred during antibiotic treatment with metronidazole and ceftazidime with an elevation of liver enzymes consistent with hepatocellular damage pattern.Interventions:Hydration with glucose 5% solution, pantoprazole and vitamin K were administered, meanwhile other causes of hepatitis were ruled out and the ongoing antibiotic treatment was stopped suspecting a drug-induced liver injury.Outcomes:Liver function nearly completely recovered 1 month later with a first rapid improvement, within few days, of aminotransferases and coagulation studies, and slower of cholestatic enzymes.Lessons:We describe the first case available in the literature of hepatotoxicity associated with metronidazole treatment in a xeroderma pigmentosum patient. Clinicians therefore, based on this report and according to the possible underlying mechanism shared by other genetic diseases characterized by alterations in the pathway of DNA-repair, should consider such adverse event also in patients affected by this rare disease.

Objective: According to some guidelines white-coat hypertension (WCH) carries little or no increase of cardiovascular (CV) risk in absence of organ damage (OD) but no data are available on this issue. Design and method: Using the population data from Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA), we evaluated CV 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 (N, normal in- and out-of-office BP) with no echocardiographic left ventricular hypertrophy and no reduction of estimated glomerular filtration rate. Analysis was extended to sustained hypertension (SH, in- and out-of-office BP elevation) and to N, WCH and SH with cardiac and renal OD. Results: During the 29 years follow-up there were in the 1423 subjects nalysed 165 CV and 526 all cause deaths. OD was detected in 10.6%, 30.5% and 43.8% of N, WCH and SH, respectively. After adjustment for confounders no-ODWCH exhibited a risk of fatal CV events lower than that of no-ODSH but greater than that of no-ODN (HR 2.0, 95% CI: 1.1-3.6, P = 0.02), this being the case also for all cause mortality. Compared with no-ODN, no-ODWCH also exhibited a greater 10 year adjusted risk to develop new SH or OD. Similar findings were obtained in N, WCH and SH with OD. The present study provides the first evidence that WCH with no cardiac and renal OD is accompanied by an increased long-term risk of mortality, new hypertension and new OD, thereby not representing a clinically innocent condition. Conclusions: The present study provides the first evidence that WCH with no cardiac and renal OD is accompanied by an increased long-term risk of mortality, new hypertension and new OD, thereby not representing a clinically innocent condition.

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.

Objective: We sought to assess the long-term changes in aortic root (AR) diameter in a population-based sample, focusing on new onset AR dilatation, as well as on the demographic and clinical variables independently related to this dynamic process. Design and method: A total of 1,122 participants with measurable echocardiographic parameters at baseline and after a ten-year follow-up were included in the analysis. Sex-specific upper limits of normality for absolute AR diameter, AR diameter indexed to body surface area (BSA) and to height were derived from 712 healthy normotensive PAMELA participants. Results: Over the ten-year follow-up new AR dilatation occurred in 3.4% (AR/BSA),4.4% (AR/height) and 7.3% (absolute AR), respectively. No substantial relationship was observed between baseline office and ambulatory BP or their changes over time and incident AR/BSA and AR/height dilatation. Baseline AR diameter and left ventricular mass index (LVMI) emerged as important predictors of AR dilation, regardless of the diagnostic criteria used. This was also the case for the 10-year change in LVMI. The strength of association between non-hemodynamic variables and new onset AR dilatation was variable, depending on the definition of the aortic phenotype. Conclusions: The incidence of AR dilatation in a general middle-aged population is a relatively infrequent but not so rare event and scarcely influenced by both office and out-office BP. On the contrary, it is strongly related to LVMI (and its variations over time). From a clinical perspective, this underlines that LVH prevention and regression can reduce the risk of AR dilatation in the community.

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 (< 70, 70–79 and ≥ 80 beats/min). 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 < 0.01, NE: 403.9 ± 6.9 vs 330.1 ± 4.3 and 258.3 ± 6.8 pg/ml, respectively, P < 0.01). A similar behavior was observed for 24-h HR. In the group as a whole both MSNA and plasma NE showed highly significant direct relationships with clinic HR, the correlation being similar for MSNA and NE (r = 0.89 and r = 0.91, P < 0.01 for both) Similar significant relationships were also found between 24-h HR values and MSNA or NE. 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.

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.

We evaluated the relationships between Berlin questionnaire (BQ) scores, hypertension and other metabolic variables in 598 subjects (age: 65.8 ± 10 years, mean ± SD) enrolled in the PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni) study representative of the general population, treated or untreated with antihypertensive drugs. Two hundred and eleven subjects (35%) had a positive BQ with two or more positive categories of the inquiry. Compared to those without sleep disorders these subjects showed a greater male prevalence (55.9%), worse serum cholesterol, triglycerides and glucose profile, greater body mass index (BMI) (28.9 ± 4.9 vs. 24.9 ± 3.4 kg/m2), higher office (and to a lesser extent 24-h) BP and HR values, higher serum creatinine values and greater rate of echocardiographic left ventricular (LV) hypertrophy (25% vs. 13%). These differences were not detected when the data analysis was restricted to treated hypertensive patients. Thus, BQ scores allow to identify among subjects belonging to a general population those with elevated BP, organ damage and altered metabolic. When antihypertensive drug treatment is present, however, the approach fails to detect differences between groups with low or high BQ index.

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.

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.

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<0.05 for all). In contrast, during unattended BP measurement, systolic BP, diastolic BP, heart rate, and skin sympathetic nerve traffic were modestly, albeit in most instances significantly, reduced, whereas muscle sympathetic nerve traffic remained almost unchanged. During unattended BP measurement, peak systolic BP was 14.1 mm Hg lower, peak heart rate was 10.6 bpm lower, and peak skin sympathetic nerve traffic was 8.5 bursts/min lower than the peak values detected during attended BP measurement. Thus the cardiovascular and neural sympathetic responses to the alerting reaction elicited by BP measurement in the presence of a doctor are almost absent during unattended BP measurement, during which, if anything, a modest cardiovascular sympathoinhibition occurs. This has important implications for comparison of studies using these different BP measurement approaches as well as for decision concerning threshold and target BP values for treatment.